Pediatrics

Porphyrias

OVERVIEW: What every practitioner needs to know

Porphyrias are a very rare group of metabolic disorders.

The disease is a consequence of defects in the normal metabolic pathway for the biosynthesis of heme, with accumulation of porphyrins, which are the intermediates in the pathway of heme synthesis.

The term Porphyria comes from the Greek word porphyra, which means purple.

Are you sure your patient has Porphyria? What are the typical findings for this disease?

There are two major types of Porphyrias, hepatic or erythropoietic, depending on whether the intermediates that accumulate come from the liver or from developing erythrocytes.

The porphyrias can also be classified based on the clinical manifestations of:

-Acute Porphyrias, with severe bouts of abdominal pain that are recurrent.

-Cutaneous Porphyrias, presenting with painful skin lesions.

The main clinical manifestations are cutaneous photosensitivity with painful skin lesions and abdominal pain as a result of a neurologic dysfunction.

-The liver plays two major roles in the metabolism of the porphyrins. It is the major site of porphyrin production as part of heme synthesis. The liver is also important in the excretion of the more lipophilic porphyrins. For example, protoporphyrin is only excreted in bile.

See Figure 1 for a diagram depicting heme synthesis, and Table I for the classification, clinical and laboratory features of the porphyrias .

Figure 1.

Heme synthesis

Table I.

Human porphyrias. Major clinical and laboratory features

Classification of the Porphyrias

There are five Hepatic Porphyrias:

-5-aminolevulinic acid (ALA) dehydratase deficiency porphyria (ADP)

-Acute intermittent porphyria (AIP)

-Porphyria cutanea tarda (PCT)

-Hereditary coproporphyria (HCP)

-Variegate porphyria (VP)

There are two Erythropoietic Porphyrias:

-Congenital erythropoietic porphyria (CEP)

-Erythropoietic protoporphyria (EPP)

Of the five hepatic porphyrias, ADP, AIP, HCP, and VP present with acute neurological attacks (abdominal pain, peripheral neuropathy) and elevated levels of one or more of the porphyrin precursors aminolevulinic acid (ALA) and porphobilinogen (PBG); these are the acute porphyrias. PCT usually presents in adults with blistering lesions in the skin but not acute attacks. It is important to know that HCP and VP also could have cutaneous manifestations.

The erythropoietic porphyrias, CEP and EPP, usually present with elevation of porphyrins in the bone marrow and erythrocytes. They present with cutaneous photosensitivity in infancy. Manifestations of CEP are similar to those of PCT. The lesions in EPP are more painful, and non-blistering. EPP causes symptoms before puberty.

ALA dehydratase deficiency porphyria (ADP)

  • Genetics: ADP is a rare autosomal recessive acute hepatic porphyria secondary to the deficiency of ALA dehydratase activity.

  • Incidence: There are only six documented cases, with five in children or adolescents with specific gene mutations identified.

  • Etiology:The affected homozygotes have less than 10% of the normal ALA dehydratase enzyme activity in the erythrocytes.

  • Frequency: The frequency is unknown, but the frequency of the heterozygotes with less than 50% of the enzyme activity was approximately 2% in a population study from Sweden.

  • Clinical features: The presentation is variable and depends of the amount of enzyme activity. All the patients had marked decrease of the ALA dehydratase activity. Four of the patients were adolescents presenting with abdominal pain and neuropathy, similar to the symptoms seen in AIP. There was one infant with more severe symptoms presenting with failure to thrive early after birth.

  • Diagnosis: Patients have increased levels of urinary ALA and COPRO III. The urinary PBG is slightly elevated or normal. ALA dehydratase activity in the erythrocytes is less than 10% than the normal level. Homozygotes have less than 10% of the enzyme activity.

  • Differential diagnosis: Tyrosinemia type 1 and lead intoxication can inhibit ALA dehydratase, increase urinary ALA, and cause symptoms similar to those seen during the acute attacks.

  • Treatment: The four males that developed attacks during adolescence were treated with intravenous hemin, as in AIP. The infant that presented with more severe symptoms and did not survive, did not respond to hemin or liver transplantation; he received supportive therapy with blood transfusions and total parenteral nutrition.

Acute intermittent porphyria (AIP)

  • Genetics: This hepatic porphyria is an autosomal dominant disorder as a result of having half the normal activity of hydroxymethylbilane (HMB)-synthase. In heterozygous individuals, the presentation is variable.

