The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–8, 2015 Copyright Ó 2015 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter

http://dx.doi.org/10.1016/j.jemermed.2015.04.034

Best Clinical Practice ACUTE PORPHYRIAS Siddesh Besur, MD,* Paul Schmeltzer, MD,†‡ and Herbert L. Bonkovsky, MD, FACP, FACG§k *Advanced Hepatology and Transplantation, †Department of Medicine, Carolinas HealthCare System, Charlotte, North Carolina, ‡Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, §Department of Medicine, University of Connecticut, Farmington, Connecticut, and kDepartment of Medicine, University of North Carolina, Chapel Hill, North Carolina Reprint Address: Herbert L. Bonkovsky, MD, FACP, FACG, Medical Center Blvd, Winston-Salem, NC 27103.

, Abstract—Background: Porphyrias are a group of eight metabolic disorders characterized by defects in heme biosynthesis. Porphyrias are classified into two major categories: 1) the acute or inducible porphyrias and 2) the chronic cutaneous porphyrias. The acute hepatic porphyrias are further classified into acute intermittent porphyria (AIP), hereditary coproporphyria, variegate porphyria, and porphyria due to severe deficiency of deltaaminolevulinic acid (ALA) dehydratase (ALADP). Discussion: AIP is the most common, and ALADP is the least common acute porphyria. The clinical presentations of acute porphyrias are nonspecific. There are no pathognomonic signs or symptoms. The most frequent presenting symptom is abdominal pain, but pain in the chest, back, or lower extremities may also occur. Hyponatremia is the most common electrolyte abnormality during acute attacks, and hypomagnesemia is also common. Both are risk factors for development of seizures, which occur in  20–30% of acute attacks. Conclusion: Once suspected, the diagnosis of porphyria can be rapidly established by checking random urinary porphobilinogen. Initial management of acute porphyria includes discontinuation of all potentially harmful drugs and management of symptoms. Acute attacks should be treated emergently with intravenous heme and glucose to avoid considerable morbidity and mortality. Acute attacks last a few days, and the majority of patients are asymptomatic between attacks. Prognosis is good if the condition is recognized early and treated aggressively. Ó 2015 Elsevier Inc.

INTRODUCTION Porphyrias are a group of eight metabolic disorders, mainly inherited inborn errors of metabolism characterized by defects in heme biosynthesis. Porphyrias have varied presentation, with a broad spectrum of clinical manifestations that may be confused with other medical conditions. Porphyrias are classified into two major categories: 1) the acute or inducible porphyrias, and 2) the chronic cutaneous porphyrias (1). There are two main ways of classifying the porphyrias; one is based upon clinical manifestations of the disease, and the other on the principal site of metabolic defect (Table 1). The discussion herein will be primarily limited to the evaluation and management of acute porphyrias, which are the major forms likely to present to emergency departments (EDs) and to be seen by emergency physicians. The acute hepatic porphyrias are four in number: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and porphyria due to severe deficiency of delta-aminolevulinic acid (ALA) dehydratase (ALADP) (1). Fortunately, most of the patients with acute porphyria, with possible exception of the very rare recessive form of ALADP, are asymptomatic most of the time. Acute porphyria symptoms rarely, if ever, occur prior to puberty, and most patients remain asymptomatic throughout their lives.

, Keywords—acute porphyria; abdominal pain; haem metabolism; Panhematin; autosomal dominant

RECEIVED: 8 September 2014; FINAL SUBMISSION RECEIVED: 31 March 2015; ACCEPTED: 18 April 2015 1

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Table 1. Usual Schemes for Classification of the Porphyrias Porphyrias According to the clinical manifestations of disease Acute or inducible porphyrias ALADP AIP HCP VP Cutaneous chronic porphyrias CEP HEP PCT (Type I) PCT (Type II) EPP XLPP According to the principal site of metabolic defect Acute hepatic porphyrias ALADP AIP HCP VP Chronic hepatic porphyrias HEP PCT (Type I) PCT (Type II) Erythropoietic porphyrias CEP EPP

Inheritance

Gene Affected

Chromosomal Location

AR AD AD AD

ALAD [PBGS] PBGD [HMBS] CPOX PPOX

9q34 11q23.3 3q12 1q22

Very rare severe disease in infancy Most severe form May also have cutaneous feature May also have cutaneous feature

AR

URO3S

10q26.1–q26.2

AR

UROD

1p34.1

Acquired AR AR X-linked

None known UROD FECH ALAS 1

None known 1p34.1 18q21.31 Xp11.21

Rare, usually manifests in infancy/ childhood Rare, usually manifests in infancy/ childhood Disease of adults Requires additional defects Common: onset in infancy Gain of function mutations

