Porphyrias

Question 1

How does AIP usually present?

Answer 1

Manifestations include colicky abdominal pain, vomiting, constipation, port wine–colored urine, and neurologic and psychiatric disturbances. Acute attacks rarely occur before puberty and may last from days to months. Photosensitivity does not occur.

Question 2

What are some precipitating factors associated with AIP attacks?

Answer 2

Barbiturates, anticonvulsants, estrogens, oral contraceptives, the luteal phase of the menstrual cycle, alcohol, or low-calorie diets.

Question 3

How is a diagnosis of AIP made?

Answer 3

Diagnosis is established by demonstrating elevation of urinary porphobilinogen (PBG) and γ-aminolevulinic acid (ALA) during an acute attack.

Question 4

How is an AIP attack managed medically?

Answer 4

As soon as possible after the onset of an attack, 3–4 mg of heme, in the form of heme arginate, heme albumin, or hematin, should be infused daily for 4 days. Heme acts by inhibiting ALA synthase, thereby restraining ALA and PBG production. Administration of IV glucose at rates up to 20 g/h or parenteral nutrition, if oral feeding is not possible for long periods, can be effective in acute attacks. Narcotic analgesics may be required during acute attacks for abdominal pain, and phenothiazines are useful for nausea, vomiting, anxiety, and restlessness.

Question 5

Describe the genetic basis of porphyria cutanea tarda.

Answer 5

Due to partial deficiency (familial, sporadic, or acquired) of hepatic uroporphyrinogen decarboxylase, it is the most common porphyria.

Question 6

How does porphyria cutanea tarda present clinically?

Answer 6

Characterized by cutaneous photosensitivity and, usually, hepatic disease. Photosensitivity causes facial pigmentation, increased fragility of skin, erythema, and vesicular and ulcerative lesions, typically involving face, forehead, and forearms. Neurologic manifestations are not observed.

Question 7

What are some of the factors that precipitate attacks of porphyria cutanea tarda?

Answer 7

Contributing factors include excess alcohol, iron, and estrogens.

Question 8

How is porphyria cutanea tarda diagnosed?

Answer 8

Plasma and urine uroporphyrin and 7-carboxylate porphyrin are increased.

Question 9

How is porphyria cutanea tarda managed medically?

Answer 9

Avoidance of precipitating factors, including abstinence from alcohol, estrogens, iron supplements, and other exacerbating drugs, is the first line of therapy. A complete response can almost always be achieved by repeated phlebotomy (every 1–2 weeks) until hepatic iron is reduced. Chloroquine or hydroxychloroquine may be used in low doses to promote porphyrin excretion in pts unable to undergo or unresponsive to phlebotomy.

Question 10

List the three types of erythropoietic porphyria.

Answer 10

1. Congenital erythropoietic porphyria (Gunther disease)
2. Hepatoerythropoietic porphyria
3. Erythropoietic protoporphyria (EPP)

Question 11

List the five types of hepatic porphyria.

Answer 11

1. Acute intermittent porphyria (AIP)
2. Porphyria cutanea tarda (PCT)
3. Hepatoerythropoietic porphyria
4. Hereditary coproporphyria
5. Variegate porphyria

Question 12

What is the genetic basis of EPP?

Answer 12

EPP is an autosomal dominant disorder due to partial deficiency of ferrochelatase, the last enzyme in the heme biosynthetic pathway.

Question 13

Describe the pathophysiologic basis of EPP.

Answer 13

Porphyrins (primarily protoporphyrin IX) from bone marrow erythrocytes and plasma are deposited in the skin and lead to cutaneous photosensitivity.

Question 14

What is the typical presentation of a patient with EPP?

Answer 14

Skin photosensitivity usually begins in childhood. The skin manifestations differ from those of other porphyrias, in that vesicular lesions are uncommon. Redness, swelling, burning, and itching can develop within minutes of sun exposure and resemble angioedema. Symptoms may seem out of proportion to the visible skin lesions. Chronic skin changes may include lichenification, leathery pseudovesicles, labial grooving, and nail changes. Liver function is usually normal, but liver disease and gallstones may occur.

Question 15

Which lab abnormalities are seen in patients with EPP?

Answer 15

Protoporphyrin levels are increased in bone marrow, circulating erythrocytes, plasma, bile, and feces; protoporphyrin in erythrocytes is free rather than zinc-complexed as it is in other types of porphyria or hematologic disorders. Urinary porphyrin levels are normal.

Question 16

How is EPP diagnosed?

Answer 16

Diagnosis is confirmed by identifying a mutation in the ferrochelatase gene.

Question 17

What is the genetic basis of Gunther disease?

Answer 17

It is caused by mutations in the gene that encodes the enzyme uroporphyrinogen III synthase (UROS). The disorder is inherited in an autosomal recessive manner.

Question 18

How do patients with Gunther disease typically present?

Answer 18

With extreme photosensitivity with blistering of the skin and extensive scarring; hemolytic anemia; red coloration of teeth (erythrodontia) which fluoresce red under ultraviolet light.

Question 19

How in EPP managed medically?

Answer 19

Avoidance of sun exposure is essential. Oral β-carotene improves tolerance to sunlight in many pts. Cholestyramine or activated charcoal may promote fecal excretion of protoporphyrin. Plasmapheresis or IV heme therapy may be beneficial.

Question 20

Describe the genetic basis of acute intermittent porphyria (AIP).

Answer 20

Autosomal dominant disorder with variable expressivity caused by partial (50%) deficiency in hydroxymethylbilane synthase.