• There is not just one porphyria; there are at least six types (and a few very rare ones because of homozygosity and dual porphyrias).
• There is not one single test covering all porphyrias. For suspected acute porphyria, screening for excessive porphobilinogen in the urine is the test of choice.
• If cutaneous porphyria is in the differential diagnosis, quantitative measurements of porphyrins in urine and stool are recommended.
• Family studies and genetic counseling are always indicated in these hereditary diseases.
• Prophylaxis is mandatory and depends on the type of porphyria.
• Abstinence from alcohol is always indicated.
• The drug list should be respected in the acute porphyrias.
• Glucose therapy for the acute attack has been superseded by the more effective, definitive treatment with hematin (hemin, Panhematin), to be instituted as soon as possible once the diagnosis has been ascertained.
The porphyrias present a group of mostly inherited diseases where disturbances along the biosynthetic pathway to heme lead to accumulations of metabolic intermediaries. Porphyria cutanea tarda usually occurs without discernible inheritance; it can also be induced by chemicals. All steps of heme synthesis are enzymatically regulated and all porphyrias are a result of specific impasses along these transitions. Not all enzymatic defects result in clinically relevant or recognizable disease manifestations in every patient. On the one hand, the severity of the enzymatic defect plays a role. On the other, some poorly understood revealing or unveiling cofactors are operational; enzyme cofactors are likely contributing as well. The prevalence of the porphyrias is not known and fluctuates in different parts of the world; for example, variegate porphyria is most common in South Africa, whereas porphyria cutanea tarda is the most common porphyria in the United States.
The porphyrias can be divided between neurovisceral (acute) and cutaneous manifestations. Two types, the very rare delta- aminolevulinic acid-dehydratase deficiency porphyria and acute intermittent porphyria (AIP), have only neurologic symptoms (acute attacks and possibly chronic manifestations). Hereditary coproporphyria and variegate porphyria can have both neurologic and dermatologic signs and symptoms. Congenital erythropoietic porphyria, porphyria cutanea tarda, and erythropoietic protoporphyria exhibit only skin lesions but can be complicated by other problems, such as anemia or hepatic insufficiency.
Succinyl coenzyme-A and glycine are the initial building blocks, subsequently transformed through eight enzymatic steps to the end product, heme, in itself essential not only for hemoglobin but also for other hemoproteins such as cytochromes, myoglobin, and other enzymes including catalase, nitric oxide synthase, and tryptophan pyrrolase. Heme synthesis happens in all cells but mostly in the liver and in the bone marrow. It is controlled by heme through feedback inhibition of the first step, delta-aminolevulinic acid synthase. Figure 1 shows the various steps, intermediaries, and resulting porphyrias.
Porphyrins and their precursors, delta-aminolevulinic acid (ALA) and porphobilinogen (PBG), are only generated during heme synthesis and not during heme catabolism toward bilirubin.
FIGURE 1 Heme biosynthetic pathway. Enzymes that have defects or deficiencies that cause the various porphyries are listed on the left side, heme and precursors are in the middle, and the resulting porphyrias are on the right side. Abbreviation: CoA = coenzyme A.
Specific enzymatic defects result in specific patterns of heme precursors and are of high diagnostic value when determining the type of porphyria. The ultimate step in ruling in or out if a person has the genetic defect for a specific porphyria is DNA testing, currently offered by the Mount Sinai Genetic Testing Laboratory ([email protected]). However, these specific tests are not necessary in the clinical evaluation of a patient in whom porphyria is suspected. Here, quick and simple tests are sufficient. The excretory pattern of heme precursors is influenced by their water solubility, which decreases toward heme; ALA and PBG are highly water soluble and measured in urine, whereas protoporphyrin is so hydrophobic that it is only excreted in stool and not in urine.
There is no single test that can reveal all types of porphyrias. The porphyric symptomatology can differ from type to type and there is considerable overlap among the various porphyrias. For this reason, highly specific and sensitive laboratory tests are necessary. All porphyrias with acute manifestations manifest with similar attacks and respond to similar treatment, but they exhibit different biochemical patterns according to their specific enzyme defect. A clinically useful grouping splits the porphyrias between acute (neurovisceral) and cutaneous.
The Acute Porphyrias
There are four types of acute porphyria to consider:
• The very rare ALA-dehydratase deficiency porphyria is inherited in an autosomal recessive fashion.
• AIP, an autosomal dominant disorder, is the most common of the acute porphyrias (except in South Africa where variegate porphyria is more common).
• Hereditary coproporphyria, an autosomal dominant disease, is commonly misdiagnosed because coproporphyrin is often moderately and nonspecifically increased in many disorders.
