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).
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 enzymes—even when less functional—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).
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.
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.
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.
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.
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.
Recent research is also showing enzyme deficiencies in coproporphyrinogen oxidase can result in a predisposition to heavy metal damage, specifically mercury toxicity.
It must be kept in mind porphyrias have been linked to several diseases including autoimmune diseases, mental illness, a predisposition to type 2 diabetes and cancers. The damage from dominantly inherited porphyrias (PCT, AIP, HCP, VP, EPP) have been known to trigger transient or sustained autoantibodies evolving to conditions such as lupus erythematosus, rheumatoid arthritis, scleroderma or Sjogren's disease.
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.
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.
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. Drug reactions to psychotropic drugs always warrant an investigation for a porphyria.
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 the conditions are linked to low melatonin levels also linked to a risk of cancer.
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, the increased blood glucose levels occurring with type 2 diabetes have shut down severe cyclical attacks in patients with acute intermittent porphyria, and there is evidence porphyrics that progress to type 2 diabetes are at decreased risk for developing primary liver cancer.
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 building blocks 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. The bulk (up to 90%)of the genetic carriers of acute hepatic porphyrias (AIP,VP,HCP) have been noted in DNA tests to be latent for classic symptoms and typically require DNA or enzyme testing.
Bile testing is more sensitive than stool testing in variegate porphyria. Prepuberty children with porphyrias should have enzyme assays or DNA testing since children do not typically produce porphyrins unless they are severely affected as with homozygous or compound heterozygous porphyrias (inheritance of a dominant porphyria from both parents.) Postpuberty active and latent genetic carriers of hereditary coproporphyria have been noted to have abnormal levels of porphyrins in the stool, however, prepuberty children require enzyme or DNA testing.
More extensive testing is done with spectroscopy (porphyrins have a characteristic absorption spectrum) and other chemical analyses. As most porphyria 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.
However, new international studies using enzyme and DNA technology are disputing the rarity of all forms of porphyria. Often, empirical treatment is required if the diagnostic suspicion is high since acute attacks can be fatal.
Further diagnostic tests of affected organs may be required, such as nerve conduction studies for neuropathy or an ultrasound of the liver.
Patients with hepatic porphyrias are at increased risk over time for hepatocellular carcinoma (primary liver cancer) and require monitoring. Also 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. Liver enzyme tests may or may not be elevated in patients with symptoms of hepatic porphyrias.
All samples 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.
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. Blood must also be protected from light and stool must be refrigerated and protected from light.
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 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.
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 also evidence of disruption of the blood/brain barrier.
Porphyrias are also associated with drug and hormone-induced pancreatitis. Pancreatitis should warrant an investigation of a porphyria and should also prompt a physician to investigate whether the condition was triggered by a drug or hormone. 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. Opiod 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.
Porphyrias have also been associated with rhabdomyolysis and lactic acidosis, both of which have been associated with drug exposures including statin (cholesterol-lowering) drugs. Since porphyrics can also have hypercholesterolemia muscle pain with statin drugs should warrant an investigation of a porphyria.
Hereditary coproporphyria has been noted to be milder and present more frequently with muscle pain and weakness. 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 conjuction with newer anti-seizure medications such as gabapentin offer a possible regime for seizure control. Magnesium sulfate and bromides have also been used in porphyria seizures, however, development of status epilepticus may not respond to magnesium alone. Heme arginate or hematin should also be added in multiple seizures. Care must be used with administration of benzodiazepines that have triggered paradoxical reactions.
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. Porphyria cutanea tarda presents clinically as a pathological sensitivity of skin exposed to light causing scarring and disfiguration. In the video game series The Elder Scrolls, "Porphyric Hemophilia" is the disease that leads to the character's vampirism after a total of three days (72 hours), if it is not cured.
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.
Modern medicine has suggested that the insanity exhibited by |King George III was the result of porphyria. Research has shown that porphyria is another hereditary disease plaguing the British royal family (besides hemophilia), apparently from the line of the monarchs of Scotland. Research has shown that both James VI and Mary I of Scotland probably suffered from the disease. Queen Anne of Great Britain], Queen Victoria's granddaughter Charlotte (a sister of Wilhelm II), and Prince William of Gloucester were also sufferers.
New research indicates that Vincent van Gogh may have suffered from acute intermittent porphyria (Loftus & Arnold 1991). It has also been suggested that King Nebuchadnezzar of Babylon suffered from some form of Porphyria (cf. Daniel 4, see Beveridge 2003).