21 - 124 - PORPHYRIAS Flashcards
Porphyria cutanea tarda is caused by inhibition of what enzyme
hepatic uroporphyrinogen decarboxylase (UROD) activity
The most common porphyria in children is treated with
A. Hemin
B. Stem cell transplant
C. Phlebotomy
D. Oral Charcoal
C
PCT is the most common porphyria, P. 2237. Treatment with phlebotomy or low-dose hydroxy- chloroquine is highly effective in both sporadic and familial forms of PCT. p. 2342
The enzyme affected in most common acute hepatic porphyria is
A. ALAD
B. UROD
C. HMBS
D. FECH
C AIP is the most common acute hepatic porphyria worldwide P.2250 At least 400 PBGD/HMBS mutations have been iden- tified in AIP P.2250
Treatment of choice in young with severe congenital erythropoietic porphyria
A. Hemin
B Stem cell transplant
C. Phlebotomy
D. Oral Charcoal
B
Hematopoietic stem cell transplantation is curative and is the treatment of choice for young patients with severe disease. P. 2244
A 50 yo female presented with skin friability and c blistering lesion on the dorsal aspects of hands. Laboratory result showed increase total plasma porphyrin and predominance of highly carboxylated porphyrins. Which factor is mostly associated with the case:
A. Alcohol use
B. Smoking
C. Chronic Hepatitis C
D. Estrogen use
In relation to the case, what enzyme is affected:
A. ALAD
B. UROD
C. HMBS
D FECH
D.
Female. Estrogen use is common in women with PCT.2239
PCT is the most common porphyria, and is characterized by the development of skin friability and chronic, blistering lesions on the dorsal aspects of the hands and other sunexposed areas of skin usually in mid- or late life.
B. UROD
develops as an acquired deficiency of the fifth enzyme in the pathway with or without a mutation
porphyria cutanea tarda
All but one arise from mutation of a pathway enzyme, the exception is?
porphyria cutanea tarda
These porphyrias are due to overproduction and accumulation of photosensitizing porphyrins.
Cutaneous porphyrias
- Most, as exemplified by PCT, cause chronic blistering and scarring on sun-exposed areas of skin, whereas protoporphyrias produce an acute, severe, and mostly nonblistering reaction to light, often leaving few if any chronic skin changes
characterized by neurologic symptoms and** elevated levels of the porphyrin precursors,** δ-aminolevulinic acid (ALA) and porphobilinogen (PBG).
Acute porphyrias
PORPHYRIA CUTANEA TARDA is caused by inhibition of what enzyme?
hepatic uroporphyrinogen decarboxylase (UROD) activity
This is the only porphyria that can develop in absence of the mutation of the affected enzyme
PORPHYRIA CUTANEA TARDA
First-line testing (ie, screening) for PCT
measurement of total plasma or urine porphyrins
the most readily treated porphyria, responding well to either phlebotomy or low-dose hydroxychloroquin
PORPHYRIA CUTANEA TARDA
the most common susceptibility factors in PCT
*** ethanol use (87%), **
* smoking (81%),
* chronic hepatitis C (69%),
* HFE (hemochromatosis) mutations (53%)
All PCT patients should be questioned or examined for the following susceptibility factors, some of which are modifiable:** alcohol and estrogen use, smoking, hepatitis C and HIV infection, and HFE and UROD mutations.**
T/F.
Iron stores are always normal or increased in PCT, whereas iron deficiency is protective
True
The porphyria most commonly misdiagnosed as PCT
variegate porphyria (VP)
highly effective in both sporadic and familial forms of PCT
phlebotomy or low-dose hydroxychloroquine
- These should be initiated only after the diagnosis is certain, because they are not effective in other porphyrias
- It may be reasonable to start treatment after plasma porphyrin results, including fluorescence scanning, are consistent with PCT and have excluded VP and pseudoporphyria
Repeated phlebotomy to reduce hepatic iron is the preferred treatment at most institutions
What is the protocol for phlebotomy?
- Removal of 450 mL blood at 2-week intervals is guided by the serum ferritin level, with a target of 15 to 20 ng/mL (ie, near the lower limit of normal).
- Phlebotomies are stopped when the ferritin from the previous visit is 25 to 30 ng/L, and ferritin is measured to confirm that the target level was reached.
