Porphyria

The porphyrias are inherited or acquired disorders of certain enzymes in the heme biosynthetic pathway (also called porphyrin pathway). They are broadly classified as hepatic porphyrias or erythropoietic porphyrias, based on the site of the overproduction and mainly accumulation of the porphyrins (or their chemical precursors).

Overview

In humans, porphyrins are the main precursors of heme, an essential constituent of hemoglobin, myoglobin, catalase, peroxidase, respiratory and P450 liver cytochromes.

Deficiency in the enzymes of the porphyrin pathway leads to insufficient production of heme. Heme metabolism plays a central role in cellular metabolism. This is, however, not the main problem; most enzymesâ€"even when less functionalâ€"have enough residual activity to assist in heme biosynthesis. Dysregulation of the neuroendocrine and cardiovascular systems can occur in attacks. An additional problem in these deficiencies is the accumulation of porphyrins, the heme precursors, which are toxic to tissue in high concentrations. The chemical properties of these intermediates determine in which tissue they accumulate, whether they are photosensitive, and how the compound is excreted (in the urine or feces).

Subtypes

There are eight enzymes in the heme biosynthetic pathway: the first and the last three are in the mitochondria, while the other four are in the cytosol. Defects in any of these can lead to some form of porphyria.

# δ-aminolevulinate (ALA) synthase# δ-aminolevulinate (ALA) dehydratase# hydroxymethylbilane (HMB) synthase (also called PBG deaminase)# uroporphyrinogen (URO) synthase# uroporphyrinogen (URO) decarboxylase# coproporphyrinogen (COPRO) oxidase# protoporphyrinogen (PROTO) oxidase# ferrochelatase

Hepatic porphyrias

Heme synthesis - note that some reactions occur in the cytoplasm and some in the mitochondrion (yellow)

The hepatic porphyrias include:
* Doss porphyria: ALA dehydratase deficiency
* acute intermittent porphyria (AIP): a deficiency in HMB synthase
* hereditary coproporphyria (HCP): a deficiency in COPRO oxidase
* variegate porphyria (VP): a deficiency in PROTO oxidase
* porphyria cutanea tarda (PCT): a deficiency in URO decarboxylase

Erythropoietic porphyria

The erythropoietic porphyrias include:
* X-linked sideroblastic anemia (XLSA): a deficiency in ALA synthase
* congenital erythropoietic porphyria (CEP): a deficiency in URO synthase
* erythropoietic protoporphyria (EPP): a deficiency in ferrochelatase

Porphyria variegata

Variegate porphyria (also porphyria variegata or mixed porphyria) results from a partial deficiency in PROTO oxidase, manifesting itself with skin lesions similar to those of porphyria cutanea tarda combined with acute neurologic attacks. It may first occur in the second decade of life; there is a cohort of sufferers living in South Africa descended from a single person from the Netherlands, Berrit Janisz, who emigrated in the 17th century.

Signs and symptoms

The hepatic porphyrias primarily affect the nervous system, resulting in abdominal pain, vomiting, acute neuropathy, seizures, and mental disturbances, including hallucinations, depression, anxiety, and paranoia. Cardiac arrhythmias and tachycardia (fast heart rate) may develop as the autonomic nervous system is affected. Pain can be severe and can, in some cases, be both acute and chronic in nature. Constipation is frequently present, as the nervous system of the gut is affected, but diarrhea can also occur.

Motor neuropathy including Guillain-Barre syndrome should always be investigated for porphyrias. Porphyrias have presented as motor-sensory neuropathy or bouts of severe muscle pain and weakness without abdominal symptoms. All acute hepatic porphyrias should be investigated. This requires urine, fecal/bile, blood, enzyme or DNA testing for porphyrias.

Since almost all antiseizure drugs are porphyrinogenic and can cause further nervous system damage all drug-resistant or drug refractory seizure disorders should be investigated for porphyrias. This includes children. Lennox-Gastaut syndrome and myoclonic seizures in children have been linked to porphyrias for at least thirty years. Children require enzyme or DNA testing.

All drug-induced liver disease and heart damage including valve disease such as mitral or aortic valve prolapse should be investigated for porphyrias.