  • Incidence: The disease is widespread, but the actual incidence is unknown. It is more common in Scandinavia and Great Britain.

  • Pathophysiology: The disease is often activated by different environmental or hormonal factors such as drugs, diet, and steroid hormones in individuals with the genetic predisposition. Once the precipitating factor is known, the attacks can be prevented by avoiding triggers.

  • Clinical features:AIP remains latent in the vast majority of patients with the mutation, especially before puberty. Apparently, having half the activity of the HMB-synthase enzyme is sufficient for normal hepatic heme synthesis. Also the induction of ALAS1 is thought to underlie acute attacks in AIP. When heme synthesis is increased in the liver, half-normal HMB-synthase may become limiting and ALA, PBG and other heme pathway intermediates may accumulate.

    The precipitating factors include endogenous and exogenous gonadal steroids, porphyrinogenic drugs, alcohol ingestion, and a low calorie diet. Symptoms are more common in females and after puberty, suggesting that hormones play an important role in clinical expression. Pregnancy is usually well tolerated. An extensive list of safe and unsafe drugs for individuals with porphyria is provided at The Drug Database for Acute Porphyria, www.drugs-porphyria.com. Attacks can be provoked by surgery, infections, and alcohol, but many patients with recurrent attacks cannot identify an instigating factor. An increase in carbohydrates may ameliorate the attacks. The disease is rarely fatal if identified promptly.

    Abdominal pain is the most common symptom; it usually is steady, dull, and poorly localized. Patients often have constipation, abdominal distension, and decreased bowel sounds. Inflammation is absent; therefore, fever and leukocytosis are not prominent. Other manifestations include nausea; vomiting; tachycardia; hypertension; extremity, neck and chest pain; headaches; muscle weakness; sensory loss; tremors; sweating; dysuria; and bladder distension. Seizures could be a neurologic manifestation of the disease but could also be secondary to hyponatremia. Long-term risks for hypertension, impaired renal function. and hepatocellular carcinoma are increased.

  • Low grade abnormalities in the liver function tests are common. The risk of hepatocellular carcinoma is increased.

  • Diagnosis:ALA and PBG are increased in plasma and urine during the acute attacks. The diagnosis of an acute attack is mostly based on the clinical findings. The levels of the porphyrin precursors decrease after an attack but usually remain elevated. Dramatic decreases of the porphyrin precursors are seen after treatment with hemin. A normal urinary PBG excludes AIP as a cause of the current symptoms. Unlike HCP and VP, fecal and plasma porphyrins are normally or minimally elevated in AIP. The deficient enzyme is detectable in the erythrocytes of most AIP heterozygotes. Any condition that increases erythropoiesis or younger erythrocytes will present levels of enzyme activity in the normal ranges. More than 240 HMB-synthase mutations have been identified in AIP. Yearly hepatic imaging to assess for hepatocellular carcinoma is recommended. In these patients, there is no elevation of α-fetoprotein.

  • Treatment: Narcotic analgesics are used for the abdominal pain seen during the attacks. Phenothiazines are useful to treat nausea, vomiting, anxiety, and restlessness. Intravenous glucose (at least 300 g/dl) is helpful in milder attacks. Hemin is very effective and should be started immediately for severe attacks and for milder attacks that do not respond to glucose infusion within 1-2 days. It is used as 3-4 mg of heme as lyophilized hematin, heme albumin, or heme arginate infused daily for 4 days. Recovery is usually rapid if treatment is started early. Patients with neuropathy could require months to recover. One teenage patient that suffered many attacks responded well to an orthotopic liver transplantation, with normalization of urinary levels of PBG and ALA, but liver transplantation should not be considered as first-line treatment in AIP.

  • Homozygous dominant AIP:This is a very rare form of porphyria. It presents in infancy. Patients have extremely low HMB-synthase (<2%) activity. This condition has been described in 4 European children from different families, except for two siblings. All patients presented with failure to thrive, developmental delay, cataracts, and/or hepatosplenomegaly, but with no acute attacks.

Porphyria cutanea tarda (PCT)

  • Genetics: Hepatic URO-decarboxylase is deficient in all types of PCT. About 80% of the patients have no mutation of the enzyme and are said to have type 1 disease, or type 3 if relatives are affected. Patients with heterozygous mutation for the enzyme have type 2 disease (familial PCT). It is important to know that having decreased enzyme activity per se is not sufficient to develop symptoms; patients also need other genetic and environmental factors.

