Porphyria: Pathophysiology, diagnosis, and treatment Abstract: Porphyrias are inherited metabolic disorders that involve alterations in enzymes utilized in the heme biosynthetic pathway. Most of these conditions are inherited; however, some are believed to be acquired through environmental exposures. Patients with porhyrias often present with a wide range of clinical symptoms, making it difficult to diagnose. Treatments vary depending on clinical presentation. A thorough and detailed history is essential and key to discovering a porphyria diagnosis.
By Tracy Gasson, MSN, APRN, OCN and Kathleen Klein, MSN, APRN, CCRN
patient complains of abdominal pain, which has gotten progressively worse over the past week. While obtaining the patient’s history, the patient mentions a previous diagnosis of porphyria. What does this mean?
A
■ Pathophysiology Porphyrias are a group of inherited metabolic disorders that involve the heme biosynthetic pathway. Most of these conditions are inherited; however, some are believed to be acquired through environmental exposures. In addition, not all gene carriers of inherited porphyrias develop clinical disease, and there is significant interplay between the primary gene defect and the secondary acquired or environmental factors.1 The metabolic conditions that arise are a result of specific alterations in one of the eight enzymes utilized in heme synthesis. Most of the heme synthesized in the body occurs in the erythropoietic cell with a small amount produced in the parenchymal cells of the liver.2 As a result of the alteration in enzyme function, there is an accumulation and measurable excretion of porphyrins and/ or porphyrin precursors.3
■ Classification by clinical manifestations There are various ways to classify the porphyrias. Porphyrias may be classified according to the location of the enzyme deficiency: erythropoietic or hepatic forms. In addition, porphyria may be divided into cutaneous or noncutaneous types. Finally, porphyria may be classified as either acute or nonacute depending on whether the patient presents with an acute life-threatening attack. For the purposes of this article, the classifications of porphyria will be discussed as nonacute and acute because the patient will present to a practitioner with either nonacute or acute symptoms (see Classification of the acute and nonacute porphyrias). ■ Nonacute porphyrias The nonacute porphyrias are an inherited group of disorders that manifest as dermatologic conditions. Symptoms result from increased photosensitivity on areas of the body that have been exposed to UV light due to porphyrin deposition in the skin.3 Nonacute porphyrias include porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP), congenital erythropoietic porphyria (CEP), and hepatoerythropoietic porphyria (HEP).
Keywords: heme, heredity, inherited metabolic disorders, porphyria
1 The Nurse Practitioner
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Porphyria: Pathophysiology, diagnosis, and treatment
PCT is the most frequent type of porphyria worldwide. It is an autosomal-dominant disorder and is diagnosed based on the cutaneous manifestations. This condition is characterized by blistering on sun-exposed areas, which lead to scarring. Areas of previous blistering appear atrophic. There is also hyperpigmentation over sun-exposed areas and facial hypertrichosis.4 Various factors have been implicated in precipitation of PCT, including alcohol consumption, estrogens, hemodialysis, factors increasing hepatic iron concentration, and viral infections (for example, hepatitis C and HIV). EPP is also an autosomal-dominant disorder involving the eighth enzyme in heme biosynthesis. It is characterized by cutaneous photosensitivity that may develop in childhood. Clinical manifestations include seasonal photosensitivity
with erythema within minutes of sun exposure and chronic lesions, such as thickening of skin and wax-like scarring on nose, cheeks, and dorsal hands.3 This condition is also associated with liver dysfunction caused by accumulation of protoporphyrin in hepatocytes and bile canaliculi, resulting in cell damage, cholestasis, and cytolysis.2 In addition, these patients are at an increased risk for developing liver failure because of the accumulation of protoporphyrin in the hepatobiliary structures.3 CEP or Günther disease is an extremely rare autosomal recessive condition resulting from a decreased activity of the fourth enzyme in heme biosynthesis. CEP manifests in early infancy as increased friability and blistering of sun-exposed skin.1 There is often ocular involvement, such as corneal scarring and ulcerative keratitis, as
Classification of the acute and nonacute porphyrias3 Classification
Gene name and locus
Mode of inheritance
Important aspects
Acute intermittent porphyria
Porphobilinogen deaminase; 11q24.1-q24.2
Autosomal dominant
Most common acute porphyria in the world; no skin symptoms
Variegate porphyria
Protoporphyrinogen oxidase; 1q22-23
Autosomal dominant
Founder mutations identified in South Africa and Chile; skin symptoms can occur
Hereditary coproporphyria
Coproporphyrinogen oxidase; 3q12
Autosomal dominant
Rare; skin symptoms can occur
ALA dehydratase deficiency porphyria
ALA dehydratase; 9q34
Autosomal recessive
Very rare (< 10 cases in the world reported)
Porphyria cutanea tarda
Uroporphyrinogen decarboxylase; 1p34
Autosomal dominant
Most frequent type of porphyria worldwide; hereditary and acquired variant exist
Erythropoietic protoporphyria
Ferrochelatase; 18q21.3
Autosomal dominant
Severe liver disease can occur in approximately 5% of cases; recessive inheritance has been reported
Congenital erythropoietic porphyria
Uroporphyrinogen III synthase; 10q25.3-q26.3
Autosomal recessive
Very severe clinical course; mutilations; hemolytic anemia; porphyrin deposition in bones and teeth
Hepatoerythropoietic porphyria
Uroporphyrinogen decarboxylase; 1p34
Autosomal recessive
Homozygous variant of porphyria cutanea tarda; highly increased photosensitivity
Acute
Nonacute
2 The Nurse Practitioner
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Porphyria: Pathophysiology, diagnosis, and treatment
