Acute intermittent porphyria

Classification and external resources

Porphobilinogen
ICD-10
E80.2
ICD-9
277.1
OMIM
176000
DiseasesDB 171
eMedicine
med/1880
MeSH
D017118
Hydroxymethylbilane Synthase
GeneReviews
(HMBS) Deficiency
Acute intermittent porphyria (AIP) is a rare autosomal dominant[1] metabolic disorder
affecting the production of heme, the oxygen-binding prosthetic group of hemoglobin. It
is characterized by a deficiency of the enzyme porphobilinogen deaminase. Acute
intermittent porphyria is the second most common form of porphyria (porphyria cutanea
tarda being the most common).[2]:525 Its incidence is estimated to be between 5 and 10 in
100,000, but this is likely underestimated because of positive cases not being induced,
and long periods of latency, with an estimation that it is latent in 90% of cases.[3]

Mechanism of disease
A Swedish study indicated that approximately 90% of cases of acute intermittent
porphyria are due to a mutation that causes decreased amounts of the enzyme, and to a
lesser degree by a mutation that causes decreased activity of each enzyme molecule.[4]
Under normal circumstances, heme synthesis begins in the mitochondrion, proceeds into
the cytoplasm, and finishes back in the mitochondrion. However, without
porphobilinogen deaminase, a necessary cytoplasmic enzyme, heme synthesis cannot
finish, and the metabolite porphobilinogen accumulates in the cytoplasm.[5]

Additional factors must also be present such as hormones, drugs, and dietary changes that
trigger the appearance of symptoms. Symptoms of AIP may include abdominal pain,
constipation, and muscle weakness.
Patients with AIP are commonly misdiagnosed with psychiatric diseases. Subsequent
treatment with anti-psychotics increases the accumulation of porphobilinogen, thus
aggravating the disease enough that it may prove fatal.

Symptoms
Symptoms in AIP can be variable. They include abdominal pain which is severe and
poorly localized (most common, 95% of patients experience), Urinary symptoms
(Dysuria, urinary retention/incontinence or dark urine), peripheral neuropathy (patchy
numbness and paresthesias), Proximal motor weakness (usually starting in upper
extremities which can progress to include respiratory impairment and death), autonomic
nervous system involvement (circulating catecholamine levels are increased, may see
tachycardia, hypertension, sweating, restlessness and tremor), neuropsychiatric symptoms
(anxiety, agitation, hallucination, hysteria, delirium, depression), Electrolyte
abnormalities (Hyponatremia may be due to hypothalamic involvement leading to
SIADH that may lead to seizures). [6] Unlike other porphyrias, rash is not typically seen in
AIP.

Treatment
A high-carbohydrate (10% glucose) infusion is recommended, which may aid in
recovery. If drugs have caused the attack, discontinuing the offending substances is
essential. Infection is one of the top causes of attacks and requires vigorous treatment.
Pain is extremely severe and almost always requires the use of opiates to reduce it to
tolerable levels. Pain should be treated early as medically possible due to its severity.
Nausea can be severe; it may respond to phenothiazine drugs but is sometimes
intractable. Hot water baths or showers may lessen nausea temporarily, but can present a
risk of burns or falls.[7]
Hematin and heme arginate are the drugs of choice in acute porphyria, in the United
States and the United Kingdom, respectively. These drugs need to be given very early in
an attack to be effective. Effectiveness varies among individuals. They are not curative
drugs, but can shorten attacks and reduce the intensity of an attack. Side-effects are rare
but can be serious. These heme-like substances, in theory, inhibit ALA synthase and,
hence, the accumulation of toxic precursors. In the United Kingdom, supplies of this drug
are maintained at two national centers. In the United States, one company manufactures
Panhematin for infusion. The American Porphyria Foundation has information regarding
the quick procurement of the drug.
Patients with a history of acute porphyria are recommended to wear an alert bracelet or
other identification at all times in case they develop severe symptoms, a result of which

may be that they cannot explain to healthcare professionals about their condition and the
fact that some drugs are absolutely contraindicated. An attack of acute intermittent
porphyria may be precipitated by one of the "four Ms": medication, menstruation,
malnutrition, maladies.
Patients that experience frequent attacks can develop chronic neuropathic pain in
extremities as well as chronic pain in the gut. This is thought to be due to axonal nerve
deterioration in affected areas of the nervous system. In these cases, treatment with longacting opioids may be indicated. Some cases of chronic pain can be difficult to manage
and may require treatment using multiple modalities. Depression often accompanies the
disease and is best dealt with by treating the offending symptoms and, if needed, the
judicious use of anti-depressants. Earl Campbell from University of Maryland performed
the first successful clinical trial. Although results for this trial are still undergoing
rigorous testing.
Seizures often accompany this disease. Most seizure medications exacerbate this
condition. Treatment can be problematic: Barbiturates and Primidone must be avoided as
they commonly precipitate symptoms.[8] Some benzodiazepines are safe, and, when used
in conjunction with newer anti-seizure medications such as gabapentin, offer a possible
regimen for seizure control.
Urine from a person experiencing an acute attack may be red or "port wine" in color
because of the presence of porphyrins. In addition, urine of AIP sufferers may turn purple
when exposed to ultraviolet light for a period of time.

