Porphyrias Flashcards
Classification
A partial enzyme deficiency causes accumulation of porphyrins
6 common prophyrias
SKIN DISEASE (3)
Porphyria cutanea tarda (PCT)
Congenital erythropoietic porphyria (CEP)
Erythropoietic protoporphyria (EPP)
BOTH SKIN DISEASE AND ACUTE ATTACKS (2) Hereditary coproporphyria (HC) Variegate prophyria (VP)
ACUTE ATTACKS ONLY (1)
Acute intermittent prophyria (AIP)
Skin disease
Local prophyrin phototoxicity reaction caused by Soret wavelength VISIBLE violet light 408nm
—> Share many clinical features
—> Histo features similar
Can only be differentiated by biochemical analysis
All skin porphyrias except erythropoeitic protoporphyria (EPP) present with fragility amd blistering of light exposed skin “bullous porphyrias” —> 4 of 5 skin porphyrias
Congenital erythropoeitic porphyria (CEP)
Porphyria cutanea tarda (PCT)
Hereditary coproporphyria (HC)
Vagiegate porphyria (VP)
Photoprotection of skin disease
Management of all subtypes of skin disease based on preventing Soret wavelength VISIBLE violet light 408nm penetrating the epidermis
Patients with erythropoetic protoporphyria (EPP) —> obvious link between sun exposure and symptoms
Patients with “bullous porphyrias” —> fragility and blistering not related to individual episodes of sun exposure
- Porphyria cutanea tarda (PCT)
- Congenital erythropoeitic porphyria (CEP)
- Hereditary coproporphyria (HC)
- Varigate porphyria (VP)
Sun avoidance
Sun protective clothes
Wide brim hat
Sunscreen to protect against VISIBLE LIGHT (includes Soret violet wavelength 408nm)
- Titanium dioxide
- Zinc oxide
- Iron oxide
Car and home Window films —> esp useful for
- Erythropoeitic protoporphyria (EPP)
- Congenital erythropoetic prophyria (CEP)
Acute attacks
SKIN DISEASE AND ACUTE ATTACKS Hereditary coproporphyria (HC) Variegate porphyria (VP)
ACUTE ATTACKS ONLY
Acute intermittent porphyria (AIP)
DEFINITION
Acute and potentially fatal illness
Characterised by acute neurotoxic illness
CLINICAL FEATURES
F > M
Rare before puberty
Age 10-40 yrs
SYMPTOMS OF ACUTE AUTONOMIC NEUROPATHY Severe Constant Abdo pain (result of acute auto - any quadrant, back, buttocks, thighs - may require opiate analgesia - Guarding, no true peritonism
Vomiting, Constipation
- D/t partial ileus
OTHER SYMPTOMS
Raised HR, BP
Dehydration
Motor neuropathy
- Heralded by aching pain in limbs
- May manifest as severe acute Guillian Barre type syndrome
- Isually occurs when porphyrinogenic drugs administered inadvertently during the developing acute attack
Convulsions from severe hyponatraemia
Bulbar palsy
Confusion, abnormal behaviour, agitation, hallucinations
Respiratory paralysis (commonest cause of death)
PRECIPITATING FACTORS/TRIGGERS
Drugs —> best to check website with up to date drug list suitable for porphyria patients
ETOH
Cannabis
Menstrual cycle (late luteal phase)
Fasting
Stress
Infection
PATHOGENESIS
Direct or indirect consequence of impaired activity of porphobilinogen (PBG) deaminase
When drugs or hormones induce cytochrome P450 —>
acutely increases liver requirement for Haem (Haem is needed to make cytochrome P450 as it is incorporated into this protein) —>
Haem deficiency exposed due to PBG deaminase deficiency —>
acute haem deficiency —>
secondary accumulation of ALA
PORPHOBILINOGEN (PBG) DEAMINASE
Primary deficiency —> acute intermittent porphyria (AIP)
Secondary deficiency (caused by inhibition of the enzyme by other accumulated porphyrins)
Accumulated coproporphyrinogen III —> Hereditary coproporphyria (HC)
Accumulated protoporphyrinogen IX —> Variegate porphyria (VP)
BIOCHEMICAL DX
Increased URINARY porphobilinogen (PBG) deaminase excretion
- quantitative assay more sensitive than screening qualitative/semi-quantitative test
Normal urinary PBG concentration exclude acute porphyria attack
Increased urinary PBG concentration not diagnostic of an acute attack —> urinary PBG falls between attacks but does not always return to normal
