21 - 124 - PORPHYRIAS

Question 1

Question 2

Porphyria cutanea tarda is caused by inhibition of what enzyme

Answer 2

hepatic uroporphyrinogen decarboxylase (UROD) activity

Question 3

Question 4

Question 5

Question 6

Question 7

Question 8

Question 9

Question 10

Question 11

Question 12

Question 13

Question 14

The most common porphyria is treated with

A. Hemin

B. Stem cell transplant

C. Phlebotomy

D. Oral Charcoal

Answer 14

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

Question 15

The enzyme affected in most common acute hepatic porphyria is

A. ALAD

B. UROD

C. HMBS

D. FECH

Answer 15

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

Question 16

Treatment of choice in young with severe congenital erythropoietic porphyria

A. Hemin

B Stem cell transplant

C. Phlebotomy

D. Oral Charcoal

Answer 16

B

Hematopoietic stem cell transplantation is curative and is the treatment of choice for young patients with severe disease. P. 2244

Question 17

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

Answer 17

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

Question 18

develops as an acquired deficiency of the fifth enzyme in the pathway with or without a mutation

Answer 18

porphyria cutanea tarda

Question 19

All but one arise from mutation of a pathway enzyme, the exception is?

Answer 19

porphyria cutanea tarda

Question 20

These porphyrias are due to overproduction and accumulation of photosensitizing porphyrins.

Answer 20

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

Question 21

characterized by neurologic symptoms and** elevated levels of the porphyrin precursors,** δ-aminolevulinic acid (ALA) and porphobilinogen (PBG).

Answer 21

Acute porphyrias

Question 22

PORPHYRIA CUTANEA TARDA is caused by inhibition of what enzyme?

Answer 22

hepatic uroporphyrinogen decarboxylase (UROD) activity

Question 23

This is the only porphyria that can develop in absence of the mutation of the affected enzyme

Answer 23

PORPHYRIA CUTANEA TARDA

Question 24

First-line testing (ie, screening) for PCT

Answer 24

measurement of total plasma or urine porphyrins

Question 24

the most readily treated porphyria, responding well to either phlebotomy or low-dose hydroxychloroquin

Answer 24

PORPHYRIA CUTANEA TARDA

Question 25

the most common susceptibility factors in PCT

Answer 25

*** ethanol use (87%), ** * smoking (81%), * chronic hepatitis C (69%), * HFE (hemochromatosis) mutations (53%) ## Footnote 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.**

Question 26

T/F. Iron stores are always normal or increased in PCT, whereas iron deficiency is protective

Answer 26

True

Question 27

The porphyria most commonly misdiagnosed as PCT

Answer 27

variegate porphyria (VP)

Question 28

highly effective in both sporadic and familial forms of PCT

Answer 28

phlebotomy or low-dose hydroxychloroquine ## Footnote * 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

Question 29

Repeated phlebotomy to reduce hepatic iron is the preferred treatment at most institutions What is the protocol for phlebotomy?

Answer 29

* 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.

Question 30

* 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.

Answer 30

HEPATOERYTHROPOIETIC PORPHYRIA (HEP)

Question 30

What is the low-dose regimen of antimalarials for PCT?

Answer 30

* 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.

Question 31

* 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

Answer 31

CONGENITAL ERYTHROPOIETIC PORPHYRIA (CEP)

Question 32

curative and is the treatment of choice for young patients with severe disease of Congenital Erythropoietic Porphyria

Answer 32

Hematopoietic stem cell transplantation

Question 33

the third most common porphyria and the most common in children

Answer 33

Erythropoietic protoporphyria (EPP)

Question 34

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

Answer 34

Erythropoietic protoporphyria (EPP)

Question 35

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

Answer 35

X-linked protoporphyria (XLP) ## Footnote mutation of d-Aminolevulinic acid synthase

Question 36

In this porphyria, there is excess **metal-free protoporphyrin** in plasma

Answer 36

Erythropoietic protoporphyria (EPP)

Question 36

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)

Answer 36

Acute cutaneous photosensitivity

Question 37

primary therapeutic intervention in EPP

Answer 37

Photoprotection, especially avoidance of sunlight exposure

Question 38

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

Answer 38

Afamelanotide

Question 39

The acute porphyrias are characterized by intermittent acute neurologic symptoms, but can develop chronic blistering lesions Enumerate the 4 acute porphyrias

Answer 39

1. δ-aminolevulinate dehydratase deficiency porphyria (ADP), 2. acute intermittent porphyria (AIP), 3. hereditary coproporphyria (HCP), 4. variegate porphyria (VP) ## Footnote *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

Question 40

blistering lesions are not observed in this acute porphyria

Answer 40

δ-aminolevulinate dehydratase deficiency porphyria (ADP) ## Footnote *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

Question 41

all acute porphyrias are autosomal dominant except?

Answer 41

δ-aminolevulinate dehydratase deficiency porphyria (ADP) ## Footnote Autosomal recessive

Question 42

Question 42

most common acute hepatic porphyria worldwide

Answer 42

acute intermittent porphyria (AIP)

Question 43

A specific feature of VP is a plasma porphyrin fluorescence maximum at neutral pH of what nm?

Answer 43

**∼626 nm,** which represents protoporphyrin bound covalently to plasma proteins ## Footnote 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

Question 44

most effective treatment for acute attacks of acute porphyrias

Answer 44

Hemin ## Footnote 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