Porphyrias Flashcards
In what range of light do porphyrias tend to absorb light?
401-410 nm (making it the short end of the visible spectrum)
What is the difference in clinical findings of water vs lipid-soluble porphyrins?
Water-soluble: Causes blisters
Lipid-soluble: Acute burning and erythema
What is the most common porphyria?
Porphyria cutanea tarda
What causes porphyria cutanea tarda?
Decreased hepatic uroporphyrinogen decarboxylase (UROD) activity
What are the 3 types of porphyria cutanea tarda?
I: familial
II: Sporadic/acquired
III: Normal UROD gene, but multiple affected family members
What type of porphyria cutanea tarda is most common?
Type II sporadic/acquired
What are the skin findings of porphyria cutanea tarda?
Skin fragility, vesicles, bullae, erosions, milia, scarring, hyperpigmentation, hypertrichosis in photo distributed areas (especially dorsal hands/forearms
What should be screened for if a patient has porphyria cutanea tarda?
Hemochromatosis
What is the plasma peak fluorescence pattern for porphyria cutanea tarda?
620nm
What is the definition of an acute vs non-acute porphyria?
Acute suggests the presence or potential for potentially life-threatening acute neurologic attacks as part of the dz
Which of the porphyrias are acute?
Acute intermittent porphyria, Variegate porphyria, Hereditary coproporphyria, ALA-D deficiency porphyria
Which porphyrias are autosomal recessive?
Most of the porphyrias are autosomal dominant. Exceptions include one XLD dz (X-linked dominant protoporphyria), and 3 autosomal recessive ones
AR ones: ALA-D deficiency porphyria, Congenital erythropoietic porphyria, Hepatoerythropoietic porphyria, and rarely erythropoietic porphyria
What porphyrias are not associated with skin findings?
ALA dehydratase deficiency porphyria and acute intermittent pophyria
What porphyria results from a homozygous mutation in uropophyrinogen decarboxylase (UROD)?
Hepatoerythropoietic porphyria
- This is opposed to porphyria cutanea tarda which is a diminished action of this same enzyme. This is why you see very exaggerated findings of PCT occurring early (starts in childhood, extreme photosensitivity, hypertrichosis, milia, vesicles/bullae/erosions/ulcers and the same plasma fluorescence emission peak (620nm)
What is the preferred lab testing to confirm the diagnosis for suspected porphyria cutanea tarda?
Serum/plasma porphyrins
What is the most common form of porphyria cutanea tarda?
Type 1 (absence of UROD mutation, 80% of cases)
What is the pathogenesis of skin lesions in porphyria cutanea tarda?
When the porphyrins accumulate that are seen in PCT, are exposed to a wavelength near 400nm the porphyrins enter an excited state and release photons that activate oxygen in the tissues to singlet oxygen which damages tissues leading to blister formation
What are some triggers for porphyria cutanea tarda?
Alcohol abuse, estrogen, iron and hemochromatosis, hepatitis C, and HIV
What is the histology of porphyria cutanea tarda?
cell-poor subepidermal bulla w/ “festooning” of dermal papillae, “caterpillar bodies” (pink BMZ material in blister cavity and epidermis)
- Festooning is from papillary fibrosis which makes that area keep its shape when you loose the epidermis
What are the DIF findings in porphyria cutanea tarda?
IgG, IgM, fibrinogen, and C3 linearly along BMZ and in superficial dermal vessels (see thickened deposits around vessels)
What is the treatment for porphyria cutanea tarda?
Avoid precipitating factors (alcohol and estrogen), photoprotection/sun avoidance, treat the underlying conditions (if any), phlebotomy, low dose hydroxychloroquine, and deferasirox
What is the best initial diagnostic test for cutaneous blistering porphyrias?
Total plasma, serum, or spot urine porphyrins (screening)
What gene is mutated in X-linked dominant protoporphyria?
ALAS2 gene that encodes 5-ALA synthase
What is the presentation of X-linked dominant protoporphyria?
Erythropoietic protoporphyria
What is the mutation leading to Hepatoerythropoietic porphyria?
Homozygous mutation of uroporphyrinogen decarboxylase (UROD)
- Remember that PCT is also UROD but not homozygous mutation
Labratory findings in hepatoerythropoietic porphyria?
Increased zinc protoporphyrin in RBCs and plasma
fluorescence emission peak at 620 nm;
Increased uroporphyrin and increased coproporphyrin in urine and stool
When does Hepatoerythropoietic porphyria start and what is the presentation?
Starts in childhood/infancy
Presents with scarring,sclerodermoid changes, photosensitivity to point of mutilation, hypertrichosis, milia, and vesicles/bullae/ erosions/ulcers
What is the treatment for hepatoerythropoietic porphyria?
Photoprotection, sun and trauma avoidance
What is the mutation in Variegate porphyria?
