Acute intermittent porphyria: Difference between revisions
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In the setting of neurospychiatric manifestation and seizures, other differential which should be ruled out is Guillian-Barre syndrome, Herpes simplex virus encephalitis, lead poisoning, alcohol abuse, neurodegenerative diseases, paraneoplasituc syndromes, hyponatremia, infectious causes, drug abuse, and psychiatric illness. | In the setting of neurospychiatric manifestation and seizures, other differential which should be ruled out is Guillian-Barre syndrome, Herpes simplex virus encephalitis, lead poisoning, alcohol abuse, neurodegenerative diseases, paraneoplasituc syndromes, hyponatremia, infectious causes, drug abuse, and psychiatric illness. | ||
Elevated levels of urinary prophobilinogen points towards diagnosis of AIP and further testing in this diagnosis should be pursued. If urinary prophobilinogen is normal and index of suspicion is high; then plasma poprhyrins level should be checked. If plasma poprhyrins comes out to be normal. AIP should be ruled out. | Elevated levels of urinary prophobilinogen points towards diagnosis of AIP and further testing in this diagnosis should be pursued. If urinary prophobilinogen is normal and index of suspicion is high; then plasma poprhyrins level should be checked. If plasma poprhyrins comes out to be normal. AIP should be ruled out.<ref name="pmid15767622">{{cite journal| author=Anderson KE, Bloomer JR, Bonkovsky HL, Kushner JP, Pierach CA, Pimstone NR et al.| title=Recommendations for the diagnosis and treatment of the acute porphyrias. | journal=Ann Intern Med | year= 2005 | volume= 142 | issue= 6 | pages= 439-50 | pmid=15767622 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15767622 }} </ref> | ||
==Epidemiology and Demographics== | ==Epidemiology and Demographics== | ||
Revision as of 22:10, 7 February 2019
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords:
Overview
Acute intermittent porphyria (AIP) is a rare metabolic disorder in the production of heme, the oxygen-binding prosthetic group of hemoglobin. Specifically, it is characterized by a deficiency of the enzyme porphobilinogen deaminase (PBGD) or hydroxymethylbilane synthase (HMBS)
Historical Perspective
One of the many hypothesized diagnoses of the artist Vincent van Gogh is that he and his siblings, particularly his brother Theo, suffered from AIP.[1] Another theorized sufferer was King George III of England, who even had a medallion struck to commemorate his "curing".
AIP makes an appearance on the television show House MD in season 1, episode 22 where Dr. House diagnoses his ex-wife's new husband with the disease.
It also makes an appearance on the television show Scrubs in season 4, episode 13 as a difficult to diagnose disease.
The TLC documentary drama mini-series, Mystery ER, features a landscaper with AIP who is repeatedly misdiagnosed.
Classification
AIP itself is a sub-category of diseases of broad group of disease describes as Porphyria.
Pathophysiology
AIP is an autosomal dominant disease with variable penetrance and expression. It is caused by variable mutation in gene encoding PBGD; it was earlier known as uroporphyrinogen I synthase. PBGD is present in hepatocytes as well Red Blood Cell.(RBC). It works in cytosol and converts porphobilinogen to porphobilingen deaminase. The PBGD is expressed in two forms depending on weather it is being expressed in hepatocytes or RBC. The manifestation of AIP typically occurs when production of PBGD is diminished or there is lack of expression gene encoding PBGD in hepatocytes.[2] PBGD enzyme deficiency alone is rarely symptomatic. The disease precipitates in the setting of another co-existing mutation as decrease in production of delta-aminolevulinic acid synthase (ALAS1) or in the presence of other precipitating factor as mentioned below.
Causes
Genetic Causes: The most commonly seen precipitating factor is co-existence of deficiency of ALAS1 because of mutation in gene encoding ALAS1.
Drug Causes: The drugs which can precipitate AIP consist of following categories as described in the table.
| Anti-Hypertension Medications | Antimicrobials | Anti-epileptics | Anesthetics | Miscellaneous |
|---|---|---|---|---|
| Nifedipine | Nitrofurantoin | Phenytoin | Etomidate | Alcohol |
| Hydralazine | Rifampin | Phenobarbital | Ketamine | Diclofenac |
| Spiranolactone | Pyrazinamide | Carbamazepine | Thiopental | NSAIDs |
| Sulfa drugs | Oxycarbamazepine | Estrogen | ||
| Trimethoprim-Sulfamethoxazole | Barbiturates | Progesterone | ||
| Griesofulvin | Clonazepam | Hydroxyzine | ||
| Ethosuximide | Tamoxifen | |||
| Valproate | Ergot derivatives | |||
| Smoking | ||||
| Carisoprodol | ||||
| Danazol | ||||
| Mebrobamate |
Contraindicated Medications:
The following medication are contraindicated with patients who have had a prior episode of AIP.