AR AD AD AD

ALAD [PBGS] PBGD [HMBS] CPOX PPOX

9q34 11q23.3 3q12 1q22

Very rare severe disease in infancy Most severe form May also have cutaneous features May also have cutaneous features

AR Acquired AR

UROD None known UROD

1p34.1 None known 1p34.1

AR

URO3S

10q26.1–q26.2

AR

UROD

18q21.31

Comments

Usually manifests in infancy Disease of adults Requires additional defects Rare, usually manifests in infancy/ childhood Common: onset in infancy

AD = autosomal dominant; AIP = acute intermittent porphyria; ALAD = ALA dehydratase; ALADP = ALA dehydratase deficiency porphyria; ALAS = ALA synthase; AR = autosomal recessive; CEP = congenital erythropoietic porphyria; CPOX = coproporphyrinogen oxidase; EPP = erythropoietic protoporphyria; FECH = ferrochelatase; HCP = hereditary coproporphyria; HEP = hepatoerythropoietic porphyria; HMBS = hydroxymethylbilane synthase; PBGS = porphobilinogen synthase; PBGD = porphobilinogen deaminase; PCT = porphyria cutanea tarda; PPOX = protoporphyrinogen oxidase; UROD = uroporphyrinogen decarboxylase; URO3S = uroporphyrinogen 3 synthase; VP = variegate porphyria; XLPP = X-linked protoporphyria

The term ‘‘acute’’ in acute porphyria is used to signify life-threatening manifestations and not to indicate duration of disease. All acute porphyrias produce similar neurovisceral manifestations regardless of associated enzymatic defects, and hence, should be managed in a similar way. It is important early on to consider the diagnosis and perform the appropriate biochemical and genetic tests to either establish or to exclude diagnosis of acute porphyria. DISCUSSION Heme Biosynthesis Acute porphyria is due to the deficiency of a specific enzyme involved in heme synthesis. The normal pathway of heme synthesis is shown in Figure 1. The first step is condensation of glycine and succinyl CoA to form delta-aminolevulinic acid (ALA), catalyzed by the mitochondrial enzyme ALA synthase, the rate controlling step in heme synthesis. There are

two forms of ALA synthase, the ubiquitous housekeeping form 1 and the erythroid-specific form 2. These two forms are products of separate genes and are under quite different regulation. ALA synthase-1 can be upregulated markedly by transcriptional and posttranscriptional mechanisms, and an ‘‘uncontrolled’’ upregulation of this enzyme in the liver is the biochemical sine qua non of acute porphyric attacks. Upregulation of ALA synthase-1 occurs due to three main known causes: 1. Lipophilic drugs and chemicals interact with nuclear receptors that, in turn, increase activation of drug-response elements in the upstream enhancer of ALA synthase-1 (2). 2. Deficiency of glucose or other gluconeogenic compounds that normally suppress gene expression of ALA synthase (the so-called ‘‘glucose effect’’) (3). 3. Deficiency of heme, the end product of the heme pathway shown in Figure 1, which not only represses transcription of the ALA synthase-1 gene,

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Figure 1. Heme biosynthetic pathway showing the sites of enzyme defects in the porphyrias and the major biochemical abnormalities in biochemically active disease. Only the major increases in the urine, stool, plasma, and erythrocytes (red blood cells [RBCs]) are shown. ALA = delta-aminolevulinic acid; COPRO = coproporphyrin; ISOCOPRO = isocoproporphyrin; PBG = porphobilinogen; PROTO = protophyrin; URO = uroporphyrin; ZN = zinc.

but also blocks translocation of the enzyme into mitochondria and decreases the stability of its mRNA and enhances breakdown of the inactive mitochondrial enzyme by Lon protease (4–6). Pathogenesis of Acute Attacks The enzyme deficiencies in AIP, HC, and VP are only partial (50% of the normal), as opposed to ALA dehydratase deficiency (< 5% of the normal). The ALA dehydratase enzyme normally has high activity in the heme biosynthetic pathway. Hence, a more severe deficiency in inactive enzyme is necessary to cause clinical manifestations. These enzymatic defects predispose affected individuals to be susceptible to acute attacks of porphyria. Some of the common triggers for acute attacks include prolonged severe fasting or dieting, alcohol, drugs (barbiturates, hydantoins, rifampin, progestins, endogenous steroid hormones, especially