• Variegate porphyria is autosomal dominant and probably the mildest of the acute porphyrias.
All acute porphyrias are sensitive to a multitude of drugs and circumstances (a short list is included in Box 1). Hereditary coproporphyria and variegate porphyria can also have skin lesions resembling porphyria cutanea tarda. Skin lesions and acute attacks can happen at the same time or one after the other, or only one manifestation may ever be present in a given patient.
|Short List of Safe and Unsafe Drugs in the Acute Porphyrias*|
• Acetaminophen (Tylenol)
• Cimetidine (Tagamet)
• Erythropoietin (Epogen, Procrit)
• Gabapentin (Neurontin)
• Narcotic analgesics
• Ranitidine (Zantac)
• Digoxin (Lanoxin)
• Labetalol (Trandate), propranolol (Inderal)
• Bupivacaine (Marcaine)
• Chloral hydrate
• Carbamazepine (Tegretol)
• Carisoprodol (Soma)
• Clonazepam (Klonopin)
• Danazol (Danocrine)
• Diclofenac (Voltaren)
• Estrogens, progesterones
• Ethchlorvynol (Placidyl)2
• Glutethimide (Doriden)
• Griseofulvin (Grifulvin)
• Mephenytoin (Mesantoin), phenytoin (Dilantin)
• Meprobamate (Equanil)
• Methyprylon (Noludar)2
• Metoclopramide (Reglan)
• Primidone (Mysoline)
• Rifampin (Rifadin)
• Valproic acid (Depakene)
2 Not available in the United States.
* Drugs not listed cannot be considered safe or unsafe.
Diagnosis of the porphyric attack hinges mainly on a keen sense of suspicion. Any inexplicable symptom complex involving abdominal pain, tachycardia, and psychological findings should be suspect for porphyria. However, no clinical presentation can be called porphyric without biochemical support. Small deviations from the narrow normal range for heme precursors are fairly common and nonspecific. PBG or ALA must be markedly elevated, at least fivefold above the normal range, and, if not, porphyria is an unlikely explanation for a patient’s acute symptoms.
Older screening mechanisms such as the Watson-Schwartz test and the Hoesch test have been replaced by easier, more specific, semiquantitative tests such as the Trace PBG kit (Thermo Fisher Scientific), but they still rely on the color reaction with Ehrlich’s aldehyde. This or a similar test must be available in all emergency departments and in all acute care hospitals. A random urine sample is sufficient for the initial diagnostic evaluation, and if it is positive it must be later followed up by more-detailed tests such as quantitative measurements of porphyrins and precursors in a 24-hour urine collection. Fecal porphyrin measurements may also be called for.
Enzyme measurements and genetic testing are rarely indicated, but they are used when more routine tests fail. Because the porphyrias are almost always hereditary, family studies are highly appropriate. The proper interpretation of any test result is best done in the context of available clinical information.
Clinical presentations of porphyric attacks vary so much that the term the little imitator has been used. Not all signs or symptoms are always present, but severe and poorly localized abdominal pain and unexplained tachycardia are so prevalent that their absence further complicates the diagnosis of an acute porphyric attack. The genesis of the attack is not well understood, but acutely increased demand for heme and production of toxic intermediary products are considered to be the culprit. Increased demand for heme and increased production of intermediary products can be due to a wide variety of circumstances, from drugs through hormones (premenstrual phase) to stress, infection, fasting, and starvation. However, most carriers of the genetic defect for an acute porphyria remain asymptomatic all their lives. Some have only one or two attacks, and only a few suffer from many attacks.
The clinical picture with pain, fast heart rate, and neurovisceral symptoms can be complicated by, at times, severe hyponatremia, heralding seizures with therapeutic dilemmas (see Box 1) and respiratory paralysis necessitating ventilatory support. Death is rare nowadays, especially when the diagnosis is made early. The recovery is usually complete, but at times it is prolonged, up to 1 year after a severe attack.
Superb nursing care, initially preferable in an intensive care unit, is necessary, and meticulous attention has to be paid to all problems.
Dehydration from vomiting is common and ileus and urinary retention are not infrequent; hyponatremia occurs in approximately half of the porphyric attacks. Muscle strength must be tested frequently. Twice-daily measurement of vital capacity helps to assess the necessity for respiratory assistance. High blood pressure and tachycardia deserve careful attention and, if appropriate, cautious treatment with a β-blocker. A negative caloric balance must be avoided, and if present initially it is best treated with carbohydrates (if necessary, intravenously with glucose, up to 300 g/day), and then later with a balanced diet.