  • Incidence: This is the most common porphyria. It could be sporadic (type 1) or familial (types 2 and 3). It is also seen after exposure to halogenated aromatic hydrocarbons.

  • Clinical features: Deficient hepatic uroporphyrinogen (URO)-decarboxylase is present in all types of PCT, and should be about or less than 20% of the normal activity. It is believed that there is a specific inhibitor of the enzyme in the liver acting in the presence of iron and under conditions of oxidative stress. There is increased prevalence of PCT type 1 and 2 in patients with the common hemochromatosis mutations. PCT is strongly associated with hepatitis C, excess alcohol ingestion, and estrogen use, as well as human immunodeficiency virus. Multiple factors that appear to act synergistically can be identified in the individual patient with PCT. The major clinical feature is blistering lesions on the back of the hands, and also on the forearms, face, legs and feet. There is hypertrichosis, hyperpigmentation, and skin friability with small white papules (milia). Sun-exposed skin usually becomes thickened. Patients have evidence of chronic liver disease with abnormal liver function tests. Cirrhosis and hepatocellular carcinoma may develop in the long term.

  • Diagnosis: Porphyrins are increased in the liver, plasma, urine, and stools. The urinary ALA is mildly elevated, but the PBG level is normal. Plasma porphyrins are also increased, which is useful for screening. There is an increase of isocoproporphyrins, especially in feces; this is diagnostic for URO-decarboxylase deficiency. This enzyme activity in the erythrocytes is about half of the normal level in type PCT and normal in type 1 and type 3. More than 65 mutations have been identified in the URO-decarboxylase gene in type 2 PCT and hepatoerythropoietic porphyria (HEP).

  • Treatment: Discontinuation of the risk factors (alcohol, estrogens, and iron supplements) is the first step in treatment, but it could take time for the patient's condition to respond. A complete resolution can almost be achieved with repeated phlebotomy to reduce the hepatic iron. A unit of blood can be removed every two weeks until the ferritin level is at the lower limit of normal. In order to document improvement in PCT, the total plasma porphyrin concentration must be followed; its value returns to normal after the target level of ferritin is reached. The plasma porphyrin levels must be followed every 6-12 months for early detection of recurrences. If the patient does not tolerate phlebotomy, an alternative is to start a low-dose regimen with chloroquine (125 mg twice weekly) or hydroxychloroquine. Treatment of patients with concurrent hepatitis C should be postponed until after the PCT is treated and in remission.

  • Hepatoerythropoietic porphyria (HEP): This is the homozygous form of type 2 PCT. Most patients have inherited mutations from unrelated parents. In HEP, the enzyme activity is approximately 3%-10% of normal. Excess porphyrins originate from the liver. Patients usually have blistering skin lesions, hypertrichosis, scarring, and red urine during infancy or childhood. Concurrent conditions that affect the liver may worsen the disease severity; this has been described in a toddler with hepatitis A. Avoidance of sunlight is very important. The outcome depends on the enzyme activity, and it is better if sunlight can be avoided. The use of phlebotomy has shown no benefit.

Hereditary coproporphyria (HCP)

  • Genetics: HCP is an autosomal dominant hepatic porphyria resulting from half the normal activity of the enzyme COPRO-oxidase.

  • Incidence: This porphyria is less common than AIP and VP. It is more common in women.

  • Clinical features: The disease presents with very similar symptoms to AIP. The attacks are less severe than those in AIP. Cutaneous photosensitivity may occur, but less commonly than in VP. HCP is influenced by the same factors as AIP. The disease is latent before puberty. Although HCP is less severe than AIP, fatal motor neuropathy may nevertheless occur. Blistering skin lesions are identical to those in PCT and VP, and begin in childhood in rare homozygous cases.

  • Diagnosis: The diagnosis is confirmed by increased fecal coproporphyrin III; this is also elevated in urine. It will remain elevated in feces even if there are no symptoms.

  • Treatment: The neurologic symptoms are treated as in AIP. Phlebotomy and chloroquine are ineffective in treating the cutaneous manifestations.