Drug-induced renal disease and early onset renal failure should be investigated for porphyrias. Malignant hypertension should be investigated for porphyrias. This also includes drug damage from illicit drugs such as cocaine and amphetamines.

Pancreatitis and rhabdomyolysis have been associated with porphyrias. All drug, alcohol and hormone induced pancreatitis should be investigated for porphyrias. Care must be taken when administering statin drugs since porphyrias can result in hypercholesterolemia and have been associated with rhabdomyolysis. Eosinophilic fasciitis has been recorded with porphyria.

The erythropoietic porphyrias primarily affect the skin, causing photosensitivity (photodermatitis), blisters, necrosis of the skin and gums, itching, and swelling, and increased hair growth on areas such as the forehead.

Drug-induced photosensitivity and drug-induced lupus should warrant an investigation for a porphyria. Severe drug-induced conditions such as the potentially deadly Stevens Johnson syndrome should be investigated for porphyrias.

Neuroendocrine disruption can occur in porphyrias including polycystic ovary syndrome, thyroid disease and sexual dysfunction. Hypogonadal hypogonadism and male pseudohermaphrodism have been reported in children and infants with porphyrias.

In some forms of porphyria, accumulated heme precursors excreted in the urine may change its color, after exposure to sunlight, to a dark reddish or dark brown color. Even a purple hue or pink urine may be seen.

Heme precursors may also accumulate in the teeth and fingernails, giving them a reddish appearance. Drug-induced photoonycholysis should be investigated for porphyrias.

Bone hypomineralization, dental enamel defects and missing adult teeth have been detected in porphyrias possibly linked to gut malabsorption syndromes including celiac disease that can occur with porphyria.

Attacks of the disease can be triggered by drugs (e.g., barbiturates, alcohol, sulfa drugs, oral contraceptives, sedatives, and certain antibiotics), other chemicals, certain foods, and exposure to the sun.

Fasting can also trigger attacks. The Scarsdale and Atkins diets have precipitated porphyria attacks in undiagnosed patients with porphyrias.

Recent research is also showing enzyme deficiencies in coproporphyrinogen oxidase, the enzyme responsible for hereditary coproporphyria, can result in a predisposition to heavy metal damage, specifically mercury toxicity.

Researchers around the world are investigating a direct link between the DNA site of variegate porphyria on chromosome 1 with autism spectrum disorders and the locus for several heme related disorders including chromosome 3 for hereditary coproporphyria, chromosome 11 for acute intermittent porphyria, chromosome 18 for erythropoietic protoporphyria and chromosome 15 for tyrosinemia type 1, a genetic disorder that impacts the second enzyme in the heme pathway, with various forms of mental illness including autism, autistic spectrum disorders, schizophrenia, catatonia and manic depression.

Catatonia has been reported in porphyrias. The potentially deadly drug-induced disorder known as neuroleptic malignant syndrome is a variation of catatonia.

The links between porphyrias and mental illness have been noted for decades. In the early 1950's patients with porphyrias and severe symptoms of depression or catatonia were treated with electroshock. Mental illness and drug reactions to psychotropic drugs always warrant an investigation for a porphyria.

It must be kept in mind porphyrias have been linked to several diseases including autoimmune diseases, a predisposition to type 2 diabetes and cancers.

For fifty years the damage from dominantly inherited porphyrias (PCT, AIP, HCP, VP, EPP) has been noted to trigger transient or sustained autoantibodies evolving to conditions such as lupus erythematosus, rheumatoid arthritis, scleroderma or Sjogren's disease.

Acute attacks of porphyrias in patients with autoimmune diseases such as lupus have been initially labeled as "lupus complications" delaying diagnosis of the underlying porphyria and treatment resulting in deaths. "Neurolupus," pancreatitis, pericarditis and acute abdomen in lupus patients may indicate a porphyria. Physicians should be on high alert for porphyrias in patients with autoimmune diseases.

Porphyrias have been detected in celiac disease (gluten intolerance) and the associated skin disorder dermatitis herpetiformis. Porphyrias have also been detected in Crohn's disease and ulcerative colitis. Care must be taken when administering porphyrinogenic drugs in patients with these conditions. Drug reactions should be investigated for porphyrias.