Famous sufferers
One of the many hypothesized diagnoses of the artist Vincent van Gogh is that he and his
siblings, in particular his brother Theo, suffered from AIP and syphilis.[9] Another
theorized sufferer was King George III of the United Kingdom [10] who even had a
medallion struck to commemorate his "curing". His great-great-great-great-grandson
Prince William of Gloucester was reliably diagnosed with variegate porphyria in 1968.[11]
Anastasia Romanovna is claimed to have had porphyria.[citation needed]

Cultural references
AIP makes an appearance on the television show House in the Season 1, finale (Episode
22), wherein House diagnoses his ex-girlfriend's husband with the disease. [12] Acute
intermittent porphyria is also mentioned briefly in Season 4, Episode 4, "Guardian
Angels." Porphyria is again briefly mentioned as the possible cause of "relapsing and
remitting" symptoms (suggesting acute intermittent porphyria) in a patient in Season 4,
Episode 6, "Whatever it Takes." Other types of porphyria also appeared on House. In
season 3 episode 9, "Finding Judas", a little girl was diagnosed with Erythropoietic
protoporphyria. In season 5 episode 10, "Let Them Eat Cake", House diagnoses another
patient as having Hereditary coproporphyria. In season 7 episode 10, "Carrot or Stick",

House diagnoses a father and a son with Variegate porphyria. In season 1 episode 6, "The
Socratic Method," porphyria is mentioned as a differential diagnosis for psychiatric
symptoms thought to be schizophrenia.
AIP has also made two appearances on the television show Scrubs: in the thirteenth
episode of season 4, "My Ocardial Infarction," [13] and in the ninth episode of season 7,
"My Dumb Luck." [14]
It later appeared in Castle: Vampire Weekend (Season 2, Episode 6), and in Grey's
Anatomy: The Time Warp (Season 6, Episode 15).
Also in CSI: Crime Scene Investigators: Justice is Served (Season 1, Episode 21) aired 26
April 2001.
Series 4, episode 2 of Doc Martin also features a patient with porphyria. Also seen in
House, "Honeymoon" episode.

References
1.

2.
3.
4.

5.

6.

7.

^ Whatley SD, Roberts AG, Llewellyn DH, Bennett CP, Garrett C, Elder
GH (2000). "Non-erythroid form of acute intermittent porphyria caused by
promoter and frameshift mutations distant from the coding sequence of exon 1 of
the HMBS gene". Hum. Genet. 107 (3): 2438. doi:10.1007/s004390000356.
PMID 11071386.
^ James, William D.; Berger, Ass; et al. (2006). Andrews' Diseases of the
Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0.
^ Medscape > Diseases of Tetrapyrrole Metabolism - Refsum Disease and
the Hepatic Porphyrias Author: Norman C Reynolds. Chief Editor: Stephen A
Berman. Updated: Mar 23, 2009
^ Lannfelt, L.; Wetterberg, L.; Gellerfors, P.; Lilius, L.; Floderus, Y.;
Thunell, S. (1989). "Mutations in acute intermittent porphyria detected by ELISA
measurement of porphobilinogen deaminase". Journal of clinical chemistry and
clinical biochemistry. Zeitschrift fur klinische Chemie und klinische Biochemie 27
(11): 857862. PMID 2607315. edit
^ Aarsand, AK; Petersen PH, Sandberg S (April 2006). "Estimation and
application of biological variation of urinary delta-aminolevulinic acid and
porphobilinogen in healthy individuals and in patients with acute intermittent
porphyria". Clinical Chemistry 52 (4): 650656.
doi:10.1373/clinchem.2005.060772. PMID 16595824.
^ Anderson KE, Sassa S, Bishop DF, Desnick RJ. Disorders of heme
biosynthesis: X-linked sideroblastic anemias and the porphyrias. In: The
Metabolic and Molecular Basis of Inherited Disease, 8th ed, Scriver CR, Beaudet
AL, Sly WS, et al. (Eds), McGraw-Hill, New York 2001. p.2991.
^ *American Porphyria Foundation. "About Porphyria: Acute Intermittent
Porhyria", 2007,

8.

^ Marcucci, Lisa (2004). PathCards. Baltimore, MD: Lippincott Willians

& Wilkins. pp. 105106. ISBN 978-0-7817-4399-0.
9.
^ Arnold, Wilfred N. Vincent van Gogh: Chemicals, Crises, and
Creativity, Birkhuser, Boston, 1992. ISBN 0-8176-3616-1.
10.
^ Macalpine, Ida and Hunter,Richard 'The Insanity of King George III: A
Classic Case of Porphyria', British Medical Journal (1966)
11.
^ Rohl, John C.G. et al, Purple Secret, London: Bantam Press (1998)
12.
^ "Honeymoon". House. Season 1. Episode 22. 2005-05-24.
13.
^
http://en.wikipedia.org/wiki/List_of_Scrubs_episodes#Season_4_.282004.E2.80.9
32005.29
14.
^ http://www.tv.com/scrubs/my-dumbluck/episode/1179430/summary.html?tag=ep_list;title;9