Variegate porphyria (VP)

  • Genetics: VP is an autosomal dominant hepatic porphyria. It is secondary to deficient PROTO-oxidase enzyme activity.

  • Incidence: This disease is very common in South Africa, where 3 of every 1000 whites have the disorder. In other countries, VP is less common than AIP.

  • Clinical features: The attacks are usually triggered by diet, drugs, or hormones. They are identical to the attacks seen in AIP, but milder and less often fatal. The skin lesions are the same as those in PCT, but usually more difficult to treat. In two large studies of VP, 59% of study subjects had only skin lesions, 20% had only acute attacks, and 22% had both.

  • Diagnosis: ALA and PBG are elevated in urine during the attacks. Coproporphyrin III is elevated in urine and feces. The fluorescence emission spectrum of porphyrins in plasma at a neutral pH in VP is distinctive and rules out other porphyrias, especially PCT, which is common.

  • Treatment: During acute attacks, the treatment is the same as in AIP. Hemin should be started early. There are few effective methods to prevent skin lesions, but sun exposure should be avoided and protective clothing should be worn. Phlebotomy, β-carotene and chloroquine are ineffective.

Congenital erythropoietic porphyria (CEP)

  • Genetics:CEP is an autosomal recessive disorder, and is also known as Gunther disease. It is secondary to a marked deficiency in the activity of URO-synthase, with accumulation of uroporphyrin I and coproporphyrin I isomers.

  • Clinical features: The symptoms start early in infancy, with severe cutaneous photosensitivity. It could cause nonimmune hydrops fetalis. The exposed skin is friable, with bullae and vesicles that are prone to rupture and infection. Skin thickening, focal hypo- or hyperpigmentation, and hypertrichosis of the face and extremities are characteristic of CEP. Skin infection and bone resorption can lead to disfigurement of the face and hands. The teeth are reddish-brown and fluorescent on exposure to long-wave ultraviolet light, due to the deposition of excess porphyrins. Patients present with hemolysis leading to splenomegaly, also due to increased deposition in the red blood cells.

  • Diagnosis: Uroporphyrin I and coproporphyrin I accumulate in the bone marrow, red blood cells, plasma, urine, and feces. The confirmation of the diagnosis is made by the identification of the specific mutations in the URO-synthase gene or by the decreased activity of the enzyme.

  • Treatment: Transfusion for anemia is required in severe cases, even in utero. Recurrent transfusions are effective to suppress erythropoiesis, but result in iron overload and other complications. Splenectomy may reduce hemolysis and decrease transfusion requirements. Protection from sunlight is essential, and minor skin trauma should be avoided. Recently, bone marrow and cord blood transplantation have proven effective in several transfusion-dependent children.

Erythropoietic protoporhyria (EPP)

  • Genetics: EPP is an autosomal dominant inherited disorder resulting from partial deficiency of ferrochelatase (FECH), approximately 15%-25% of the enzyme activity. A polymorphism in intron 3 of the wild-type allele affects the level of enzyme activity and clinical expression.

  • Incidence: It is the most common porphyria in children and the second most common in adults.

  • Pathophysiology: Protoporphyrin accumulates in the bone marrow, then appears in plasma, is taken up in the liver, and is excreted in bile and feces. It is also transported to the skin, causing photosensitivity.

  • Clinical features: Skin photosensitivity starts in childhood. The skin becomes painful, erythematous, and itchy very soon after sun exposure, similar to angioedema. Vesicular lesions are uncommon. Vesicles and bullae occur in only 10% of cases. Chronic lesions are lichenification, labial grooving, leathery pseudovesicles, and nail changes. The skin photosensitivity remains stable over many years in most patients. There are no other factors that exacerbate EPP, as seen in hepatic porphyrias. Up to 20% of the patients have minor liver function abnormalities. It has been reported that 5% of the cases have rapid progression of liver disease, with acute liver failure and death. This liver disease may cause abdominal pain, especially in the RUQ, and back pain.

  • Diagnosis: An increase of the free erythrocyte protoporphyrin, not complexed with zinc, is the hallmark of the disease. Protoporphyrin levels are also elevated in bone marrow, plasma, bile, and feces. Plasma and fecal porphyrins are less increased or sometimes normal; this is in contrast to other cutaneous porphyrias. Erythrocyte protoporphyrin concentrations are increased lead poisoning, iron deficiency, various hemolytic disorders and all homozygous forms of porphyria, but in all these other conditions is always complexed with zinc.