Also drug reactions in cancer treatment may be due to underlying porphyrias. It has been noted cells with heme defects, in particular porphyrias, are at increased risk from developing cancers. Free radical damage can occur in porphyrias and porphyrias are linked to low melatonin levels, a risk for cancer.

Keep in mind the heme system is also impacted by iron deficiency and iron disorders including hemochromatosis or secondary genetic disorders relying on heme metabolism including hemoglobinopathies such as sickle cell and thalassemia. Porphyrias have been inherited along with hemochromatosis, sickle cell trait and thalassemia minor resulting in mixed genetic disorders with disease.

Cancers linked to porphyrias have included primary liver cancer, bile duct cancer, pancreatic cancer, stomach cancer, intestinal cancer, astrocytoma, glioblastoma multiforme, leukemia, lymphoma and possibly an increased risk of lung cancer and chronic obstructive pulmonary disease.

Ironically, but also logically, since glucose is part of the treatment for porphyria the increased blood glucose levels occurring with type 2 diabetes have shut down severe cyclical attacks in patients with acute intermittent porphyria. There is also evidence porphyrics that progress to type 2 diabetes are at decreased risk for developing primary liver cancer.

Diagnosis

Porphyria is diagnosed through tests on blood, urine, and stool. In general, urine estimation of porphobilinogen (PBG) is the first step if acute porphyria is suspected. As a result of feedback, the decreased production of heme leads to increased production of precursors, PBG being one of the first substances in the porphyrin synthesis pathway. In nearly all cases of acute porphyria syndromes, urinary PBG is markedly elevated except for the very rare ALA dehydratase deficiency or in patients with symptoms due to lead poisoning or hereditary tyrosinemia type I.

However, since the water solubility of porphyrin precursors decreases with enzyme deficiencies in the latter part of the heme pathway, stool and blood porphyrin testing should be performed in all suspected cases of porphyrias to detect hereditary coproporphyria and variegate porphyria.

Repeat testing during an attack and subsequent attacks may be necessary in order to detect a porphyria. The urine screening test has been known to fail in the initial stages of a severe life threatening attack of acute intermittent porphyria.

The bulk (up to 90%)of the genetic carriers of the more common, dominantly inherited acute hepatic porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria) have been noted in DNA tests to be latent for classic symptoms and typically require DNA or enzyme testing. The exception to this may be latent postpuberty genetic carriers of hereditary coproporphyria.

Bile testing is more sensitive than stool testing in variegate porphyria.

The red blood cell enzyme assay used to detect acute intermittent porphyria will fail to detect 15% of those with AIP who have the genetic variant with normal red cell enzyme levels. They require other testing including DNA testing.

Postpuberty active and latent genetic carriers of hereditary coproporphyria have been noted to have abnormal levels of porphyrins in the stool. However, prepuberty children with hereditary coproporphyria require enzyme or DNA testing.

Prepuberty children with porphyrias require enzyme assays or DNA testing since children do not typically excrete porphyrins unless they are severely affected as with homozygous or compound heterozygous porphyrias (inheritance of a dominant porphyria from both parents.)

More extensive testing is done with spectroscopy (porphyrins have a characteristic absorption spectrum) and other chemical analyses.

As most porphyrias are believed to be rare conditions hospital labs have not devoted the time, technology or space to development of testing, so testing typically involves sending samples of blood, stool and urine to a reference laboratory.

All samples to detect porphyrins must be handled properly. Urine samples should be taken during an acute attack, otherwise a false negative result may occur. Urine must be protected from light and either refrigerated or preserved.

Blood must also be protected from light and stool must be refrigerated and protected from light.

Further diagnostic tests of affected organs may be required, such as nerve conduction studies for neuropathy or an ultrasound of the liver.

Liver enzyme tests may or may not be elevated in patients with symptoms of hepatic porphyrias.

Patients with hepatic porphyrias (PCT, AIP, HCP, VP) are at increased risk over their life for hepatocellular carcinoma (primary liver cancer) and require monitoring. This also includes latent genetic carriers of AIP, HCP or VP, although the cancer may occur later in life.

Typical risk factors for liver cancer need not be present in acute hepatic porphyrias (AIP, HCP, VP) to develop this cancer such as hepatitis B or C, iron overload, hormonal exposures, chemical exposures or alcoholic cirrhosis.