well as erythrodontia, osteodystrophia, and hypercellular bone marrow.2 The most noticeable clinical manifestation is the pink to red-brown urine, which is a result of the increased urinary porphyrins. HEP is an extremely rare and recessive form of porphyria. HEP is caused by a homozygous or compound heterozygous deficiency of uroporphyrinogen decarboxylase.2 Clinically, this disorder manifests in infancy or early childhood. The most noticeable sign is dark urine. Subsequently, severe cutaneous photosensitivity develops that includes blistering, pruritus, hypertrichosis, hyperpigmentation, and scleroderma-like scarring.3 ■ Acute porphyrias The acute porphyrias are a predominately autosomaldominant group of disorders. Acute porphyrias comprise acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and delta-aminolevulinic acid (ALA) dehydratase deficiency porphyria (ADP). Acute attacks can occur with all the acute porphyrias. Patients with these disorders often present with a wide range of clinical symptoms, making it very difficult to diagnose. Patients may present with long-lasting colicky abdominal pain, nausea and vomiting, diarrhea, tachycardia, hypertension, seizures, muscle weakness, paraplegia/quadriplegia, as well as a variety of other neurologic and psychiatric signs.3 These incidents can be life threatening. AIP is an autosomal-dominant inherited disorder involving a deficiency of the third enzyme in heme biosynthesis, porphobilinogen deaminase (PBGD). This is the most important acute hepatic porphyria, both in its incidence and clinical severity.1 It is more common in northern European countries, affecting about 1 in 75,000 people with the incidence even higher in Sweden (1 in 1,000). 2 The prevalence of AIP in the United States is thought to be 5 to 10 per 100,000.1 AIP is more common in women than men and usually manifests after puberty. Acute attacks are rare after menopause, and peak occurrence is seen in the third decade.2 An acute attack of AIP may start off with vague symptoms of anxiety, restlessness, insomnia, or abdominal pain and may occur over a period of hours or days. The majority of AIP clinical manifestations, including abdominal pain and other neurovisceral and circulatory disturbances, are due to effects on the nervous system.1 Abdominal pain is usually severe, steady, and poorly localized.1 Other symptoms, such as nausea, vomiting, tachycardia, and changes in mentation/muscle weakness may also be seen in these 3 The Nurse Practitioner
patients. Patients may become dehydrated and experience electrolyte disturbances—especially hyponatremia. If untreated, the muscle weakness can progress to quadriplegia, with respiratory and bulbar paralysis and death.2 The mortality of undiagnosed patients with AIP has been approximated to be between 20% and 25% within the first 5 years of the first attack.5 Not everyone with this inherited deficiency of the enzyme will develop clinical manifestations of acute intermittent porphyria. The great majority (approximately 90%) of individuals who inherit a deficiency of PBGD never develop porphyric symptoms.1 However, for those that develop symptoms, many precipitating factors may be to blame. There is considerable evidence that endocrine factors and steroid hormones play an important role in an acute attack of AIP.1 One study on women of Swedish origin utilizing a combination estradiol and progesterone oral contraceptive showed a 66% occurrence rate of AIP before the age of 21 years.5 Other factors associated with AIP may be drugs, nutritional factors, smoking, alcohol, infections, surgery, and stress. The first reported case of a drug-induced porphyria was in 1889 on a woman who had received a sulfonyl, a medication used for its hypnotic properties.6 Drugs are among the most important factors that precipitate acute attacks of acute porphyria, with barbiturates and sulfonamide antibiotics being most common.1 However, any drug that activates the cytochrome P450 enzyme system should be used with caution in these patients. It is important to remember that all of the heme pathway intermediates are potentially toxic.1 Therefore, any condition that triggers this process is potentially toxic to the individual with a heme pathway enzyme deficiency. Nutritional factors—especially a reduced caloric intake, such as fasting or dieting—may precipitate an acute AIP attack because these conditions may induce heme oxygenase-1 (HO-1) activity.7 HO-1 activity can lead to depletion of regulatory hepatic heme pools, which may lead to aminolevulinic acid synthase (an enzyme in heme production) induction.1 The hydrocarbons generated from smoking are known to induce the hepatic cytochrome P450 enzymes and heme synthesis; therefore, smoking should be avoided. Alcohol ingestion has also been associated with an acute AIP attack. Finally, infections, surgery, and psychological stress are known to increase hepatic HO-1 activity and therefore can precipitate an acute AIP episode.1 VP is an autosomal dominant, inherited porphyria that involves the seventh enzyme in the heme biosynthesis
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Porphyria: Pathophysiology, diagnosis, and treatment
pathway. This disease is termed variegate because it can present itself either with neurologic manifestations, cutaneous photosensitivity, or both.1 It is difficult to differentiate cutaneous clinical findings of VP with those of PCT and HCP. Likewise, an acute attack of VP is very similar to AIP, although these attacks are generally milder than in AIP, and recurrent attacks are less common.1 HCP is a very rare, autosomal dominant, inherited porphyria involving a deficiency in the sixth enzyme in heme biosynthesis. HCP has identical clinical symptoms as AIP, except for its cutaneous photosensitivity, which is entirely absent in AIP.1 Therefore, triggers for AIP (such as certain drugs, hormones, alcohol, and dieting) should also be avoided in patients with HCP. The risk of hepatocellular carcinoma may be increased in this porphyria, as in AIP and VP.1 ADP is the rarest form of porphyria and is an autosomal recessive disorder. The disease is also known as plumboporphyria or Doss porphyria and can manifest early in childhood as well as in adulthood. 