progesterone), and other intercurrent illnesses or stress (Table 2). More extensive lists of drugs that may trigger acute attacks are available at the following Web sites: American Porphyria Foundation (www. porphyriafoundation.com/drug-database), the European Porphyria Initiative Web site (www.porphyriaeurope. org), and the Porphyria South Africa Web site (www. porphyria.uct.ac.za). These trigger factors cause increased demand for hepatic heme or reduce heme concentration, resulting in increased synthesis of ALA synthase (shown in Figure 1), causing accumulation of proximal intermediate products. The exact mechanism for the neurologic damage in acute porphyrias is not completely understood. However, the preponderance of evidence favors the idea that ALA (or perhaps, a metabolite of ALA) is the chief neurotoxin (6,7). The principal group affected is women in their child-bearing years (20–45 years of age). The attacks are often cyclical, linked to

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Table 2. Factors Known to Trigger or Exacerbate Acute Porphyric Attacks Porphyrias Drugs and chemicals, especially: Excess alcohol Barbiturates Estrogens Hydantoins Progestagens Sulfonamides All drugs that are suicide substrates or potent inducers of cytochrome P450 Dieting; fasting; deficiency of carbohydrate intake (gastric bypass surgery) Exhaustion—emotional or physical Intercurrent acute illnesses Cigarette smoking

menstrual cycles, highlighting the importance of endogenous steroids, especially progesterone, in pathogenesis. However, pregnant women typically do not suffer severe attacks despite increased levels of estrogen and progesterone (8). Rather, acute attacks have more of a tendency to occur in the postpartum period, for still unknown reasons. Epidemiology In most countries, AIP is the most common and ALADP is the least common acute porphyria. All acute porphyrias are autosomal dominant, with the exception of ALADP, which is an autosomal recessive disorder (Table 1) (9,10). Clinical Features Abdominal pain and tachycardia are the most common presenting symptoms and signs in acute porphyria. Abdominal pain is usually colicky, affecting the lower abdomen and lasting hours to days. It typically comes on gradually and escalates in severity. Other frequent symptoms, signs, and their characteristics are listed in Table 3 (1315). Neurologic manifestations of acute porphyrias are listed in descending order of frequency in Table 3. Other neurological manifestations may include muscle weakness, difficulty swallowing, other bulbar signs, confusion, delirium, and seizures. Generalized weakness may sometimes progress rapidly to quadriparesis and acute respiratory insufficiency, especially if the correct diagnosis is missed and patients are treated with barbiturates or hydantoins (e.g., for treatment of seizures). Many patients with acute porphyric attacks, when asked, will describe passing reddish to brownish urine. The urine may darken considerably if exposed to air, light, and warmth. Such findings should alert astute clinicians to think of the diagnosis.

Hyponatremia is a common electrolyte abnormality that occurs during acute attacks. Although the hyponatremia, which may be severe (serum Na < 125 mEq/L), has been ascribed to syndrome of inappropriate antidiuretic hormone secretion (SIADH), blood volumes have been found to be reduced (16). Therefore, all criteria for SIADH may not be met. Other contributing factors may include vomiting and resuscitation with high-volume dextrose. Skin manifestations do not occur in acute intermittent porphyria, with the exception of patients with end-stage renal disease, who may develop blistering skin lesions (17). Cutaneous manifestations may occur in active hereditary coproporphyria (HCP) or VP due to accumulation of coproporphyrins or harderoporphyrin. Laboratory Evaluation of Acute Porphyrias The clinical presentations of acute porphyrias are nonspecific in the absence of pathognomonic signs or symptoms. Random urinary porphobilinogen (PBG) is the most important rapid test for diagnosis of acute porphyria (part TR52001; PBG test kit, Thermo Scientific, Waltham, MA) (18). The results from this test are usually available in < 10 min. Unfortunately, this test is currently not available in most hospitals or urgent care clinics. In the setting of a positive urinary PBG screening test, the diagnosis of acute porphyria should be confirmed by measuring quantitative ALA, PBG, and total porphyrins from the same urine sample that was used for the initial rapid screening test. In anuric patients, diagnosis of acute porphyria can be established by measuring serum PBG. All patients with true manifestations of AIP will have markedly increased urinary ALA and PBG levels during an attack (up to 25–100 mg of ALA and 50–200 mg PBG per day; normal range 0–4 mg/day). An alternate diagnosis such as HCP, VP, lead poisoning, or hereditary tyrosinemia should be considered if urinary ALA excretion (in mg/g creatinine) exceeds that of PBG. PBG in urine may be converted nonenzymatically to uroporphyrin, and hence, although the defect in AIP lies in hepatic PBG deaminase, there may be increased urinary uro- and coproporphyrin levels. Urine may turn pink or even dark red or black (due to porphyrin or porphobilin formation) after exposure to air and light (16,19–21). The major increases in porphyrins and their precursors that occur in biochemically manifest porphyrias are summarized in Figure 1. The second line of diagnostic evaluation includes testing for plasma and urine fecal porphyrins, and erythrocyte PBG deaminase levels, along with DNA genetic analysis for mutation in the relevant genes. AIP can be differentiated from other porphyrias by