More recent research is linking smoking to an increased risk for primary liver cancer. Smoke, charcoal broiled foods and even activated charcoal are porphyrinogenic agents.

About 5% of patients with erythropoietic protoporphyria are at increased risk for acute liver failure because of homozygous or compound heterozygous inheritance of the condition.

Recently, new international studies using enzyme and DNA technology to detect latent porphyrias are disputing the rarity of all forms of porphyria.

Enzyme and DNA technology for porphyrias are restricted to a few laboratories and medical facilities in the United States.

Often, empirical treatment is required if the diagnostic suspicion of a porphyria is high since acute attacks can be fatal.

Treatment

Acute porphyria

A high-carbohydrate diet is typically recommended; in severe attacks, a glucose 10% infusion is commenced, which may aid in recovery.

However, any sign of low blood sodium (hyponatremia) or weakness should be treated with the addition of hematin or heme arginate as these are signs of impending syndrome of inappropriate antidiuretic hormone (SIADH) or peripheral nervous system involvement that may be localized or severe progressing to bulbar paresis and respiratory paralysis.

If drugs or hormones 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, frequently out of proportion to physical signs 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, though caution should be used to avoid burns or falls.

Hematin and haem 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 and even genetic carriers are recommended to wear an alert bracelet or other identification at all times in case they develop severe symptoms or in case of accidents where there is a potential for drug exposure: a result of which may be they cannot explain to healthcare professionals about their condition and the fact that some drugs are absolutely contraindicated.

Patients who experience frequent attacks can develop chronic neuropathic pain in extremities as well as chronic pain in the gut. Gut dysmotility, ileus, intussusception, aganglionosis, encopresis in children and intestinal pseudo-obstruction have been associated with porphyrias. This is thought to be due to axonal nerve deterioration in affected areas of the nervous system and vagal nerve dysfunction.

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. Opioid dependence may develop.

Depression often accompanies the disease and is best dealt with by treating the offending symptoms and if needed the judicious use of anti-depressants. Keep in mind psychotropic drugs may be porphyrinogenic.

Exercise is useful during recovery after acute attacks, although intense exercise may trigger attacks. Recent evidence has shown long airline flights have also triggered attacks of acute intermittent porphyria, although the cause is unknown.

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. Care must be used with administration of benzodiazepines that have triggered paradoxical reactions in porphyrias.

Magnesium sulfate and bromides have also been used in porphyria seizures, however, development of status epilepticus in porphyria may not respond to magnesium alone. The addition of hematin or heme arginate has been used during status epilepticus

Recent evidence has also shown arterial vasospasms occurring in cerebral, mesenteric and renal arteries resulting in ischemia, and in worse case scenarios, infarction of the brain, gut or a kidney.

There is evidence of disruption of the blood/brain barrier in acute hepatic porphyria attacks. Porphyrias have been detected in Parkinson's disease and porphyrias may be present in cases of multiple sclerosis. Drug induced tics, parkinsonism and tardive dyskinesia warrant an investigation for porphyria.

Patients with porphyrias should also be investigated for both iron deficiency and iron overload in case of concomitant inheritance of iron disorders. Iron deficiency should be corrected as it will aggravate acute hepatic porphyrias.

The ferritin test is the only reliable test to determine body iron stores. False positive testing with high levels of serum iron have occurred in patients with low body iron stores.

Patients with porphyrias may also have anemia of chronic disease with inappropriate low levels of erythropoietin. Erythropoietin treatment may be necessary to combat ACD, however, adequate iron levels must be present for this treatment to be effective.

Hormonal fluctuations that contribute to cyclical attacks in women have been treated with oral contraceptives and luteinizing hormones to shut down menstrual cycles. However, oral contraceptives have also triggered photosensitivity and withdrawal of oral contraceptives has triggered attacks. Androgens and fertility hormones have also triggered attacks.

Pregnancy complications including hyperemesis gravidarum, hydatid mole, eclampsia and postpartum attacks with seizures have occurred with porphyrias. Surgery for endometriosis has triggered an attack.

