Porphyria Flashcards

Question

CEP clinical

Answer 1

1. Cutaneous - features of PCT and EPP 1. Birth - 38%, can come on later (40) 2. Urine and teeth fluoresce with Woods lamp 3. Severe cutaneous photosensitivity: friability and blistering of epidermis on hands, face and other sun exposed sites 4. Blisters rupture, progress to scarring and thickening, with dyspigmentation 5. Photomutilation: loss of fingers, eyelids, nose, ears 6. Hypertrichosis of face and extremities, 7. Erythematous papules on face 8. Secondary infections 9. At birth: brown amniotic fluid, blistering on light, 10. In utero: hydrops fatalis 2. Extra-cutaneous 1. Haemolysis 1. Haemolytic anaemia resulting in marrow hyperplasia and visible expansion of maxillary bones in the face 2. In neonates can cause jaundice --> phototherapy --> accelerates skin damage 3. Hypersplenism, can worsen anaemia and cause leukopaenia, thrombocytopaenia 2. Ocular: keratoconjunctivitis, blepharitis, cataracts, ulcers, scars, ectropion, eyelids can be destroyed by photomutilation 3. Bones and teeth: 1. Teeth stain brown: erythrodontia, thinning of enamel 2. Decreased bone density 3. Resorption of terminal phalanges 4. Vit D deficiency 4. Pink urine 3. I think when older increased risk of haem malignancy 4. Most die by age 40, although prognosis is improving with BM transplants - now pushed out to 60 5. No increased risk of skin malignancy

Answer 2

- Photoprotection - Vitamin D - Prevention of secondary infection - MDT - Ophthal - Dental - Ortho - Haem: - hypertransfusion - complicated by iron overload --> splenomegaly - Allogenic BM transplant - difficult, need to find HLA-compatible donor - has been curative - Splenectomy - Haem arginate to bypass defect - Oral charcoal may increase faecal loss of porphyrins and may be useful for patients who are not transfusion dependent - Emerging - Gene therapy: cliclopirox, proteasome inhibitors - Prognosis: - reduced life span (40 years) - Genetic counselling: - chance of sibling having 25%, and 50% chance of being a carrier - can detect in utero via amniotic fluid or chorionic villous biopsy - Individuals with CEP can have children

Answer 3

- 1/5000 - 1/25000 - Adults - M=F

Answer 4

1. Sporadic: 75-80% - absence of UROD, in liver only 2. Familial: 20-25%, inheritance of UROD mutation affecting one allele, autosomal dominant with low penetrance, in all tissues. Often other factors present to push UROD from 50% function to 30% 3. Familial: apparent familial inheritance without UROD mutation - may be from HFE or shared acquired factors

Answer 5

- Acquired inhibition of hepatic UROD to less than 30% of normal, which occurs in the presence of iron and variable combination of acquired factors - Predisposition in some: - genetic UROD mutation which predisposes by reducing UROD activity by 50% of normal in all tissues from birth - HFE mutation which increases iron absorption - Reduced UROD activity --> accumulation of porphyrinogens in liver --> oxidised to mostly uroporphyrin and hepatacarboxyl porphyrins --> appear in plasma and are excreted mostly in the urine - You also have some porphyrin which goes into the next pathway and is metabolised to isocoproporphyrinogen --> appears in faces and urine as isocoproporphyrin - Porphyrins are transported from the liver to the skin - accumulated uroporphyrin (hydrophilic) diffuses from plasma into surrounding tissues - causes phototoxic reaction in the upper dermis of the skin --> cell lysis in the superficial dermis, formation of membrane limited vacuoles which merge to produce a blister - Central importance of iron: increased hepatic iron plays a central role in pathogenesis - When liver has too much iron, it makes an enzyme inhibitor - i think the UROD inhibitor - which is how they show up

Answer 6

Promote iron accumulation or oxidative stress in hepatocytes - Alcohol - Infectious: HCV, HIV, HAV, HBV - Oestrogen exposure: OCP, HRT, tamoxifen, prostate cancer therapy, late pregnancy - Smoking - Medical conditions: - Diabetes - Hepatic steatosis - Haemachromatosis - Myeloproliferative disorders, sideroblastic anaemia, thalassaemia - Advanced renal disease: dialysis, often with iron overload - AICTD: SLE, DM