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Table 3. Common Presenting Symptoms and Signs of Acute Porphyria Symptoms and Signs Gastrointestinal Abdominal pain

Frequencies of Symptoms and Signs (%) 85–95

Vomiting

43–88

Constipation

48–84

Diarrhea Neurologic Pain in extremities, back

Paresis Respiratory paralysis

Usually unremitting (for hours or longer) and poorly localized but can be cramping. Neurologic in origin and rarely accompanied by peritoneal signs, fever, or leukocytosis. Nausea and vomiting often accompany abdominal pain. May be accompanied by bladder paresis.

5–12 50–70

42–68 9–20

Mental symptoms

40–58

Convulsions

10–20

Cardiovascular Tachycardia Systemic arterial hypertension

Comment

64–85 36–55

Pain may begin in the chest or back and move to the abdomen. Extremity pain chest, neck, or head indicates involvement of sensory nerves; objective sensory loss reported in 10–40% of cases. May occur early or late during a severe attack. Muscle weakness usually begins proximally rather than distally and more often in the upper than lower extremities. Preceded by progressive peripheral motor neuropathy and paresis. May range from minor behavioral changes to agitation, confusion, hallucinations, and depression. A central neurologic manifestation of porphyria or due to hyponatremia, which often results from syndrome of inappropriate antidiuretic hormone secretion or sodium depletion. May require treatment during acute attacks, and sometimes becomes chronic.

Reprinted with permission from Anderson et al. (11). Adapted from Anderson et al. (12) Annals of Internal Medicine, p.441, by Anderson KE etal, 2005 Mar 15; 142(6):439450.

measuring erythrocyte PBG deaminase activity. However, this alone cannot be relied upon for diagnosis of AIP because various factors like gene mutations (5%) causing selective PBG deaminase deficiencies in liver, with normal levels in erythrocytes or increase in erythrocyte levels due to concomitant hemolytic anemia, may lead to false-negative results. Molecular methods and DNA analysis for gene mutations to identify gene-encoding PBG deaminase is not only helpful in confirming AIP, but also assists in identifying other gene carriers in the family. DNA analysis assists in the diagnosis when a specific mutation within a family or geographic area is already known. Lists of updated mutations are available at the human gene mutation database (http://www.hgmd.cf.ac.uk/ac/index.php). In the United States, genetic testing for all forms of porphyria is available through the laboratory of R.J. Desnick, MD, PhD, department of genetics and genomics, Icahn School of Medicine at Mt. Sinai, New York, NY. A recommended approach to make a correct diagnosis of acute porphyria and to distinguish among the several types accurately is outlined in Figure 2. Misdiagnosis is common, often due to poor lab technique, inappropriate work-up, or lack of clinical experience. Laboratory data must be reviewed and confirmed irrespective of the degree of clinical suspicion.

Nonspecific elevations in urine porphyrins are seen in patients with hepato-biliary disease and lead toxicity. Alcohol and P-450-inducing drugs may also increase urinary porphyrin excretion. Fecal porphyrins may be increased in those with gastrointestinal bleeding or in patients who consume large amounts of red meat. Increased erythrocyte porphyrins, especially zinc protoporphyrin, may be seen in patients with iron deficiency and lead. Management Patients with well-documented acute porphyria who present to the ED with typical clinical features and without high fever, white cell count, or peritoneal signs should be treated immediately with high carbohydrate intake (at least 300 g/day), narcotic analgesics, and phenothiazines. Panhematin, preferably reconstituted in human serum albumin, should be administered as quickly as it can be prepared, at a dose of 3 mg hematin/kg body weight/day, by way of central, high-flow vein (12,22). They should be monitored at least hourly for the first 6–8 h. If they show signs or symptoms of progressive confusion, delirium, or weakness, they should be admitted to the intensive care unit.

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Figure 2. Summary diagnostic algorithm for the acute porphyrias. AIP = acute intermittent porphyria; ALA = Delta-aminolevulinic acid; CPO = coproporphyrinogen; HCP = hereditary coproporphyria; PBG = porphobilinogen; PPO = protoporphyrinogen; VP = variegate porphyria.