Unexplained cyclical abdominal/pelvic pain associated with menstrual cycles should warrant an investigation for porphyria. A total hysterectomy may mask evidence of a porphyria in a woman by shutting down hormonal cycles that contribute to attacks.

Culture and history

Vampires and werewolves

Porphyria has been suggested as an explanation for the origin of vampire and werewolf legends, based upon a number of similarities between the condition and the folklore that was first speculated upon by biochemist David Dolphin in 1985. His ruminations gave rise to a popular urban legend which accepts this association as factual, though it is historically and factually baseless. ([1]) Porphyria cutanea tarda presents clinically as a pathological sensitivity of skin exposed to light causing scarring, hair growth and disfiguration. Additionally, it was believed that the patients' missing heme could be absorbed through the stomach, correlating with the legends' hematophagy.

Porphyrias have been detected in all races, multiple ethnic groups on every continent including Caucasians, Asians, Blacks, Peruvian/Mexican Hispanics, Native Americans, Laplanders and Australian aborigines. There are high incidence reports of AIP in areas of India and Scandinavia and over 200 genetic variants of AIP, some of which are specific to families, although some strains have proven to be repeated mutations.

The Scandinavian source of porphyria has been traced to Laplanders. The languages of Finland and Laps, Estonia, Hungary and Transylvania, Romania have ties to languages in small groups of Russians on both sides of the Urals and are branches of Uralic languages and Altaic languages. They have been referred to as "The Outsiders" and have Asian origins.

There are multiple genetic variants of all porphyrias. More advanced technology has revealed patients inheriting two different types of porphyria known as dual porphyrias and evidence of genetic errors in closely linked biochemical pathways such as hemoglobinopathies (sickle cell trait or thalassemia minor) or glucose 6 phosphate dehydrogenase deficiency combining with porphyrias creating mixed genetic disorders.

The potential for gene combinations and for porphyrias modifying other genetic disorders coupled with environmental stressors is staggering.

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"Ida Macalpine & Richard Hunger, "The Insanity of King George III: A Classic Case of Porphyria", British Medical Journal, 1966, pp. 65-71., with a follow-up in 1968, "Porphyria in the Royal Houses of Stuart, Hanover and Prussia"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.. 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 SecretRöhl, John C.G., Warren Martin,& David Hunt, Purple Secret, Bantam Press, London, 1998 ISBN 0593041488, which documents the ultimately unsuccessful search for genetic evidence of porphyria in the remains of royals suspected to suffer from it.The authors demonstrated a single point mutation in the PPOX gene, but not one which has been associated with disease. Despite the lack of 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.

Other commentators have suggested that Vincent van Gogh may have suffered from acute intermittent porphyria (Loftus & Arnold 1991). Erik Vachon, the little-known builder whose character was combined with that of Svengali to create The Phantom of the Opera may have suffered from erythropoietic porphyria.

It has also been imagined that King Nebuchadnezzar of Babylon suffered from some form of porphyria (cf. Daniel 4, see Beveridge 2003). The symptoms of the various porphyrias are so wide-ranging that nearly any constellation of symptoms can be attributed to one or more of them.

References

* Adams C. Did vampires suffer from the disease porphyria--or not? The Straight Dope 7 May 1999 Article
* Anderson KE, Bloomer JR, Bonkovsky HL, Kushner JP, Pierach CA, Pimstone NR, Desnick RJ. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med 2005;142:439-50. PMID 15767622.
* Beveridge A. The madness of politics. J R Soc Med 2003;96:602-4. PMID 14645615.
* Kauppinen R. Porphyrias. Lancet 2005;365:241-52. PMID 15652607.
* Lane, N. Born to the purple: the story of porphyria Scientific American Fulltext.
* Loftus LS, Arnold WN. Vincent van Gogh's illness: acute intermittent porphyria? BMJ 1991;303:1589-91. PMID 1773180.
* Thadani H, Deacon A, Peters T. Diagnosis and management of porphyria. BMJ 2000;320:1647-51. Fulltext. PMID 10856069.

External links

* American Porphyria Foundation
* European Porphyria Initiative
* Porphynet - informative site on porphyrins and the porphyrias
* The Drug Database for Acute Porphyria - comprehensive database on drug porphyrinogenicity