3 Clinically, ADP closely resembles AIP. ■ Diagnostic testing Lab testing is required for a definitive diagnosis and to determine which type of disease the patient has once a suspicion of porphyria is determined.8 A thorough medical history and complete physical exam, followed by urine and blood samples being collected, should begin the assessment. Patients complaining of red-colored urine, severe abdominal pain, which may or may not be accompanied by vomiting or constipation, muscle pain, confusion, disorientation, painful red skin, swelling, or skin blisters that occur quickly after sun exposure, are all common complaints. Physical exam may reveal tachycardia, absence of deep tendon reflexes, or scarring of the skin from previous blistering. A skin biopsy may also reveal characteristic changes that would differentiate PCT from other blistering diseases.9 Urine testing is the most routine and common way to help establish a diagnosis of porphyria. Urine samples must be protected from light and refrigerated at all times.5 A 24-hour quantitative urine and/or stool sample is tested for porphyrin and porphobilinogen (PBGD) and delta-aminolevulinic acid (ALA). When ALA is exposed to air during urination, the urine color becomes a dark red wine color. This red-colored urine is a definitive clinical sign to look for during acute attacks. A urine result with an elevated PBGD of two to five times above normal is considered diagnostic for an acute attack of porphyria.5 Other diagnoses must be considered if the urine result is absent of elevated PBGD. 4 The Nurse Practitioner
Molecular analysis is the “gold standard” for diagnosis, being 100% sensitive and specific.5 DNA analysis can be done while having an acute attack or when no symptoms are present.10 DNA testing also sets the stage for any future genetic counseling that may be necessary. Although DNA testing is the most precise way to screen for porphyria, it is rarely done. Mainly, due to the fact that there are over 120 mutations for polyethylene glycol deaminase, plus very few labs in the United States are able to perform the test.5 DNA testing costs approximately $1,850 if there is an acute attack with no previous testing ever done. If only testing for one specific gene mutation, DNA testing can be done for about $850.10 An erythrocyte porphobilinogen deaminase blood test may be performed to determine if someone is at risk for porphyria, to detect a latent-phase intermittent porphyria, or to confirm a diagnosis.5 Any result greater than two times the normal is considered diagnostic. Normal values for women are between 5.3 and 9.2 nmol/L and for men 3.4 and 8.5 nmol/L.5 It should be noted that ethyl alcohol and specific medications can falsely increase or decrease serum levels, such as aminosalicylic acid, barbiturates, oral contraceptives, chloral hydrate, chlorpropamide, griseofulvin, morphine, phenazopyridine, procaine, and sulfonamides.11 If serum testing is done between attacks, the levels are expected to be normal; thus, diagnosis is made by clinical findings and a physical exam.5 ■ Treatment and management Treatment options depend on the type of porphyria that is being treated. Treatments include lifestyle changes to help manage and prevent precipitants that may cause an acute attack. In mild attacks (mild pain, no vomiting, no paralysis, no hyponatremia), a high-carbohydrate diet and supportive measures may be used for up to 48 hours.12 Hemin for injection (Panhematin) is used as heme therapy and is the only heme commercially available in the United States.10 Heme works by decreasing porphyrin production through negative feedback by suppressing the ALA synthesis.5 Clinical improvement is seen in most patients within 2 to 4 days of receiving heme. It is given as an I.V. infusion over 15 minutes. When administering heme, it is important to monitor creatinine and ammonia levels due to possible anuria and nitrogen retention.5 INR should be monitored for any patient receiving anticoagulation therapy and heme, as prolonged clotting time has been noted in these patients.5 Carbohydrate loading was the standard treatment for an acute attack prior to the availability of I.V. heme.12 I.V. glucose loading (at least 3 L of 10% glucose daily) should be used only for mild attacks (pain controlled with little or no opioid
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Porphyria: Pathophysiology, diagnosis, and treatment
analgesics, and without hyponatremia, motor weakness, and so on) or while waiting for Panhematin to become available.10 The exact mechanism in which I.V. glucose helps is not known, although it is suspected to work in the same way that heme works.5 Approximately 35% of patients experiencing an acute porphyria attack will have hyponatremia. This can be the result of dehydration related to excessive vomiting, and rarely, a sign that porphyria has caused kidney damage.8 A 0.9% sodium chloride I.V. infusion is administered for this reason. Pain management during an acute porphyria attack is managed with the use of phenothiazines, specifically for patients with abdominal pain. The exact reason this class of drugs works best is unclear, although it is speculated that it somehow works on the autonomic system. Patients that are diagnosed with acute type porphyria and who have a chronic elevation in liver enzymes should be screened periodically for alpha-fetoprotein. These patients are at increased risk for developing hepatocarcinoma. Nonacute porphyria treatments focus on reducing the amount of porphyrins in the body in an effort to prevent symptoms from occurring. Phlebotomy is standard treatment and may be required several times to put nonacute porphyrias into remission. This works by removing a certain amount of blood from the body. Usually 5 to 6 pints of blood must be removed (over a 1- to 2-week time frame). When blood is removed, so is iron; thus, a decrease in iron stores in the body causes a decrease in porphyrins.8 Serum ferritin and plasma porphyrins are measured following phlebotomy. A response is indicted, and phlebotomies are stopped with a fall in ferritin to approximately 20 ng/mL.10 