Therapy must always start with a careful look at the drugs recently taken by the patient. It is best to discontinue as many drugs as possible, especially those deemed unsafe (see Box 1). Appropriate lists of safe and unsafe drugs in porphyria are readily available from websites (www.porphyriafoundation.com and www.porphyria- europe.com). An infection must be diligently searched for and treated at once. Seizure precautions are especially indicated if hyponatremia is found. Analgesics should be adequately dispensed; opiates are often necessary in fairly large doses.
Specific therapy was introduced a generation ago in the form of hematin (hemin, Panhematin), available from Lundbeck Inc. (847-282- 1000 or www.lundbeckinc.com). This has largely replaced glucose (300 g/day), which had the main advantages of availability, relatively low cost, and the possibility of curbing an early or mild attack.
But one must not wait for quick improvement in a patient’s condition and should at once take steps to obtain the definitive medication, hematin. This represents the equivalent to the end product, heme, and exerts its beneficial effect through repression of the deranged, and in the porphyric attack, markedly activated pathway to heme. It is still unclear whether the quick suppression of potentially toxic heme precursors (in 1–2 days) or a postulated replenishment of an assumed heme deficiency is the effective mechanism. Early administration of hematin is strongly advocated because the course of a porphyric attack is unpredictable, and a point of no return can unfortunately be reached quickly. Thus, the infusion of hematin must start as soon as possible.
A daily dose of 2 to 4 mg/kg body weight is recommended for up to 4 days. Longer treatment periods are of questionable value but may be tried in severe cases for up to 2 weeks. The infusion must be strictly intravenous and with ample flushing because hematin can cause thrombosis and phlebitis. Because it is a procoagulant and anticoagulant, frequent measurements of coagulation parameters are advisable. Anticoagulants such as warfarin (Coumadin) should if possible be avoided. Admixture of 5% human serum albumin (Albuminar-5) has been advocated to stabilize the final hematin solution and to lessen side effects. Hematin is available in many countries as heme arginate (Normosang).2
A beneficial clinical effect can be expected in 1 to 2 days, accompanied by a decrease in all heme precursors, most notably ALA and PBG. Many patients have received many treatment courses with hematin without apparent loss of effectiveness. Prophylactic use of hematin can be helpful in the treatment of women with frequent premenstrual exacerbations of their acute porphyria. Hematin should never be given as a diagnostic test to see if unexplained symptoms reminiscent of porphyria lessen. The diagnosis of a porphyric attack must be as quick, precise, and certain as possible, especially in new cases.
Partial liver transplantation has been successfully undertaken and found to be curative in patients with unrelenting porphyric attacks.
Prophylaxis of porphyric attacks is of great importance and can be accomplished to a large extent by avoidance of unsafe drugs, by stable caloric intake, and by prompt attention to intercurrent illnesses. It is a difficult decision if unsafe drugs have to be administered for a vital indication such as seizures. Here, consultation with an expert in porphyria is strongly advised.
The Cutaneous Porphyrias
The symptomatology of cutaneous porphyrias is mainly photosensitivity, often combined with skin fragility and blisters. All these findings occur because of porphyrin toxicity, resulting in cutaneous light absorption at the wavelength of 400 to 410 nm and subsequent formation of damaging reactive oxygen species. Thus, two therapeutic approaches are plausible: decrease of porphyrins and protection of the skin from sunlight. The usual sunscreens are, however, ineffective, and reflective agents containing zinc or titanium, although better, are less popular because of their appearance.
In three porphyrias—porphyria cutanea tarda, hereditary coproporphyria, and variegate porphyria—the skin lesions are rather similar, but erythropoietic protoporphyria and congenital erythropoietic porphyria can lead to very painful nonblistering skin lesions, and, in congenital erythropoietic porphyria, even to mutilations.
Porphyria Cutanea Tarda
Porphyria cutanea tarda is the most common porphyria and occurs because of uroporphyrinogen-decarboxylase deficiency and accumulation of mostly uroporphyrin. It can be inherited autosomal dominantly but more often occurs sporadically. It can also be due to toxins such as halogenated aromatic hydrocarbons.
The most prominent skin manifestations are seen on the dorsa of the hands and on the face, consisting of blisters filled with mostly clear fluid; shallow, slow-healing ulcers; whitish plaques; and tiny inclusion bodies, milia. Hypertrichosis and hyperpigmentation are often seen.
Unveiling factors promote the manifestation of the disease and consist mainly of liver disease, often due to alcohol. Hepatitis, often type C, and HIV infections are also common revealers. The drug list (see Box 1) is not applicable to the cutaneous porphyrias. The diagnosis is easily suspected at inspection and confirmed by measurement of urinary uroporphyrin excretion, typically manifold increased above the normal range.