- the homozygous form of familial (type 2) PCT, with mutation of both UROD alleles resulting in severely deficient UROD activity
- Biochemical findings resemble PCT, but with substantial** elevation of erythrocyte zinc protoporphyrin**
- Patients should avoid sunlight. Treatment with phlebotomy or low-dose hydroxychloroquine is not effective
- presents with onset of blistering skin lesions, hypertrichosis, scarring, hemolytic anemia, and red urine typically in early childhood.
- Sclerodermoid skin changes are sometimes prominent.
HEPATOERYTHROPOIETIC PORPHYRIA (HEP)
What is the low-dose regimen of antimalarials for PCT?
- A low-dose regimen (hydroxychloroquine 100 mg or chloroquine 125 mg [one half of a standard tablet] twice weekly) is recommended to achieve remission and avoid the side effects of full doses of these drugs
- Treatment is continued until plasma or urine porphyrins are normalized for at least a month.
- These medications are associated with a small risk of retinopathy, 73 which may be lower with hydroxychloroquine. Therefore, patients should be screened by an ophthalmologist before treatment.
- As a result of mutation of both uroporphyrinogen III synthase (UROS) alleles resulting in severe loss of activity of UROS and elevations of uroporphyrin I and coproporphyrin I
- Characterized by subepidermal scarring and bullous lesions affecting light-exposed areas
- Diagnosis is established by markedly **elevated uroporphyrin I and coproporphyrin I in erythrocytes, **urine, plasma, and feces and identification of causative mutations
CONGENITAL ERYTHROPOIETIC PORPHYRIA (CEP)
curative and is the treatment of choice for young patients with severe disease of Congenital Erythropoietic Porphyria
Hematopoietic stem cell transplantation
the third most common porphyria and the most common in children
Erythropoietic protoporphyria (EPP)
It results from loss-of-function mutation of** ferrochelatase (FECH),** which catalyzes insertion of iron into protoporphyrin IX, the last step of the heme biosynthetic pathway
Erythropoietic protoporphyria (EPP)
less common and results from gain-offunction mutations of ALAS2, the erythroid-specific form of the first enzyme in the pathway, and comprises ∼5% of protoporphyria cases
X-linked protoporphyria (XLP)
mutation of d-Aminolevulinic acid synthase
In this porphyria, there is excess metal-free protoporphyrin in plasma
Erythropoietic protoporphyria (EPP)
the most prominent symptom of EPP described as stinging, burning, or tingling pain that may develop within minutes of sunlight exposure, followed by erythema and edema (described as solar urticaria)
Acute cutaneous photosensitivity
primary therapeutic intervention in EPP
Photoprotection, especially avoidance of sunlight exposure
currently approved for restricted use in the European Union and Switzerland and is under review by the US Food and Drug Administration for use in patients with EPP and XLP
Afamelanotide
The acute porphyrias are characterized by intermittent acute neurologic symptoms, but can develop chronic blistering lesions
Enumerate the 4 acute porphyrias
- δ-aminolevulinate dehydratase deficiency porphyria (ADP),
- acute intermittent porphyria (AIP),
- hereditary coproporphyria (HCP),
- variegate porphyria (VP)
*chronic blistering skin lesions resembling PCT can occur in 3 of these conditions. They are common in VP, uncommon in HCP, in AIP occur only with advanced renal disease, and are not described in ADP
blistering lesions are not observed in this acute porphyria
δ-aminolevulinate dehydratase deficiency porphyria (ADP)
*chronic blistering skin lesions resembling PCT can occur in 3 of these conditions. They are common in VP, uncommon in HCP, in AIP occur only with advanced renal disease, and are not described in ADP
all acute porphyrias are autosomal dominant except?
δ-aminolevulinate dehydratase deficiency porphyria (ADP)
Autosomal recessive
most common acute hepatic porphyria worldwide
acute intermittent porphyria (AIP)
A specific feature of VP is a plasma porphyrin fluorescence maximum at neutral pH of what nm?
∼626 nm, which represents protoporphyrin bound covalently to plasma proteins
This fluorometric scanning method is more effective than examination of fecal porphyrins for detecting asymptomatic VP, 189 and is especially useful for rapidly differentiating VP from PCT, which displays a fluorescence peak at ∼620 nm
most effective treatment for acute attacks of acute porphyrias
Hemin
Intravenously infused hemin is taken up primarily by hepatocytes where it reconstitutes the regulatory heme pool and represses the synthesis of ALAS1, leading to dramatic reduction in ALA, PBG, and porphyrins, and more rapid resolution of symptoms