Medications may also help to treat nonacute porphyria. Malaria drugs (hydroxychloroquine [Plaquenil] and chloroquine [Aralen]) are typically used.9 These drugs treat nonacute cutaneous porphyria by absorbing excess porphyrins and helping the body remove them faster. It should be noted that the use of malaria drugs for the treatment of porphyria is currently not an FDA-approved indication for these medications. In addition, these medications are only used in patients that are unable to tolerate phlebotomy.8 Beta—carotene or other carotenoids (such as canthaxanthin) taken daily are also used in some patients for long-term management. The body converts beta-carotene to vitamin A, which may increase the skin’s tolerance to sunlight exposure.8 ■ Prognosis The diagnosis of porphyria is lifelong, and symptoms are intermittent. Acute porphyria can be life threatening, and acute, intermittent porphyria is considered the most 5 The Nurse Practitioner
severe.13-16 Approximately two-thirds of patients diagnosed with porphyria state they have a family history of the disease.5 It is recommended that screening of siblings and family members be done. Obtaining a history, including a detailed family history, is essential. Performing a proper assessment for porphyria is extremely difficult. Most people will have no signs or symptoms unless having an acute attack. Even if an acute attack does happen, it mimics multiple, more common conditions, and porphyria is not commonly considered. ■ Patient education Patients should be instructed to avoid known triggers that may precipitate an acute attack. These include illicit drugs, smoking, alcohol, fasting/dieting, sunlight exposure, and stress.8 Additional potential triggers include medications, changes in female hormones, and infections.13 Patients are advised to wear a medical-alert bracelet in case of future attacks.5 Receiving heme on a weekly or biweekly basis has been shown to decrease the number of acute porphyria attacks. Consulting with a dietitian is also recommended to help maintain ideal body weight as well as a diet that is well balanced and consists of 60% to 70% carbohydrates. Iron deficiency should be evaluated and treated if present due to hepatic heme synthesis impairment.5 Finally, these patients should be given information about support groups available through the American Porphyria Foundation. ■ Implications for practice Porphyria is a life-long inherited disease, and no cure currently exists. The symptoms and treatments vary depending on clinical presentation and which gene mutation is present. The goal for patients is to focus on preventing acute attacks and managing signs and symptoms if or when they appear. Although porphyria is a rare and complicated disease, and it needs to be considered as a differential diagnosis when pieces of the puzzle are not fitting together. Symptoms such as abdominal pain, cramping, light sensitivity, rashes, blistering on the skin, and nervous system problems are very similar to a variety of common complaints. Porphyria can be easily missed. As nurse practitioners, obtaining a thorough and detailed history is essential to discovering a porphyria diagnosis. REFERENCES 1. Sassa S. Modern diagnosis and management of the porphyrias. Br J Haematol. 2006;135(3):281-292. 2. Puy H, Gouya L, Deybach JC. Porphyrias. Lancet. 2010;375(9718):924-937. 3. Poblete-Gutiérrez P, Wiederholt T, Merk HF, Frank J. The porphyrias: clinical presentation, diagnosis and treatment. Eur J Dermatol. 2006;16(3):230-240. 4. Dogra S, Jindal R. Cutaneous manifestations of common liver diseases. J Clin Exp Hepatol. 2011;1(3):177-184.
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Porphyria: Pathophysiology, diagnosis, and treatment
5. Palmer KM. Abdominal pain due to acute intermittent porphyria: when is the sound of hoof-beats not horses, but zebras? A case report. Dimens Crit Care Nurs. 2006;25(3):103-109. 6. Hift RJ, Thunell S, Brun A. Drugs in porphyria: from observation to a modern algorithm-based system for the prediction of porphyrogenicity. Pharmacol Ther. 2011;132(2):158-169. 7. Fields JM, Dean AJ. Systemic causes of abdominal pain. Emerg Med Clin North Am. 2011;29(2):195-210. 8. Mayo Clinic. Porphyria. http://www.mayoclinic.org/diseases-conditions/ porphyria/basics/definition/CON-20028849. 9. DermNet New Zealand. Porphyria cutanea tarda. As cited 1-23-2014. http:// www.dermnetnz.org/systemic/porphyria-cutanea-tarda.html. 10. American Porphyria Foundation. Testing for Porphyria and treatment options.h ttp://www.porphyriafoundation.com/about-porphyria/types-ofporphyria/PCT. 11. The New York Times. Porphyrins–urine. http://health.nytimes.com/health/ guides/test/pbg/overview.html. 12. Stein P, Badminton M, Barth J, Rees D, Stewart MF. Best practice guidelines on clinical management of acute attacks of porphyria and their complications. Ann Clin Biochem. 2013;50(Pt 3):217-223.
6 The Nurse Practitioner
13. González Estrada A, García-Morillo S, Gómez Morales L, Stiefel GarcíaJunco P. Chronic elevation of liver enzymes in acute intermittent porphyria initially misdiagnosed as autoimmune hepatitis. Int J Hepatol. 2011;2011: 392049. 14. Cappellini MD, Brancaleoni V, Graziadei G, Tavazzi D, Di Pierro E. Porphyrias at a glance: diagnosis and treatment. Intern Emerg Med. 2010;5(suppl 1):S73-S80. 15. Gross U, Hoffmann GF, Doss MO. Erythropoietic and hepatic porphyrias. J Inherit Metab Dis. 2000;23(7):641-661. 16. Pietrangelo A. The porphyrias: pathophysiology. Intern Emerg Med. 2010;5(suppl 1):S65-S71. Tracy Gasson is a registered nurse and nurse clinician at Mercy Health Partners, Bone Marrow Transplant Program, Cincinnati, Ohio. Kathleen Klein is a staff nurse at CVICU Good Samaritan Hospital, Cincinnati, Ohio. The authors have disclosed no financial relationships related to this article. DOI-10.1097/01.NPR.0000469257.36238.36
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
By Tracy Gasson, MSN, APRN, OCN and Kathleen Klein, MSN, APRN, CCRN
patient complains of abdominal pain, which has gotten progressively worse over the past week. While obtaining the patient’s history, the patient mentions a previous diagnosis of porphyria. What does this mean?