There are two treatment options with different principles but rather similar effectiveness. Repeat phlebotomies of 350 to 450 mL at 1- to 2- week intervals are performed and followed by hemoglobin and ferritin measurements. Overt anemia should be avoided. Ferritin usually reaches the lower end of the normal range after approximately 8 to 10 phlebotomies, and clinical remission can be expected after approximately half a year. Remission can be long lasting, especially when unveiling factors are avoided; total abstinence from alcohol is advocated. Patients should not take iron-enriched vitamins because iron plays a critical role in porphyria cutanea tarda.
If phlebotomies are contraindicated (due to anemia or pulmonary or cardiac disease) or are very inconvenient, low-dose chloroquine (Aralen)1 (125 mg twice weekly) can be given orally. This flushes porphyrins from the liver and can be continued until remission is reached. In such low doses, the drug is virtually free from side effects.
Patients on chronic dialysis can develop porphyria cutanea tarda and also pseudoporphyria. Here, plasma porphyrin measurements establish the correct diagnosis. Patients with porphyria cutanea tarda and end-stage renal disease respond well to erythropoietin (Epogen, Procrit),1 probably via iron depletion through incorporation of iron into hemoglobin. Pseudoporphyria is also seen as a side effect of many drugs, mostly nonsteroidal antiinflammatory drugs and diuretics. Although it is phenotypically identical to porphyria cutanea tarda, pseudoporphyria does not respond to phlebotomies or chloroquine.
Patients with porphyria cutanea tarda have a much higher incidence of hepatocellular carcinoma and should be checked twice annually with hepatic imaging and measurement of alpha fetoprotein.
Congenital Erythropoietic Porphyria (Günther Disease)
Congenital erythropoietic porphyria (Günther disease), a rare autosomal recessive disorder, is usually apparent shortly after birth when brick-colored urine in diapers is observed because of excessive amounts of uroporphyrin (even more impressive under UV light).
This porphyria and the rare homozygous porphyria cutanea tarda, hepatoerythropoietic porphyria, can be progressive and severely mutilating. Therapy is limited to sun protection and blood transfusion if hemolytic anemia is present.
Erythropoietic protoporphyria is an autosomal dominant disorder due to a deficiency of ferrochelatase, the last enzyme in heme biosynthesis. Urinary porphyrins are normal, but protoporphyrin is markedly elevated in red cells and in stool. These patients suffer from instantly painful sun sensitivity, followed by edema and wrinkles in the thickened, light-exposed skin. In contrast to porphyria cutanea tarda, blisters are not seen here. Approximately one fifth of these patients develop progressive liver disease secondary to hepatic accumulation of protoporphyrin. Liver transplantation can become necessary.
Therapy is often beneficial with oral β-carotene1 (up to 400 mg/day for adults). This leads to a harmless slight orange-yellow discoloration of the skin and often effective sun protection. Ideally, the β-carotene dose should be adjusted to a plasma level between 11 and 15 mmol/L.
1. American Porphyria Foundation Home page. Available at: http://www.porphyriafoundation.com (accessed August 5, 2015).
2. Anderson K.E., Bonkovsky H.L., Bloomer J.R., Shedlofsky S.I. Reconstitution of hematin for intravenous infusion. Ann Intern Med. 2006;144:537–538.
3. Anderson K.E., Bloomer J.R., Bonkovsky H.L., et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. 2005;142:439–450.
4. Anderson K.E., Sassa S., Bishop D.F., et al. Disorders of heme biosynthesis: X-linked sideroblastic anemia and the porphyrias. In: Scriver C.R., Beaudet A.L., Sly W.S., et al., eds. 8th ed. New York: McGraw-Hill; 2961–3062. The Molecular and Metabolic Bases of Inherited Disease. 2001;vol. 1.
5. Badminton M.N., Elder G.H. Management of acute and cutaneous porphyrias. Int J Clin Pract. 2002;56:272–278.
6. Balwani M., Desnick R.J. The porphyrias: advances in diagnosis and treatment. Blood. 2012;120(23):4496–4504. doi:10.1182/blood-2012-05-423186 Epub 2012 Jul 12. Review. Erratum in: Blood. 2013;122(17):3090.
7. Chemmanur A.T., Bonkovsky H.L. Hepatic porphyrias: Diagnosis and management. Clin Liver Dis. 2004;8:807–838.
8. European Porphyria Initiative. Home page. Available at: http://www.porphyria-europe.com/ (accessed August 5, 2015). Kauppinen R. Porphyrias. Lancet. 2005;365:241–252.
9. Puy H., Gouya L., Deybach J.C. Porphyrias. Lancet. 2010;375:924– 937.
2 Not available in the United States.
1 Not FDA approved for this indication.