AD mutation in protoporphyrinogen oxidase
(located in mitochondria)
Where is Variegate porphyria more common?
Chile and South Africa (found effects)
What are the clinical findings of Variegate porphyria?
Similar to PCT but you can also have neurovisceral attacks
What is the peak plasma fluorescence emission peak of Variegate porphyria?
626 nm
What are the laboratory findings in Variegate porphyria?
Increased ALA/ increased PBG/increased coproporphyrin in urine; Increased protoporphyrin IX/increased coproporphyrin III : I ratio (protoporphyrin > coproporphyrin) in stool
What is the treatment for variegate porphyria?
Avoid triggers (e.g., porphyrinogenic drugs, alcohol, and hormones)
- For acute porphyric attacks, supportive care in ICU with sufficient caloric supplementation, IV hemin or heme arginate infusion, and supportive medical treatments (β-blockers, narcotics, phenothiazines, gabapentin, and laxatives); LHRH or GHRH agonists, prophylactic hemin and cimetidine may help prevent future attacks
What is the mutation in Hereditary coproporphyria?
AD mutation in coproporphyrinogen III oxidase
(located in mitochondria)
What are the sex differences in acute attack rates for hereditary coproporphyria?
More common in women than in men
Clinical findings for hereditary coproporphyria?
Neurovisceral attacks + skin findings like PCT
What are the laboratory findings in hereditary coproporphyria?
Increased ALA/increased PBG in urine; increased coproporphyrin III : I ratio (coproporphyrin III > protoporphyrin)
Treatment of hereditary coproporphyria?
Same as variegate porphyria: ICU for acute neurovisceral attacks, avoid triggers, and can consider supportive medical treatments
What is the mutation and effect of the mutation for Congenital erythropoietic porphyria?
AR deficiency of uroporphyrinogen III synthetase (UROS)
- Leads to overproduction of uroporphyrin I and coporphyrin I in erythrocytes, plasma, urine, and feces
There is also a XLR mutation in GATA1 (transcription factor that regulates expression of UROS)
What are the cutaneous findings in Congenital erythropoietic porphyria?
Photosensitivity with blistering, scarring, mutilating cutaneous deformity, sclerodermatous changes, hypertrichosis, dyschromia, and alopecia
What feature of Congenital erythropoietic porphyria can be seen in infancy and why does it occur?
Red urine: caused by increased porphyrins in urine that are excited by 400-410nm light and emit red fluorescence
What other features are seen in Congenital erythropoietic porphyria?
Splenomegaly, cholelithiasis, and hemolytic anemia Pathologic fractures, osteopenia, vertebral compression, and contractures of fingers.
- Conjunctivitis and corneal scarring
- Erythrodontia: teeth fluoresce red/purple under Wood’s lamp examination
Laboratory findings in Congenital erythropoietic porphyria?
Increased urinary/erythrocyte uroporphyrin I; increased urinary and fecal coproporphyrinogen I and uroporphyrinogen I
What is the treatment for Congenital erythropoietic porphyria?
Strict photoprotection, hypertransfusions, and iron chelation such as with deferoxamine; splenectomy may be considered, use of ascorbic acid and α-tocopherol has been advocated; ocular lubricants, and allogeneic bone marrow transplantation
What is the prognosis of Congenital erythropoietic porphyria?
Poor for those with severe hematologic disease or if they present early (unless treated with hematopoietic cell transplant)
What is the most common form of porphyria seen in children?
Erythropoietic protoporphyria
What mutation is seen in Erythropoietic protoporphyria and what forms of inheritance does it follow?
AD/AR mutations in ferrochelatase
When do children with Erythropoietic protoporphyria most commonly present?
Between 1-6 years of age
What is the most common presentation of Erythropoietic protoporphyria?
Burning/stinging/or itching 5-30 minutes after exposure to sunlight
- Causes pruritic erythematous/edematous plaques that last 1-2 days post-sunlight exposure
leads to hypo-hyperpigmentation, photonycholysis
Can also get linear pits on the face along with appular eruptions on the knuckles
Systemic findings in Erythropoietic protoporphyria?
Hemolytic anemia, cholelithiasis protoporphyrin accumulation in the liver may lead to hepatotoxicity and progressive hepatic dysfunction
What is the treatment for Erythropoietic protoporphyria?
strict photoprotection, oral β-carotene may be helpful in some patients, and hypertransfusion/plasmapheresis/exchange transfusion may be helpful in some patients; liver transplantation may be necessary with hepatic failure
If screening for blistering porphyrias is positive, what tests are done next?
Plasma porphyrins, fractionate urine and/or plasma porphyrins, urinary ALA, PBG and porphyrins, erythrocyte total porphyrins, fecal total porphyrins (fractionate if these are elevated)
Depending on what is found, gene sequencing for suggested porphyria