A
■ Pathophysiology Porphyrias are a group of inherited metabolic disorders that involve the heme biosynthetic pathway. Most of these conditions are inherited; however, some are believed to be acquired through environmental exposures. In addition, not all gene carriers of inherited porphyrias develop clinical disease, and there is significant interplay between the primary gene defect and the secondary acquired or environmental factors.1 The metabolic conditions that arise are a result of specific alterations in one of the eight enzymes utilized in heme synthesis. Most of the heme synthesized in the body occurs in the erythropoietic cell with a small amount produced in the parenchymal cells of the liver.2 As a result of the alteration in enzyme function, there is an accumulation and measurable excretion of porphyrins and/ or porphyrin precursors.3
■ Classification by clinical manifestations There are various ways to classify the porphyrias. Porphyrias may be classified according to the location of the enzyme deficiency: erythropoietic or hepatic forms. In addition, porphyria may be divided into cutaneous or noncutaneous types. Finally, porphyria may be classified as either acute or nonacute depending on whether the patient presents with an acute life-threatening attack. For the purposes of this article, the classifications of porphyria will be discussed as nonacute and acute because the patient will present to a practitioner with either nonacute or acute symptoms (see Classification of the acute and nonacute porphyrias). ■ Nonacute porphyrias The nonacute porphyrias are an inherited group of disorders that manifest as dermatologic conditions. Symptoms result from increased photosensitivity on areas of the body that have been exposed to UV light due to porphyrin deposition in the skin.3 Nonacute porphyrias include porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP), congenital erythropoietic porphyria (CEP), and hepatoerythropoietic porphyria (HEP).
Keywords: heme, heredity, inherited metabolic disorders, porphyria
1 The Nurse Practitioner
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Porphyria: Pathophysiology, diagnosis, and treatment
PCT is the most frequent type of porphyria worldwide. It is an autosomal-dominant disorder and is diagnosed based on the cutaneous manifestations. This condition is characterized by blistering on sun-exposed areas, which lead to scarring. Areas of previous blistering appear atrophic. There is also hyperpigmentation over sun-exposed areas and facial hypertrichosis.4 Various factors have been implicated in precipitation of PCT, including alcohol consumption, estrogens, hemodialysis, factors increasing hepatic iron concentration, and viral infections (for example, hepatitis C and HIV). EPP is also an autosomal-dominant disorder involving the eighth enzyme in heme biosynthesis. It is characterized by cutaneous photosensitivity that may develop in childhood. Clinical manifestations include seasonal photosensitivity
with erythema within minutes of sun exposure and chronic lesions, such as thickening of skin and wax-like scarring on nose, cheeks, and dorsal hands.3 This condition is also associated with liver dysfunction caused by accumulation of protoporphyrin in hepatocytes and bile canaliculi, resulting in cell damage, cholestasis, and cytolysis.2 In addition, these patients are at an increased risk for developing liver failure because of the accumulation of protoporphyrin in the hepatobiliary structures.3 CEP or Günther disease is an extremely rare autosomal recessive condition resulting from a decreased activity of the fourth enzyme in heme biosynthesis. CEP manifests in early infancy as increased friability and blistering of sun-exposed skin.1 There is often ocular involvement, such as corneal scarring and ulcerative keratitis, as
Classification of the acute and nonacute porphyrias3 Classification
Gene name and locus
Mode of inheritance
Important aspects
Acute intermittent porphyria
Porphobilinogen deaminase; 11q24.1-q24.2
Autosomal dominant
Most common acute porphyria in the world; no skin symptoms
Variegate porphyria
Protoporphyrinogen oxidase; 1q22-23
Autosomal dominant
Founder mutations identified in South Africa and Chile; skin symptoms can occur
Hereditary coproporphyria
Coproporphyrinogen oxidase; 3q12
Autosomal dominant
Rare; skin symptoms can occur
ALA dehydratase deficiency porphyria
ALA dehydratase; 9q34
Autosomal recessive
Very rare (< 10 cases in the world reported)
Porphyria cutanea tarda
Uroporphyrinogen decarboxylase; 1p34
Autosomal dominant
Most frequent type of porphyria worldwide; hereditary and acquired variant exist
Erythropoietic protoporphyria
Ferrochelatase; 18q21.3
Autosomal dominant
Severe liver disease can occur in approximately 5% of cases; recessive inheritance has been reported
Congenital erythropoietic porphyria
Uroporphyrinogen III synthase; 10q25.3-q26.3
Autosomal recessive
Very severe clinical course; mutilations; hemolytic anemia; porphyrin deposition in bones and teeth
Hepatoerythropoietic porphyria
Uroporphyrinogen decarboxylase; 1p34
Autosomal recessive
Homozygous variant of porphyria cutanea tarda; highly increased photosensitivity
Acute
Nonacute
2 The Nurse Practitioner
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Porphyria: Pathophysiology, diagnosis, and treatment