  • Treatment: Avoiding sunlight exposure and wearing appropriate clothing are essential. Oral ß-carotene (120-180 mg/dL) improves tolerance to sunlight in many patients if the dose is adjusted to maintain a serum carotene level in the range of 10-15 µmol/L (600-800 µg/dL). Oral ß-carotene causes mild skin decoloration due to carotenemia. Treatment of the hepatic complications is difficult. Cholestyramine and activated charcoal may interrupt the enterohepatic circulation of protoporphyrin and promote its fecal excretion, leading to some improvement. Plasmapheresis and intravenous hemin are sometimes helpful. Splenectomy may be indicated in the presence of splenomegaly and hemolysis. Liver transplantation is sometimes necessary and often successful in the short term; however, EEP often recurs in the transplanted liver due to reaccumulation of protoporphyrin. Treatment with hemin and plasmapheresis may prevent or delay the reaccumulation. Bone marrow transplantation has been successful in humans with EPP, this should be considered after liver transplantation if a suitable donor can be found.

What other disease/condition shares some of these symptoms?

  • It is always important to rule out a more common etiology for abdominal pain since many patients present with recurrent abdominal pain.

  • Patients with chronic liver disease could have some similar findings in the urine analysis of the porphyrins.

  • Tyrosinemia type 1 and lead intoxication should be ruled out in patients presenting with symptoms similar to those seen in ADP.

What caused this disease to develop at this time?

  • The accumulation of metabolic intermediates in these patients is the reason why the disease develops and symptoms start. The elucidation of the pathway of the heme synthesis clarified the abnormal accumulation of metabolic intermediates in patients with porphyrias.

  • Knowing the properties of the porphyrins is important in order to understand the clinical manifestations of the disease.

  • There is an excessive accumulation and excretion of porphyrins and their precursors as a result of specific enzymatic defects in the heme synthetic pathway.

  • The condition could be inherited or acquired. There are many patients with no clinical manifestations who have the enzymatic defect.

  • There are several precipitating factors for an acute and potentially fatal attack, such as drugs, alcohol, fasting, or stress. This is the reason why it is very important to try to identify these patients and prevent an attack.

  • A rapid screening of porphobilinogen (PBG) is very useful when a patient presents with a suspected visceral attack.

  • In patients with suspected cutaneous porphyria, screening tests for increased erythrocytic porphyrins should be performed, as well as screening tests for urinary porphyrins.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • Positive screening tests always must be confirmed with specific quantitative tests.

  • Porphyrins have a unique photo optic property that allows them to absorb light in the long ultraviolet range and emit an intense fluorescence. This is very useful in detecting porphyrins in biologic specimens and forms the basis of many diagnostic screening tests for the porphyrias.

  • DNA-based tests as well as enzymatic assays are helpful for evaluation, genetic diagnosis, and identifying the particular defect. But these are not useful when trying to provide a rapid diagnosis in a symptomatic patient.

Would imaging studies be helpful? If so, which ones?

  • Some patients with different types of porphyrias like AIP and ADP have an increased incidence of hepatocellular carcinoma (HCC). For these patients, an imaging study of the abdomen (ultrasound or CT scan) is necessary, especially during adulthood.

Confirming the diagnosis

  • An acute porphyria should be suspected in patients with recurrent neurovisceral symptoms after puberty, such as abdominal pain. If an initial evaluation does not yield any other diagnosis, then urinary ALA and PBG should be checked.

  • Urinary PBG is almost always elevated during an acute attack in AIP, HCP, and VP.

  • A spot urine test for PBG could be very helpful in obtaining a diagnosis of porphyria. A 24-hour collection may delay the diagnosis.

  • Patients with chronic liver disease could have elevation of urinary porphyrins; therefore, measurements of the porphyrins alone should be avoided.

  • Blistering skin lesions are almost always accompanied by elevation of total plasmaporphyrins.

  • Confirmation at the DNA level by identifying the mutation or mutations is important after the diagnosis is established, and permits family studies.

If you are able to confirm that the patient has a porphyria, what treatment should be initiated?

  • The treatment will always depend on the type of porphyria (see above for specific treatments in each different type of the disease).

What causes this disease and how frequent is it?

  • See above for each type of porphyria.