- the higher the PBG, the more likely an acute attack
- in the presence of increased PBG —> Dx of acute attack can only be made based on clinical grounds
RX OF ACUTE ATTACK
Early Dx important
Avoid acute attack inducing drugs to prevent exacerbation of the acute attack
Seek advice from specialist centre
Supportive measures
- Analgesia (safe to use in porphyria)
- Sedatives (safe to use in porphyria)
- Antiemetics (safe to use in porphyria)
Fluid balance
- Rehydration
- Correction of hyponatraemia
IV Haematin or Haem arginate
- corrects the Haem deficiency in the liver
- suppress liver ALA synthase activity —> reduce ALA and PBG accumulation
LONG TERM MX OF PATIENTS WITH ACUTE PORPHYRIA
Patient to be given a list of drugs with info on safety in acute porphyria “Safe Drugs” vs “Unsafe drugs”
- Expert advice to be sought if a drug in not on the “safe list” as these should not be blindly witheld if they are needed in a life threatening or emergency situation
Avoid ETOH
Avoid Cannabis
Afoid prolonged calorie restricted diets
Wear MedicAlert bracelet
Screen relatives to identify those with clinically latent disease (who may be at risk pf acute attacks)
General lab testing in porphyria
Precise Dx essential d/t differences in clinical mx between porphyrias that can be clinically indistinguishable
Accurate Dx based on porphyrin analyses by experienced lab
Screen relatives for latent prophyria if Dx of index case involves acute attacks
SAMPLES TO SEND Children - Urine AND - Whole blood (plasma + RBC) for Plasma AND - Faeces AND
Adult with suspected “bullous porphyria”
- Urine AND
- Whole blood for plasma (if fluorimetry available) OR
- Faeces (if fluorimetry not available)
—> Porphyria cutanea tarda (PCT)
—> Congenital erythropoeitic porphyria (CEP)
—> Hereditary coproporhyria (HC)
—> Variegate porphyria (VP)
Suspected erythropoeitic protoporphyria (EPP)
- Red cells (for total and free protoporphyrins) AND
- Plasma or faeces
- Urine normal
In setting of renal failure
- Plasma analysis not helpful —> renal failure increases plasma porphyrins
HANDLING OF SAMPLES
All specimens kept at room temp OR at 4 degree celsius
In the dark
Ideally analysed within 48 hrs of collection
Urine and faecal samples
- Fresh random specimens preferable to 24 hr collections (delayed time reaching lab)
- Very dilute urine unsuitable
LAB ANALYSIS OF PORPHYRINS
Quatitative analysis using spectrophotometric OR fluorimetric technique —> yields results as total prophyrin concentration
Urine, faeces —> measure porphyrin concentration —> if raised —> subjected to High Performance Liquid Chromatography (HPLC) to identify the specific porphyrin
Plasma —> for spectrofluorimetric scanning to identify porphyrin
Whole blood or red cell (for EPP) —> measured for free and total protoporphyrins
Urine PBG deaminase enzyme detection in acute attack —> quantitative mesurement
Qualitative screening for porphyrins using Wood’s light insensitive, neg result not of value
RESULT INTERPRETATION
Excreted into urine
- Uroporphyrin (Congenital erythropoetic porphyria, CEP; porphyria cutanea tarda, PCT)
- Coproporphyrin (Congenital erythropoetic porphyria, CEP; hereditary coproporphyria, HC; variegate porphyria, VP)
—> increased total porphyrin indicates Dx of porphyria, HPLC then subtypes porphyrin
Excreted into faeces
- Coproporphyrin (Congenital erythropoetic porphyria, CEP; hereditary coproporphyria, HC; variegate porphyria, VP)
- Isocoproporphyrin (porphyria cutanea tarda, PCT)
- Protoporphyrin (variegate porphyria, VP; erythropoeitic protoporphyria, EPP)
—> increased total porphyrin indicates Dx of porphyria, HPLC then subtypes porphyrin
Accumulate in red cells
- protoporphyrin (Erythropoeitic protoporphyria, EPP)
Plasma spectrofluorimetry (sample excited by 410nm light and fluorescent emissions detected)
615nm - 620nm —> indicates presence of uroporphyrin, coproporphyrin
