Porphyria

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The porphyrias are a "diverse group of metabolic diseases characterized by errors in the biosynthetic pathway of heme in the liver, the bone marrow, or both. They are classified by the deficiency of specific enzymes, the tissue site of enzyme defect, or the clinical features that include neurological (acute) or cutaneous (skin lesions)."[1][2][3]

Etiology / cause

Porphyrias are metabolic diseases in the heme biosynthetic pathway characterized by buildup of porphyrin precursors such as porphobilinogen (PBG).

"Porphyrias can be hereditary or acquired as a result of toxicity to the hepatic or erythropoietic marrow tissues."[1]

Medications may precipitate attacks, especially medications that induce cytochrome P-450.[3] Cytochrome P-450 is a hemeprotein that consists of a heme group and heme is iron with a porphyrin ring. A database of relevant medications is online.[4]

Classification

Classification of porphyrias
Name Onset Other
Cutaneous involvement
Congenital erythropoietic porphyria
(Guenther's disease)
Infancy Erythropoietic origin.
Erythropoietic protoporphyria Infancy Erythropoietic origin.
Hepatoerythropoietic porphyria Infancy
Porphyria cutanea tarda (PCT) Adulthood Most common porphyria. May be acquired
Neurovisceral involvement
ALA-dehydratase deficient porphyria (ADP)
OMIM 125270
Childhood
Acute intermittent porphyria (AIP)
OMIM 176000
Adulthood Most common neurovisceral porphyria.
Hereditary coproporphyria (HCP)
OMIM 121300
Adulthood Sometimes has cutaneous involvement.
Variegate porphyria (VP)
OMIM 176200
Adulthood Sometimes has cutaneous involvement.

Diagnosis

Patients may have pink or red urine from the porphyrins.

Neurovisceral attacks

The frequency of various signs and symptoms have been tabulated.[2]

Although the three adult onset neurovisceral porphyrias are autosomal dominant, only 80% of carriers are symptomatic so patients may not report a family history of porphyria.

Laboratory tests

Rapid urine tests during an acute neurovisceral attack are the Trace and the Hoesch or Watson–Schwartz test for porphobilinogen (PBG).

The best laboratory tests during an acute neurovisceral attack are the 5-aminolevulinic acid (ALA) and PBG in urine or serum.

When considering adult patients with neurovisceral symptoms, all three of the relevant porphyrias (AIP, HCP, VP) have elevated urinary PBG levels (20 to 200 mg/L; 220 to 880 µmol/d).[2] This level may be elevated to a lesser degree between attacks.

Treatment

Treatment is administration of hemin and glucose. Precipitating causes should be removed.[2]

Historical patients

The insanity exhibited by King George III evidenced in the regency crisis of 1788 has inspired several attempts at retrospective diagnosis. The first, written in 1855, thirty-five years after his death, concluded he suffered from acute mania. M. Guttbacker, in 1941, suggested manic-depressive psychosis as a more likely diagnosis, The first suggestion that a physical illness was the cause of King George's mental derangements came in 1966, in a paper "The Insanity of King George III: A Classic Case of Porphyria"[5], with a follow-up in 1968, "Porphyria in the Royal Houses of Stuart, Hanover and Prussia"[6]. The papers, by a mother/son psychiatrist team, were written as though the case for porphyria had been proven, but the response demonstrated that many, including those more intimately familiar with actual manifestations of porphyria, were unconvinced. The theory is treated in Purple Secret[7], which documents the ultimately unsuccessful search for genetic evidence of porphyria in the remains of royals suspected to suffer from it.[8] In 2005 it was suggested that arsenic (which is known to be porphyrogenic) given to George III with antimony may have caused his porphyria.[9] Despite the lack of direct evidence, the notion that George III (and other members of the royal family) suffered from porphyria has achieved such popularity that many forget that it is merely a hypothesis.

It is also suspected that Mary Queen of Scots--George III's grandmother six times removed--also suffered from acute intermittent porphyria, although this is subject to much debate.

Other commentators have suggested that Vincent van Gogh may have suffered from acute intermittent porphyria.[10]

References

  1. 1.0 1.1 Anonymous (2015), Porphyria (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. 2.0 2.1 2.2 2.3 Anderson KE, Bloomer JR, Bonkovsky HL, et al (March 2005). "Recommendations for the diagnosis and treatment of the acute porphyrias". Ann. Intern. Med. 142 (6): 439–50. PMID 15767622[e]
    Table that quantifies frequency of symptoms
    Table of precipitating medications
  3. 3.0 3.1 Bonkovsky HL, Siao P, Roig Z, Hedley-Whyte ET, Flotte TJ (June 2008). "Case records of the Massachusetts General Hospital. Case 20-2008. A 57-year-old woman with abdominal pain and weakness after gastric bypass surgery". N. Engl. J. Med. 358 (26): 2813–25. DOI:10.1056/NEJMcpc0803190. PMID 18579817. Research Blogging.
  4. The Drug Database for Acute Porphuria (Multiple languages). The Norwegian Porphyria Centre. Retrieved on 2008-09-10.
  5. Ida Macalpine & Richard Hunger, "The Insanity of King George III: A Classic Case of Porphyria", British Medical Journal, 1966, pp. 65-71.
  6. Ida Macalpine, Richard Hunger, & Claude Rimington, "Porphyria in the Royal Houses of Stuart, Hanover and Prussia: A Followup Study of George III's Illness", British Medical Journal, 1968, pp. 7-18.
  7. Röhl, John C.G., Warren Martin,& David Hunt, Purple Secret, Bantam Press, London, 1998 ISBN 0-593-04148-8
  8. The authors demonstrated a single point mutation in the PPOX gene, but not one which has been associated with disease.
  9. Cox TM, Jack N, Lofthouse S, Watling J, Haines J, Warren MJ. King George III and porphyria: an elemental hypothesis and investigation. Lancet 2005;366(9482):332-5. PMID 16039338.
  10. Loftus LS, Arnold WN. Vincent van Gogh's illness: acute intermittent porphyria? BMJ 1991;303:1589-91. PMID 1773180.

External links