Answer 7

1. Cutaneous 1. Chronic photosensitivity with blisters, skin fragility, atrophic scars 2. Dyspigmentation 3. Hands, forearms, face, ears, neck and feet 4. Itching 5. Milia 6. Hypertrichosis - particularly cheeks and forearms 7. Sclerodermoid changes 8. Can be itchy or painful 9. Alopecia can occur 10. Photodistributed onycholysis 11. Variant: homozygous is HEP --> more severe, photosensitivity at birth, blisters, scarring, shortened phalanges, milder haemolysis than CEP, life expectancy normal 2. Extracutaneous 1. Accumulated porphyrins in liver are carcinogenic 2. Liver biopsy: stainable iron, fatty change, intracellular porphyrin crystals 3. 15% develop cirrhosis 4. 3% develop HCC. Risk factors are: 1. Symptoms >10 years 2. Severe changes on histo 3. HCV 4. Male 5. >50 years 5. Monitor with USS, fibroscan and alpha-foetal protein

Answer 8

- FBC generally normal, Hb might be elevated - Ferritin usually normal or modestly increased - Alost always mild elevations in ALT > AST --> from porphyrins as well as risk factors - Erythrocyte UROD activity: normal in type 1, and half normal in type 2 - Genetic testing for UROD will be normal in the majority of patients with PCT - those with familial disease typically will have heterozygosity for UROD mutation And liver things

Answer 9

1. Subepidermal bullae with sparse inflammatory infiltrate 2. Festooning of the dermal papillae in the bullae: the papillae protrude up 3. Thickened upper dermal capillary walls: this is due to deposition of fibrillar glycoprotein, is PAS positive and diastase negative 4. May have caterpillar bodies in the blister roof: linear, eosinophilic PAS positive globules composed of basement membrane material and degenerating keratinocytes

Answer 10

1. Prevention 1. Photoprotection 2. Eliminate risk factors - treat HBV, HCV, minimise ETOH and smoking 3. Genetic counselling: difficult to justify screening as no acute attacks 2. MDT 1. Gastroenterology 3. Physical methods 1. Venesection 1. ~500 mL every 1-2 weeks, monitoriing ferritin and Hb, although Ludi's tute says every 4 weeks 2. done until ferritin <20 ng/mL 3. takes blistering 2-3 months to resolve, and skin fragility 6-9 months 4. relapse 2.5 years later 5. Iron chelation less efficient than phlebotomy 6. Phlebotomy preferred over low dose plaquenil due to greater experience 7. usually do not need more phleobotomy unless HFE gene issues 8. monitor plasma or urine porphyrins ever 6-12 months, and re-initiate phlebotomy if porphyrin levels become elevated 2. Excision and graft of sclerodermoid lesions 3. Iron chelation - less efficient 4. Medical 1. Hydroxychloroquine 1. Low dose 100 mg twice weekly 2. promotes uroporphyrin excretion in bile 3. May be contraindicated in advanced liver disease, regular ETOH, G6PD deficiency, psoriasis, retinal disease, ESRF 4. Compliance better with plaquneil 5. Need to be careful, don't want to cause biliary duct obstruction 2. Desferrioxamine 1. Chelates hepatic ion, requires S/C pump at night 2. Expensive 3. Erythropoieitin 1. Treatment of choice in renal failure 4. Modify iron: stopping iron supplemnentation 5. Genetic counselling 1. If have UROD or HFE mutation Monitoring - Monitor serum ferritin during phlebotomy and plasma porphyrins at time of each phlebotomy - If on plaquenil - monthly plasma and urine porphyrins - stop drug after levels have been normal for several month, monitoring ferritin is't helpful

Answer 11

Genetic counseling is important in families with a known pathogenic variant in UROD, emphasizing that disease penetrance of familial (type 2) PCT is low and that HEP results from inheritance of URODvariants from both parents. Acquired susceptibility factors should also be discussed

Answer 12

- venesection doens't help - ?plaquenil - photoprotection etc - BM stem cell transplant

Answer 13

- super rare - some have been associated with haem malignancy - Autosomal dominant but variable penetrance - So need one mutation from one parent, and then inherit a polymorphism from another parent - Heterozygous ferrochelatase gene mutation and polymorphism of other parent - 10% in Caucasian population, more common in Asia

Answer 14

- Only those who inherit a heterozygous ferrochelatase gene mutation involving one parent allele and specific intronic polymorphism of the other parental allele develop skin symptoms - The gene is called FECH: ferrochelatase, less commonly ALAS2 causing XLP - FECH insufficiency results in excessive accumulation of protoporphyrin that lacks iron or other metals - particularly zinc - Primary source of excess plasma and erythrocyte protoporphyrin is metal-free protoporphyrin preoduced by the BM reticulocytes - In conditions where erythropoiesis is stimulated, production of protoporphyrin by the bone marrow may increase further - Accumulation of metal free protoporphyrin >85% total erythrocyte protoporphyrin is a distinctive feature of EPP (also a characteristic of XLP) - Excess protoporphyrin in plasma in EPP and XLP is bound to albumin, and taken by liver to secrete into bile --> only way to remove - Protoporphyrins are hydrophobic, deposited in lipid layers - don't cause blistering