Initial management of acute porphyria includes discontinuation of all potentially harmful drugs and management of symptoms. Many commonly used drugs can worsen symptoms or even may have deleterious effects. Hence, it is imperative that providers consult the Web sites of the American Porphyria Foundation (www.porphyriafoundation. com) and the European Porphyria Network (EPNET: www.porphyria-europe.com), to avoid drugs that are harmful to the patient. Tachycardia, hypertension secondary to sympathetic hyperactivity, can be managed with beta-blockers in the absence of other contraindications. Chlorpromazine or ondansetron are the preferred antiemetics. Treatment of seizures includes gradual correction of hyponatremia, hypomagnesemia, and anticonvulsants. Gabapentin and vigabatrin can be safely used. Pain is treated with narcotic analgesics. The other measures include providing at least 300 g carbohydrate per day (enterally or parenterally), hydration, and correction of electrolyte abnormalities. At least 3 L of 10% glucose solution is given daily for mild attacks or while awaiting heme therapy (see below) to become available. The aim of the definitive treatment of an acute attack is to reduce the activity of ALAS-1, and this is best achieved by administering intravenous heme. This results in rapid reduction of ALA and PBG. Typically, about 4–5 days of treatment with heme is required to resolve symptoms after an acute attack.

Panhematin is supplied as a lyophilized powder cake in amber vials. It can be reconstituted either with sterile water or albumin. When reconstituted with sterile water, it should be administered quickly (within 1 h) due to the inherent instability of aqueous solutions. Heme therapy can result in obliterative thrombophlebitis and coagulopathy. Most authorities recommend that it be reconstituted with albumin (132 mL of 25% human serum albumin) as per recommendations of the United States Porphyria Consortium. Reconstitution with albumin improves stability (at least 24 h) and reduces side effects (12,22). Adverse effects of repeated courses of heme may include iron overload and, perhaps, development of tachyphylaxis when used frequently and for long periods. Patients should be screened for iron overload when heme therapy is used frequently or for long periods (> 3 years). Fortunately, the incidence of iron overload, even among patients receiving prophylactic repeated infusions of heme, is low (23,24). Orthotopic liver transplantation should be considered in patients who have frequent, nearly continuous and unremitting attacks. Rapid and complete resolution of symptoms and biochemical abnormalities has been seen in patients who undergo transplantation (2527). Prevention Patients are encouraged to wear a medical alert bracelet, and gene-defect carriers should be counseled to avoid

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known drugs and precipitants with minimal use of medications that are considered to be ‘‘safe.’’ Adequate diet, prompt treatment of infections, and avoidance of stress are recommended. Leuprolide, a gonadotropin-releasing hormones analog, can be used in women with cyclical attacks related to the luteal phase of their menstrual cycles by blocking endogenous cyclic sex hormone production (2830). Prognosis Acute attacks last a few days to weeks, and most patients are asymptomatic between attacks. Prognosis is good if the condition is recognized early and treated aggressively. Residual deficits like foot/wrist drop or wasting of intrinsic hand muscles may be seen in some patients. There is increased risk of development of cirrhosis and hepatocellular cancer (HCC) among patients with acute porphyria, especially AIP (3133). Hence, all patients older than 50 years of age with acute porphyria should undergo life-long screening for HCC, which is liver ultrasound and measurement of serum alpha-fetoprotein every 6–12 months. CONCLUSION Acute porphyrias are genetic disorders characterized by defective heme biosynthesis. They may have a wide range of neurovisceral manifestations. Patients with acute porphyric attacks are usually women aged 18–45 years who present with severe, recurrent abdominal pain lasting hours to days. Tachycardia and systemic arterial hypertension are common during acute attacks. Such patients are often erroneously thought to have acute appendicitis, ruptured ovarian cysts, or cholecystitis. The diagnosis should be suspected, especially in women who present more than once to the ED or to Urgent Care. Once suspected, the diagnosis of porphyria can be rapidly established by measuring urinary PBG [not porphyrins] in a single random urine sample. Acute porphyria should be treated emergently with intravenous glucose and heme to avoid considerable morbidity and mortality. Acknowledgments—This work was supported by a grant (R15 HL117199) and cooperative agreement (U01 DK 065201) from the National Institutes of Health to HLB; supported by a clinical research award from The American College of Gastroenterology to PS; and supported by funds for education and research on the porphyrias from the American Porphyria Foundation to HLB.

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