What complications might you expect from the disease or treatment of the disease?

  • The increased predisposition for hepatocellular carcinoma is seen in various types of porphyria.

Evaluation of the patient with abdominal pain and suspected porphyria

  • Porphyria should suspected in the pediatric population, particularly in adolescents who present with abdominal pain and no obvious clinical explanation.

  • The symptoms are very similar to the ones seen in functional abdominal pain, poorly localized pain, no rebound tenderness, constipation, and psychological instability. Due to these non-specific symptoms, a high index of suspicion is necessary for the diagnosis of porphyria.

  • Patients with true acute porphyria excrete increased amounts of urinary ALA and usually PBG. The absence of these during an acute attack rules out the diagnosis of porphyria.

  • An incorrect diagnosis of porphyria could be made in patients with functional abdominal pain with the finding of elevated total porphyrins in urine, which is a laboratory abnormality commonly found in secondary porphyrinuria.

  • Measurement of fecal porphyrins is also helpful in discriminating HCP and VP in remission from patients with secondary porphyrinurias. Fecal coproporphyrin is markedly elevated in these porphyrias, whereas it is normal in patients with secondary porphyrinuria.

How can Porphyrias be prevented?

  • Prevention is the central component in the management of patients with this condition.

  • The use of high carbohydrate intake, intravenous hematin, and pain control are crucial in the treatment of acute visceral attacks.

  • Sun avoidance and strong skin protection are very important in reducing cutaneous manifestations and complications.

  • Avoidance of certain drugs, surgery, certain diets, and steroid hormones are of crucial importance.

What is the evidence?

As described above, there are different treatments for the different types of porphyrias. The evidence is difficult to gather since this is a very rare condition, but treatments such as hemin and intravenous glucose infusion in AIP have been shown to be effective in these patients. It is very important to avoid triggers of the attacks, such as certain drugs.

The following references are recommended for further information in porphyrias:

-Classification of the Porphyrias

Anderson, KE, Bloomer, JR, Bonkovsky, HL. "Recommendations for the diagnosis and treatment of the acute porphyrias". Ann Intern Med. vol. 142. 2005. pp. 439-50.

Kauppinen, R. "Porphyrias". Lancet. vol. 365. 2005. pp. 241-52.

-ALA dehydratase deficiency porphyria (ADP)

Shady, AA, Colby, BR, Cunha, LF. "Congenital erythropoietic porphyria: identification and expression of eight novel mutations in the uroporphyrinogen III synthase gene". Br J Haematol. vol. 117. 2002. pp. 980-7.

Anderson, KE, Bloomer, JR, Bonkovsky, HL. "Recommendations for the diagnosis and treatment of the acute porphyrias". Ann Intern Med. vol. 142. 2005. pp. 439-50.

Sassa, S. "ALAD porphyria". Semin Liver Dis. vol. 18. 1998. pp. 95-101.

Doss, MO, Stauch, T, Gross, U. "The third case of Doss porphyria (delta-amino-levulinic acid dehydratase deficiency) in Germany". J Inherit Metab Dis. vol. 27. 2004. pp. 529-36.

Akagi, R, Kato, N, Inoue, R. "delta-Aminolevulinate dehydratase (ALAD) porphyria: the first case in North America with two novel ALAD mutations". Mol Genet Metab. vol. 87. 2006. pp. 329-36.

-Acute intermittent porphyria (AIP)

Handschin, C, Lin, J, Rhee, J. "Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha". Cell. vol. 122. 2005. pp. 505-15.

Anderson, KE, Bloomer, JR, Bonkovsky, HL. "Recommendations for the diagnosis and treatment of the acute porphyrias". Ann Intern Med. vol. 142. 2005. pp. 439-50.

Soonawalla, ZF, Orug, T, Badminton, MN. "Liver transplantation as a cure for acute intermittent porphyria". Lancet. vol. 363. 2004. pp. 705-6.

-Porphyria cutanea tarda (PCT)

Elder, GH. "Porphyria cutanea tarda". Semin Liver Dis. vol. 18. 1998. pp. 67-75.

Bonkovsky, HL, Poh-Fitzpatrick, M, Pimstone, N. "Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America". Hepatology. vol. 27. 1998. pp. 1661-9.

Mehrany, K, Drage, LA, Brandhagen, DJ. "Association of porphyria cutanea tarda with hereditary hemochromatosis". J Am Acad Dermatol. vol. 51. 2004. pp. 205-11.