Answer 15

- Baby: - usually only physical sign is oedema, with severe attacks they can have purpuric lesions, crusted erosions and vesicles - immediate pain to bright light --> crying in pram, worse in spring and summer - pain, tingling, discomfort, itching - partial relief with cold water and wet clothes - Older: - Signs: thickening over MCP and IP joints, vermicular scarring on nose, shallow linear/punctate/circular scars on cheeks, forehead, radial scars around lips, skin roughened and pebbly - 50% still have no physical signs - Adult onset is very unusual - will have history of either a myeloproliferative disorder or MDS - Psychosocial ++ - May improve with pregnancy due to anaemia - Variant: associated with palmar keratoderma - Liver: - PPP can precipitate and form gallstones in ~ 12% patients --> cholestasis - PPP is also hepatotoxic --> 1% severe liver damage, some may require liver transplant but can still get disease back in graft - LFTs may remain normal until late in the course of the disease - Peripheral neuropathy - May develop in late stages of hepatopathy and progress to resp failure - very rare - Vitamin D deficiency and osteoporosis - Anaemia - Pregnancy - can improve

Answer 16

- endothelial damage in superficial dermal vessels in acute phase - chronic phase: deposition of hyaline material (PAS positive) in walls of blood vessels of upper dermal and papillary vascular plexuses --> can be so extensive looks like coloid milia - IF: IgG

Answer 17

- Prevention: - Photoprotection - Monitoring - LFTs and red cell PPP checked annually - Genetic counselling: autosomal dominant with incomplete penetrance, probability of offspring acquiring and suffering is under 10%, testing for partner is now available - Acute attacks - analgesia - severe --> admission - Medical therapy: - Oral beta-carotene - believed to scavenge free radicals involved in the acute phototoxic reaction - can cause reversible skin pigmentation - PUVA - may be useful in that it induces epidermal thickening and pigmentation - Afamelanotide - alpha-melanocytic stimulating hormone analogue --> has shown promising results - Physical: - Allogenic bone marrow transplant - Liver transplant in liver issues

Answer 18

- Gain of function mutations in ALAS2 on the X chromosome - Looks like EPP, but not as fatal - Higher total protoporphyrin levels in erythrocytes, with ~ 40% being zinc protoporphyrin

Answer 19

- Really common in South Africa --> 1/20, much less in Europe and elsewhere - at least 80% of south africans carry a pathogenic mutation of VP but are asymptomatic

Answer 20

- Autosomal dominant inherited deficiency of PPP oxidase (PPOX) - Accumulated CPP and PPP inhibit PBG --> resulting in acute attacks

Answer 21

- Cutaneous - 70% have cutaneous involvement - adolescence/young adulthood onset - indistinguishable from PCT: skin fragility, tense blistering in photo-distributed sites, pigment changes, scarring, scleroderma, milia, hypertrichosis - Nail: occasionally photo-onycholysis - No seasonal variation - Acute photosensitivity when hepatic injury (due to increased porphyrins I guess) - Extracutaneous - Intercurrent biliary obstruction --> exacerbated cutaneous diease - Protoporphyrin is toxic to the bile duct, can't be excreted in the urine --> this is how it is toxic - Increased lifetime risk of hepatocellular carcinoma - Acute attacks --> occurs more in women, declined in recent times due to prophylactic measures - Sometimes goes into clinical and biochemical remission in old age - Variants: - homozygous VP mutation --> clinically much worse, occurs in neonates and have significant neurological issues --> epilepsy, delayed development, nystagmus, hand deformities

Answer 22

- Prevention - Photoprotection - Avoid medications and low calorie diets and alcohol - Emergency identification bracelet - Genetic counselling: - identify relatives - negative test is uninformative but positive means they have it - Risk of passing to offspring is 50%, 20% of those will have symptoms - Medications - Beta-carotene and canthaxanthin? limited protection - Physical - Liver transplant for acute attacks

Answer 23

- Photosensitising drugs - FIND - Frusemide - Isotretinoin and other retinoids - NSAIDS - naproxen, nabumetone - Dapsone, doxycycline (other tetracyclines) - Haemodialysis - Sunbeds ``` Other acronym - STANDARD Sunbeds Tanning Alcohol Nsaids Diuretics - particularly frusemide Amiodarone Retinoids Dialysis ```

Answer 24

- Not actually porphyria, and is clinically and histologically indistinguishable from PCT - No biochemical abnormalities - Skin fragility, erosions, blisters and scarring to dorsa of hands, face and extensor surfaces of legs - Commonly seen in stage 4 or 5 chronic kidney disease Clinically indistinguishable from PCT, however less likely to see hyperpigmentation, hypertrichosis and sclerodermoid changes