- Congenital erythropoeitic porphyria (CEP)
- Porphyria cutanea tarda (PCT)
- Hereditary coproporphyria (HC)
624nm - 627nm
- Variegate porphyria (VP)
626nm - 634nm —> indicates presence of protoporphyrin
- Erythropoeitic protoporphyria (EPP)
Congenital erythropoeitic porphyria (CEP) - Skin disease only
A
Porphyria cutanea tarda (PCT) - Skin disease only
Commonest porphyria
Acquired
A liver disorder witn secondary effects on the skin
Fragility and blistering of sun exposed skin
Does not cause acute attacks
CLINICAL FEATURES
4 forms
*Sporadic (type I)
*familial (type II) —> AD inheritance with low penetrance
- type III —> inherited form with emzyme deficiency localised to the liver
- toxic porphyria
Sporadic PCT —> Presents in middle age
Familial form —> Occur at young age
Increase fragility on light-exposed skin
- Particularly backs of the hands and forearms
- Minor trauma shear the skin away —> leaves sharply marginated erosions
Bullae
- can be >1cm
- May be painful
- Crust and resolve over a few weeks
- Leaves atrophic scars, milia, mottled hyper or hypopigmentation
Patients rarely assoc development of new lesions with sun exposure
But symptoms generally worse in the summer
OTHER CLINICAL FEATURES
Patches of scarring alopecia following resolution of bullae on the scalp
Hypertrichosis
- Usually on upper face and forehead
- Sometimes ears, arms
- Ocassionally whole body
Hyperpigmentation
- In a melasma-like pattern on the cheeks and around the eyes
- In a diffuse pattern on light-exposed skin
- Occasionally in a reticulate pattern
Photo-induced onycholysis
Accelerated solar elastosis
Long-standing untreated disease —> morphoea-like plaques mainly on head, upper trunk
- histologically undistinguishable from true scleroderma
- postulated to arise as a result of induction of collagen synthesis by uroporphyrin I
- plaques may calcify —> if ulcerate —> excision + grafting
- on the scalp may cause slowly expanding scarring alopecia starting from frontoparietal and occipital areas
RARE CLINICAL PRESENTATIONS
Cicatricial conjunctivitis
Hair darkening
CLINICAL VARIANTS Hepatoerythropoeitic porphyria (HEP) - Homozygous form of familial PCT (UROD gene mutations different to those found in type II familial PCT) - 90% reduction in UROD enzyme activity - clinically similar to congenital erythropoeitic porphyria (CEP) - Photosensitivity during infancy - immediate pain on sun exposure - blisters on sun-exposed skin - Mutilating scarring of the face and fingers - Prominent hypertrichosis - Fluorescent teeth - Eye involvement - Shortened distal phalanges - Haemolysis milder than CEP - life expectancy normal - Can occasionally present with a milder disease similar to PCT
PATHOGENESIS
Results from deficiency of the enzyme uroporphyrinogen decarboxylase (UROD) —>
Causes accumulation of uroporphyrin —>
Diffuses from plasma into surrounding tissues —>
Phototoxic reaction in the uoper dermis in sun-exposed skin —>
Lysis of cells in the superficial dermis —>
Formation of membrane-limited vacuoles which merge to produce a bluster cavity under the basal lamina
Sporadic (type I)
- enzyme deficiency acquired, restricted to hepatocytes d/t inhibition of normal UROD enzyme
Familial (type II)
- enzyme deficiency hereditary, present in all tissues, assoc with UROD gene mutation
Type III
- Rare
- enzyme deficiency hereditary, localised to liver
Toxic porphyria
- Halogenated aromatic hydrocarbons inhibit UROD
- affects workers making herbicides
COMMON RISK FACTORS FOR DEVELOPING PCT —> predispose to inhibition of liver UROD enzyme in sporadic and familial forms
Most will have more than 1 risk factor
Subclinical genetic haemochromatosis
- Homozygosity for Cys282Tyr haemochromatosis mutation
- Clinical relevance of heterozygosity for the mutation is unclear
Hep C infection (esp in M)
ETOH (esp in M)
- Those who consume > 40g daily
- Alcoholics with cirrhosis