well as erythrodontia, osteodystrophia, and hypercellular bone marrow.2 The most noticeable clinical manifestation is the pink to red-brown urine, which is a result of the increased urinary porphyrins. HEP is an extremely rare and recessive form of porphyria. HEP is caused by a homozygous or compound heterozygous deficiency of uroporphyrinogen decarboxylase.2 Clinically, this disorder manifests in infancy or early childhood. The most noticeable sign is dark urine. Subsequently, severe cutaneous photosensitivity develops that includes blistering, pruritus, hypertrichosis, hyperpigmentation, and scleroderma-like scarring.3 ■ Acute porphyrias The acute porphyrias are a predominately autosomaldominant group of disorders. Acute porphyrias comprise acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and delta-aminolevulinic acid (ALA) dehydratase deficiency porphyria (ADP). Acute attacks can occur with all the acute porphyrias. Patients with these disorders often present with a wide range of clinical symptoms, making it very difficult to diagnose. Patients may present with long-lasting colicky abdominal pain, nausea and vomiting, diarrhea, tachycardia, hypertension, seizures, muscle weakness, paraplegia/quadriplegia, as well as a variety of other neurologic and psychiatric signs.3 These incidents can be life threatening. AIP is an autosomal-dominant inherited disorder involving a deficiency of the third enzyme in heme biosynthesis, porphobilinogen deaminase (PBGD). This is the most important acute hepatic porphyria, both in its incidence and clinical severity.1 It is more common in northern European countries, affecting about 1 in 75,000 people with the incidence even higher in Sweden (1 in 1,000). 2 The prevalence of AIP in the United States is thought to be 5 to 10 per 100,000.1 AIP is more common in women than men and usually manifests after puberty. Acute attacks are rare after menopause, and peak occurrence is seen in the third decade.2 An acute attack of AIP may start off with vague symptoms of anxiety, restlessness, insomnia, or abdominal pain and may occur over a period of hours or days. The majority of AIP clinical manifestations, including abdominal pain and other neurovisceral and circulatory disturbances, are due to effects on the nervous system.1 Abdominal pain is usually severe, steady, and poorly localized.1 Other symptoms, such as nausea, vomiting, tachycardia, and changes in mentation/muscle weakness may also be seen in these 3 The Nurse Practitioner
patients. Patients may become dehydrated and experience electrolyte disturbances—especially hyponatremia. If untreated, the muscle weakness can progress to quadriplegia, with respiratory and bulbar paralysis and death.2 The mortality of undiagnosed patients with AIP has been approximated to be between 20% and 25% within the first 5 years of the first attack.5 Not everyone with this inherited deficiency of the enzyme will develop clinical manifestations of acute intermittent porphyria. The great majority (approximately 90%) of individuals who inherit a deficiency of PBGD never develop porphyric symptoms.1 However, for those that develop symptoms, many precipitating factors may be to blame. There is considerable evidence that endocrine factors and steroid hormones play an important role in an acute attack of AIP.1 One study on women of Swedish origin utilizing a combination estradiol and progesterone oral contraceptive showed a 66% occurrence rate of AIP before the age of 21 years.5 Other factors associated with AIP may be drugs, nutritional factors, smoking, alcohol, infections, surgery, and stress. The first reported case of a drug-induced porphyria was in 1889 on a woman who had received a sulfonyl, a medication used for its hypnotic properties.6 Drugs are among the most important factors that precipitate acute attacks of acute porphyria, with barbiturates and sulfonamide antibiotics being most common.1 However, any drug that activates the cytochrome P450 enzyme system should be used with caution in these patients. It is important to remember that all of the heme pathway intermediates are potentially toxic.1 Therefore, any condition that triggers this process is potentially toxic to the individual with a heme pathway enzyme deficiency. Nutritional factors—especially a reduced caloric intake, such as fasting or dieting—may precipitate an acute AIP attack because these conditions may induce heme oxygenase-1 (HO-1) activity.7 HO-1 activity can lead to depletion of regulatory hepatic heme pools, which may lead to aminolevulinic acid synthase (an enzyme in heme production) induction.1 The hydrocarbons generated from smoking are known to induce the hepatic cytochrome P450 enzymes and heme synthesis; therefore, smoking should be avoided. Alcohol ingestion has also been associated with an acute AIP attack. Finally, infections, surgery, and psychological stress are known to increase hepatic HO-1 activity and therefore can precipitate an acute AIP episode.1 VP is an autosomal dominant, inherited porphyria that involves the seventh enzyme in the heme biosynthesis
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Porphyria: Pathophysiology, diagnosis, and treatment
pathway. This disease is termed variegate because it can present itself either with neurologic manifestations, cutaneous photosensitivity, or both.1 It is difficult to differentiate cutaneous clinical findings of VP with those of PCT and HCP. Likewise, an acute attack of VP is very similar to AIP, although these attacks are generally milder than in AIP, and recurrent attacks are less common.1 HCP is a very rare, autosomal dominant, inherited porphyria involving a deficiency in the sixth enzyme in heme biosynthesis. HCP has identical clinical symptoms as AIP, except for its cutaneous photosensitivity, which is entirely absent in AIP.1 Therefore, triggers for AIP (such as certain drugs, hormones, alcohol, and dieting) should also be avoided in patients with HCP. The risk of hepatocellular carcinoma may be increased in this porphyria, as in AIP and VP.1 ADP is the rarest form of porphyria and is an autosomal recessive disorder. The disease is also known as plumboporphyria or Doss porphyria and can manifest early in childhood as well as in adulthood. 