Barbiturates, Carbamazepine, Carisoprodol, Danazol, Diclofenac, Estrogen, Griesofulvin, Mebrobamate, Phenytoin, Phenobarbital, Primidone, Progeterone, Pyrazinamide, Rifampin, Sulfonamide, Valproate.
Differentiating Acute intermittent porphyria from other Diseases
The classical presentation of AIP is abdomen pain associated with other gastrointenstinal symptoms of nausea, vomiting, constipation and rarely diarrhea.
Other associated symptoms are neuropsychiatric manifestation of seizure, sensory loss, agitation, anxiety, hallucination, insomnia along with cardiac mainfestation of hypertension tachycardia. Other findings in some cases are respiratory paralysis, fever, generalized myalgia. Diagnosis of AIP is rare and should be pursued in the setting of high suspicion. When suspicion is high, urine porphyrins should be the first test of choice to be done.
In the setting of elevated urine porphyrins and abdomen pain, other possibility could be lead poisoning or hereditary tyrosinemia type 1 is possible.
In the setting of neurospychiatric manifestation and seizures, other differential which should be ruled out is Guillian-Barre syndrome, Herpes simplex virus encephalitis, lead poisoning, alcohol abuse, neurodegenerative diseases, paraneoplasituc syndromes, hyponatremia, infectious causes, drug abuse, and psychiatric illness.
Elevated levels of urinary prophobilinogen points towards diagnosis of AIP and further testing in this diagnosis should be pursued. If urinary prophobilinogen is normal and index of suspicion is high; then plasma poprhyrins level should be checked. If plasma poprhyrins comes out to be normal. AIP should be ruled out.[3]
Epidemiology and Demographics
Age: AIP manifests in the age group of 30-50 years but isolated case report have been reported prior to puberty and in the elderly as well.
Gender: The mutation is equally present in male and females. But, disease manifests more in the females in view of estrogen and progesterone being a natural risk factor for AIP.
Race: AIP is seen in all the races. Yet, more commonly in people of Northern European descent.
Risk Factors
The presence of mutation of gene PBGD in association with exposure to the medication mentioned above and co-existence of mutation or deficiency in ALAS1 is known to precipitate AIP.
Starvation and decreased intake of carbohydrate rich food can also exacerbate or precipitate AIP frequently.
Natural History, Complications and Prognosis
Normally, heme synthesis begins in the mitochondrion, proceeds into the cytoplasm, and finishes back in the mitochondrion. However, without PBGD, a necessary cytoplasmic enzyme, heme synthesis cannot finish, and the metabolite porphyrin accumulates in the cytoplasm.
Diagnosis
Diagnostic Criteria
Additional factors must also be present such as hormones, drugs and dietary changes that trigger the appearance of symptoms.
Symptoms
Symptoms of AIP may include abdominal pain, constipation, and muscle weakness.
Patients who 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 long-acting 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.
Physical Examination
Urine from a person experiencing an acute attack will be red or "port wine" in color because of the presence of porphyrins. This condition is known as Porphyrinuria or Pyroluria.
Laboratory Findings
Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
A high-carbohydrate diet is typically recommended; in severe attacks, a glucose 10% 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/showers may lessen nausea temporarily, but can present a risk of burns or falls.
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 amongst 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 theoretically 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 they cannot explain to healthcare professionals about their condition and the fact that some drugs are absolutely contraindicated. An attack of acute intermittant porphyria may be precipitated by one of the "four M's": medication, menstruation, malnutrition, maladies.
Contraindicated medications
History of acute intermittent porphyria is considered an absolute contraindication to the use of the following medications:
Seizures often accompany this disease. Most seizure medications exacerbate this condition. Treatment can be problematic: barbiturates must be avoided. Some benzodiazepines are safe, and, when used in conjunction with newer anti-seizure medications such as gabapentin offer a possible regime for seizure control.
Surgery
Prevention
See also
Template:Endocrine, nutritional and metabolic pathology
References
- ↑ Arnold, Wilfred N. Vincent van Gogh: Chemicals, Crises, and Creativity, Birkhãuser, Boston, 1992. ISBN 0-8176-3616-1.
- ↑ Grandchamp B, Picat C, Kauppinen R, Mignotte V, Peltonen L, Mustajoki P; et al. (1989). "Molecular analysis of acute intermittent porphyria in a Finnish family with normal erythrocyte porphobilinogen deaminase". Eur J Clin Invest. 19 (5): 415–8. PMID 2511016.
- ↑ Anderson KE, Bloomer JR, Bonkovsky HL, Kushner JP, Pierach CA, Pimstone NR; et al. (2005). "Recommendations for the diagnosis and treatment of the acute porphyrias". Ann Intern Med. 142 (6): 439–50. PMID 15767622.
de:Akute intermittierende Porphyrie