Oestrogens
- OCP or oral HRT in F patients
- Stopping the hormone may be sufficient to induce remission if the duration of oestrogen therapy short
- If not possible to stop hormone therapy —> transdermal drug delivery is a safer alternative than oral route
LESS COMMON RISK FACTORS
Haemodialysis
- pseudoporphyria is more common than PCT in renal failure (differentiated by faecal isocoproporphyrins in PCT)
HIV
- May be d/t co-infection with Hep C
Hep A infection
Hep B infection
NIDDM
SLE
Dermatomyositis
Thalassaemia
Haem malignancy
Tamoxifen
DDX
Variegate porphyria (VP) —> has both skin disease and acute attack
Hereditary coproporphyria (HC) —> has both skin disease and acute attack
Mild hepatoerythropoeitic porphyria (jhomozygous familial form of PCT)
Drug-induced pseudoporphyria
Renal pseudoporphyria
AIMS OF IX
To determine other systemic diseases predisposing to PCT
Assess severity of liver disease
BIOCHEMICAL FINDINGS
Urinary porphyrin increased —> consists mainly of uroporphyrins
Plasma spectrofluorimetry peak at 615nm - 620nm
Faeces isocoproporphyrins
Biochemical Marker of disease activity + response to Rx = quatitative urinary porphyrin excretion in random urine sample
Hepatoerythropoeitic porphyria (HEP) findings
- as in PCT +
- raised red cell zinc protoporphyrin +
- lower red cell UROD activity than usual type II familial form
HISTO
Subepidermal bullae with sparse inflammatory infiltrate
Festooning of dermal papillae into the bullae
Deposition of PAS positive firbillar glycoprotein material in and around the upper dermal blood vessel walls
Morphoea-like lesions in PCT indistinguishable from other forms of morphoea
DIF
IgG, little IgM, fibrinogen, complement at DEJ
LIVER DISEASE Most severe disease in - Alcoholism - hep C infection - Iron overload (haemochromatosis)
Risk of hepatocellular CA
- Accumulated porphyrins carcinogenic to the liver
- Concurrent Hep C infection in many patients
Monitoring/screening
- LFTs (in all PCT patients)
- Regular liver USS + serum alpha fetoprotein (PCT patients at high risk of hepatic malignancy)
Hepatologist to monitor and manage
MX Photoprotection - Visible light sunscreens with pigmentary grade titanium dipzide, zinc oxide, iron oxide - Car and home window filter films - Gloves - Wide brim hat - Protective clothing
Eliminate risk factors
- Stop oestrogens —> this can induce remission if has not been used for > 2 yrs
- Abstaining from ETOH or treating Hep C with interferon may nor always induce remission, but can prevent exacerbation of disease
Specific Rx
*Low dose chloroquine (Rx of choice)
—> Complexes with uroporphyrin —> promote excretion into bile
—> 125mg or 250mg 2x per week (daily doses cause potentially dangerous acute hepatitis
—> Retinopathy does not seem to occur with low doses
—> Clinical remission within 6 months
—> Biochemical remission 6-15 months —> Rx stopped
—> Remission lasts 17 - 24 months
Low dose HCQ 100mg 2 x per week (alternative to chloroquine)
Venesection preferable in following situations -
- In patients who do not respond to chloroquine
- Patients who have a pathologically high serum ferritin or homozygous for haemochromatosis mutation —> require iron depletion to protect internal organs (also Chloroquine less effective in haemochromatosis patients)
- Patients with significant Hep C liver disease —> require iron depletion —> as hepatic siderosis/haemosiderin deposition increases their virally induced liver damage + reduces efficacy of interferon Rx for the Hep C
- Chloroquine not C/I in above scenarios —> may be needed if venesection not possible in Hep C liver disease patients where venous access impaired by previous IVDU
—> depletes iron stores —> eliminates liver iron overload —> restores normal enzyme activity
—> Approx 500ml of blood removed every week to 2 weeks
—> Aim to reduce transferrin sat to 15%, Hb to 11-12 g/dL, plasma ferritin to <25 ug/L