3 Clinically, ADP closely resembles AIP. ■ Diagnostic testing Lab testing is required for a definitive diagnosis and to determine which type of disease the patient has once a suspicion of porphyria is determined.8 A thorough medical history and complete physical exam, followed by urine and blood samples being collected, should begin the assessment. Patients complaining of red-colored urine, severe abdominal pain, which may or may not be accompanied by vomiting or constipation, muscle pain, confusion, disorientation, painful red skin, swelling, or skin blisters that occur quickly after sun exposure, are all common complaints. Physical exam may reveal tachycardia, absence of deep tendon reflexes, or scarring of the skin from previous blistering. A skin biopsy may also reveal characteristic changes that would differentiate PCT from other blistering diseases.9 Urine testing is the most routine and common way to help establish a diagnosis of porphyria. Urine samples must be protected from light and refrigerated at all times.5 A 24-hour quantitative urine and/or stool sample is tested for porphyrin and porphobilinogen (PBGD) and delta-aminolevulinic acid (ALA). When ALA is exposed to air during urination, the urine color becomes a dark red wine color. This red-colored urine is a definitive clinical sign to look for during acute attacks. A urine result with an elevated PBGD of two to five times above normal is considered diagnostic for an acute attack of porphyria.5 Other diagnoses must be considered if the urine result is absent of elevated PBGD. 4 The Nurse Practitioner
Molecular analysis is the “gold standard” for diagnosis, being 100% sensitive and specific.5 DNA analysis can be done while having an acute attack or when no symptoms are present.10 DNA testing also sets the stage for any future genetic counseling that may be necessary. Although DNA testing is the most precise way to screen for porphyria, it is rarely done. Mainly, due to the fact that there are over 120 mutations for polyethylene glycol deaminase, plus very few labs in the United States are able to perform the test.5 DNA testing costs approximately $1,850 if there is an acute attack with no previous testing ever done. If only testing for one specific gene mutation, DNA testing can be done for about $850.10 An erythrocyte porphobilinogen deaminase blood test may be performed to determine if someone is at risk for porphyria, to detect a latent-phase intermittent porphyria, or to confirm a diagnosis.5 Any result greater than two times the normal is considered diagnostic. Normal values for women are between 5.3 and 9.2 nmol/L and for men 3.4 and 8.5 nmol/L.5 It should be noted that ethyl alcohol and specific medications can falsely increase or decrease serum levels, such as aminosalicylic acid, barbiturates, oral contraceptives, chloral hydrate, chlorpropamide, griseofulvin, morphine, phenazopyridine, procaine, and sulfonamides.11 If serum testing is done between attacks, the levels are expected to be normal; thus, diagnosis is made by clinical findings and a physical exam.5 ■ Treatment and management Treatment options depend on the type of porphyria that is being treated. Treatments include lifestyle changes to help manage and prevent precipitants that may cause an acute attack. In mild attacks (mild pain, no vomiting, no paralysis, no hyponatremia), a high-carbohydrate diet and supportive measures may be used for up to 48 hours.12 Hemin for injection (Panhematin) is used as heme therapy and is the only heme commercially available in the United States.10 Heme works by decreasing porphyrin production through negative feedback by suppressing the ALA synthesis.5 Clinical improvement is seen in most patients within 2 to 4 days of receiving heme. It is given as an I.V. infusion over 15 minutes. When administering heme, it is important to monitor creatinine and ammonia levels due to possible anuria and nitrogen retention.5 INR should be monitored for any patient receiving anticoagulation therapy and heme, as prolonged clotting time has been noted in these patients.5 Carbohydrate loading was the standard treatment for an acute attack prior to the availability of I.V. heme.12 I.V. glucose loading (at least 3 L of 10% glucose daily) should be used only for mild attacks (pain controlled with little or no opioid
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Porphyria: Pathophysiology, diagnosis, and treatment
analgesics, and without hyponatremia, motor weakness, and so on) or while waiting for Panhematin to become available.10 The exact mechanism in which I.V. glucose helps is not known, although it is suspected to work in the same way that heme works.5 Approximately 35% of patients experiencing an acute porphyria attack will have hyponatremia. This can be the result of dehydration related to excessive vomiting, and rarely, a sign that porphyria has caused kidney damage.8 A 0.9% sodium chloride I.V. infusion is administered for this reason. Pain management during an acute porphyria attack is managed with the use of phenothiazines, specifically for patients with abdominal pain. The exact reason this class of drugs works best is unclear, although it is speculated that it somehow works on the autonomic system. Patients that are diagnosed with acute type porphyria and who have a chronic elevation in liver enzymes should be screened periodically for alpha-fetoprotein. These patients are at increased risk for developing hepatocarcinoma. Nonacute porphyria treatments focus on reducing the amount of porphyrins in the body in an effort to prevent symptoms from occurring. Phlebotomy is standard treatment and may be required several times to put nonacute porphyrias into remission. This works by removing a certain amount of blood from the body. Usually 5 to 6 pints of blood must be removed (over a 1- to 2-week time frame). When blood is removed, so is iron; thus, a decrease in iron stores in the body causes a decrease in porphyrins.8 Serum ferritin and plasma porphyrins are measured following phlebotomy. A response is indicted, and phlebotomies are stopped with a fall in ferritin to approximately 20 ng/mL.10 Medications may also help