Egger, NG, Goeger, DE, Payne, DA. "Porphyria cutanea tarda: multiplicity of risk factors including HFE mutations, hepatitis C, and inherited uroporphyrinogen decarboxylase deficiency". Dig Dis Sci. vol. 47. 2002. pp. 419-26.

Bonkovsky, HL, Barnard, GF. "Diagnosis of porphyric syndromes: a practical approach in the era of molecular biology". Semin Liver Dis. vol. 18. 1998. pp. 57-65.

Thunell, S, Harper, P. "Porphyrins, porphyrin metabolism, porphyrias. III. Diagnosis, care and monitoring in porphyria cutanea tarda--suggestions for a handling programme". Scand J Clin Lab Invest. vol. 60. 2000. pp. 561-79.

-Hereditary coproporphyria (HCP)

Martásek, P. "Hereditary coproporphyria". Semin Liver Dis. vol. 18. 1998. pp. 25-32.

Anderson, KE, Bloomer, JR, Bonkovsky, HL. "Recommendations for the diagnosis and treatment of the acute porphyrias". Ann Intern Med. vol. 142. 2005. pp. 439-50.

-Variegate porphyria (VP)

Schmitt, C, Gouya, L, Malonova, E. "Mutations in human CPO gene predict clinical expression of either hepatic hereditary coproporphyria or erythropoietic harderoporphyria". Hum Mol Genet. vol. 14. 2005. pp. 3089-98.

Hift, RJ, Meissner, PN, Corrigall, AV. "Variegate porphyria in South Africa, 1688-1996--new developments in an old disease". S Afr Med J. vol. 87. 1997. pp. 722-31.

Bonkovsky, HL, Barnard, GF. "Diagnosis of porphyric syndromes: a practical approach in the era of molecular biology". Semin Liver Dis. vol. 18. 1998. pp. 57-65.

Poh-Fitzpatrick, MB. "A plasma porphyrin fluorescence marker for variegate porphyria". Arch Dermatol. vol. 116. 1980. pp. 543-7.

-Congenital erythropoietic porphyria (CEP)

Piomelli, S, Poh-Fitzpatrick, MB, Seaman, C. "Complete suppression of the symptoms of congenital erythropoietic porphyria by long-term treatment wtih high-level transfusions". N Engl J Med. vol. 314. 1986. pp. 1029-31.

Davenport, C, Dillon, WP, Sze, G. "Neuroradiology of the immunosuppressed state". Radiol Clin North Am. vol. 30. 1992. pp. 611-37.

Shaw, PH, Mancini, AJ, McConnell, JP. "Treatment of congenital erythropoietic porphyria in children by allogeneic stem cell transplantation: a case report and review of the literature". Bone Marrow Transplant. vol. 27. 2001. pp. 101-5.

-Erythropoietic protoporhyria (EPP)

Cox, TM, Alexander, GJ, Sarkany, RP. "Protoporphyria". Semin Liver Dis. vol. 18. 1998. pp. 85-93.

Rank, JM, Carithers, R, Bloomer, J. "Evidence for neurological dysfunction in end-stage protoporphyric liver disease". Hepatology. vol. 18. 1993. pp. 1404-9.

Poh-Fitzpatrick, MB, Wang, X, Anderson, KE. "Erythropoietic protoporphyria: altered phenotype after bone marrow transplantation for myelogenous leukemia in a patient heteroallelic for ferrochelatase gene mutations". J Am Acad Dermatol. vol. 46. 202. pp. 861-6.

-Other important references

Chemmanur, AT, Bonkovsky, HL. "Hepatic porphyrias: diagnosis and management". Clin Liver Dis. vol. 8. 2004. pp. 807-38.

Bloomer, JR, Bonkovsky, HL. "The porphyrias". Dis Mon. vol. 35. 1989. pp. 1-54.

Morton, KO, Schneider, F, Weimer, MK. "Hepatic and bile porphyrins in patients with protoporphyria and liver failure". Gastroenterology. vol. 94. 1988. pp. 1488-92.

Bonkovsky, HL, Barnard, GF. "Diagnosis of porphyric syndromes: a practical approach in the era of molecular biology". Semin Liver Dis. vol. 18. 1998. pp. 57-65.

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