—> Blistering resolves within 2-3 months
—> Skin fragility resolves within 6-9 months
—> Porphyrin concentrations normalise within 13 months —> cease Rx
—> relapse usually occur around 2.5 yrs after end of Rx
—> Hypertrichosis and sclerodermoid lesions respond more slowly during the yrs Rx has stopped
Excision and grafting for ulcerated sclerodermoid lesions
Desferrioxamine
—> Rapidly chelates iron
—> Leads to earlier remission than venesection
—> May be of value for PCT in renal failure (too anaemic for venesection, cannot excrete chloroquine)
—> Expensive
—> Requires use of subcut pump at night
Erythropoeitin
—> Mobilises liver iron into Hb
—> Rx of choice for PCT in renal failure (too anaemic for venesection, cannot excrete chloroquine)
Follow up long term
- measure urinary porphyrin excretion (monitor for relapse)
- Mx co-existing liver disease
Genetic counselling
- There is lack of evidence that identifying latent PCT in relatives alters outcomes
- Familial type II PCT has very low penetrance —> difficult to justify family screening
- Identical mx for sporadic and familial type II PCT
Erythropoetic protoporphyria (EPP) - Skin disease only
A
Hereditary coproporphyroa (HC) - Skin disease and acute attacks
A
Variegate porphyria (VP) - Skin disease and acute attacks
A
Pseudoporphyria (non-porphyric dermatoses)
Non-porphyric dermatosis
UV radiation esp UVA causes photosensitive reaction (in contrast with porphyrias where Soret violent wavelength 408nm is VISIBLE light)
Clinically and histologically indistinguishable from PCT
Porphyrin concentrations normal
One of the clinical presentation of drug-induced hypersensitivity + other non-drug related causes
CAUSES
Photosensitising drugs (generally recognised photosensitisers)
*NSAIDS (most common) esp naproxen, nabumetone, oxaprozin, ketoprofen, mefenamic acid
- Tetracyclines incl minocycline
- Diuretics i.e. bumetanide, frusemide
- Isotretinoin
- Dapsone
Chronic renal failure undergoing Haemodialysis (or less commonly peritoneal dialysis)
Sunbeds/UVA tanning beds
- Predominantly F
CLINICAL FEATURES
Indistinguishable from PCT
- Vesicles, Bullae
- Fragility
- Milia
- Scarring —> facial scarring in children can resemble erythropoeitic porphyria (EPP) but w/o the painful bouts of photosensitivity
- On exposed skin, particularly dorsal hands, also face, chest, occasionally other sites
Less commonly seen features
- Hypertrichosis
- Hyperpigmentation
- Sclerodermoid changes
- Dystrophic calcification
No extracutaneous manifestations
DDX PCT erythropoeitic porphyria (EPP) if there is EPP type scarring Epidermolysis bullosa acquisita (EBA) Bullous pemphigoid (BP)
DIAGNOSIS
Presence of clinical features of PCT in the skin
Normal urine, faecal, plasma porphyrin reported by experienced lab
Preferable (but not essential) to identify recognised dause of pseudoporphyria
Diagnosis more complex in renal failure patients
- Haemodialysis is assoc with increased plasma porphyrin concentrations (not indicative of PCT)
- Urine may be unavailable to test
- PCT can also be induced by chronic renal failure
- Conclusive differentiation of PCT from pseudoporphyria in renal failure patients on haemodialysis not always possible —> can sometimes be achieved on basis of DEGREE of increase in porphyrin in plasma, faeces, urine
IX
Urine, plasma, faecal porphyrins (normal)
Skin bx lesional skin for histo + perilesional skin for DIF (Identical to PCT)
- blood vessel thicknening, sclerosis of collagen less common
MX
Remove provoking factor
- Stop relevant drug
- Stop sunbed usage
Broad spectrum UV protection until disease resolves
PCT Rx i.e. chloroquine, venesection not effective in pseudoporphyria
COURSE/PROGNOSIS
Symptoms may continue for several months after discontinuation of causative drug
Scarring persists
Dialysis-related pseudoporphyria
- Generally persists until renal transplant removes need for dialysis