to treat nonacute porphyria. Malaria drugs (hydroxychloroquine [Plaquenil] and chloroquine [Aralen]) are typically used.9 These drugs treat nonacute cutaneous porphyria by absorbing excess porphyrins and helping the body remove them faster. It should be noted that the use of malaria drugs for the treatment of porphyria is currently not an FDA-approved indication for these medications. In addition, these medications are only used in patients that are unable to tolerate phlebotomy.8 Beta—carotene or other carotenoids (such as canthaxanthin) taken daily are also used in some patients for long-term management. The body converts beta-carotene to vitamin A, which may increase the skin’s tolerance to sunlight exposure.8 ■ Prognosis The diagnosis of porphyria is lifelong, and symptoms are intermittent. Acute porphyria can be life threatening, and acute, intermittent porphyria is considered the most 5 The Nurse Practitioner
severe.13-16 Approximately two-thirds of patients diagnosed with porphyria state they have a family history of the disease.5 It is recommended that screening of siblings and family members be done. Obtaining a history, including a detailed family history, is essential. Performing a proper assessment for porphyria is extremely difficult. Most people will have no signs or symptoms unless having an acute attack. Even if an acute attack does happen, it mimics multiple, more common conditions, and porphyria is not commonly considered. ■ Patient education Patients should be instructed to avoid known triggers that may precipitate an acute attack. These include illicit drugs, smoking, alcohol, fasting/dieting, sunlight exposure, and stress.8 Additional potential triggers include medications, changes in female hormones, and infections.13 Patients are advised to wear a medical-alert bracelet in case of future attacks.5 Receiving heme on a weekly or biweekly basis has been shown to decrease the number of acute porphyria attacks. Consulting with a dietitian is also recommended to help maintain ideal body weight as well as a diet that is well balanced and consists of 60% to 70% carbohydrates. Iron deficiency should be evaluated and treated if present due to hepatic heme synthesis impairment.5 Finally, these patients should be given information about support groups available through the American Porphyria Foundation. ■ Implications for practice Porphyria is a life-long inherited disease, and no cure currently exists. The symptoms and treatments vary depending on clinical presentation and which gene mutation is present. The goal for patients is to focus on preventing acute attacks and managing signs and symptoms if or when they appear. Although porphyria is a rare and complicated disease, and it needs to be considered as a differential diagnosis when pieces of the puzzle are not fitting together. Symptoms such as abdominal pain, cramping, light sensitivity, rashes, blistering on the skin, and nervous system problems are very similar to a variety of common complaints. Porphyria can be easily missed. As nurse practitioners, obtaining a thorough and detailed history is essential to discovering a porphyria diagnosis. REFERENCES 1. Sassa S. Modern diagnosis and management of the porphyrias. Br J Haematol. 2006;135(3):281-292. 2. Puy H, Gouya L, Deybach JC. Porphyrias. Lancet. 2010;375(9718):924-937. 3. Poblete-Gutiérrez P, Wiederholt T, Merk HF, Frank J. The porphyrias: clinical presentation, diagnosis and treatment. Eur J Dermatol. 2006;16(3):230-240. 4. Dogra S, Jindal R. Cutaneous manifestations of common liver diseases. J Clin Exp Hepatol. 2011;1(3):177-184.
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Porphyria: Pathophysiology, diagnosis, and treatment
5. Palmer KM. Abdominal pain due to acute intermittent porphyria: when is the sound of hoof-beats not horses, but zebras? A case report. Dimens Crit Care Nurs. 2006;25(3):103-109. 6. Hift RJ, Thunell S, Brun A. Drugs in porphyria: from observation to a modern algorithm-based system for the prediction of porphyrogenicity. Pharmacol Ther. 2011;132(2):158-169. 7. Fields JM, Dean AJ. Systemic causes of abdominal pain. Emerg Med Clin North Am. 2011;29(2):195-210. 8. Mayo Clinic. Porphyria. http://www.mayoclinic.org/diseases-conditions/ porphyria/basics/definition/CON-20028849. 9. DermNet New Zealand. Porphyria cutanea tarda. As cited 1-23-2014. http:// www.dermnetnz.org/systemic/porphyria-cutanea-tarda.html. 10. American Porphyria Foundation. Testing for Porphyria and treatment options.h ttp://www.porphyriafoundation.com/about-porphyria/types-ofporphyria/PCT. 11. The New York Times. Porphyrins–urine. http://health.nytimes.com/health/ guides/test/pbg/overview.html. 12. Stein P, Badminton M, Barth J, Rees D, Stewart MF. Best practice guidelines on clinical management of acute attacks of porphyria and their complications. Ann Clin Biochem. 2013;50(Pt 3):217-223.
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13. González Estrada A, García-Morillo S, Gómez Morales L, Stiefel GarcíaJunco P. Chronic elevation of liver enzymes in acute intermittent porphyria initially misdiagnosed as autoimmune hepatitis. Int J Hepatol. 2011;2011: 392049. 14. Cappellini MD, Brancaleoni V, Graziadei G, Tavazzi D, Di Pierro E. Porphyrias at a glance: diagnosis and treatment. Intern Emerg Med. 2010;5(suppl 1):S73-S80. 15. Gross U, Hoffmann GF, Doss MO. Erythropoietic and hepatic porphyrias. J Inherit Metab Dis. 2000;23(7):641-661. 16. Pietrangelo A. The porphyrias: pathophysiology. Intern Emerg Med. 2010;5(suppl 1):S65-S71. Tracy Gasson is a registered nurse and nurse clinician at Mercy Health Partners, Bone Marrow Transplant Program, Cincinnati, Ohio. Kathleen Klein is a staff nurse at CVICU Good Samaritan Hospital, Cincinnati, Ohio. The authors have disclosed no financial relationships related to this article. DOI-10.1097/01.NPR.0000469257.36238.36
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
