The Journal of Emergency Medicine, Vol. 49, No. 3, pp.

305–312, 2015
Copyright Ó 2015 Elsevier Inc.
Printed in the USA. All rights reserved
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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 INTRODUCTION

metabolic disorders characterized by defects in heme
biosynthesis. Porphyrias are classified into two major cate- Porphyrias are a group of eight metabolic disorders,
gories: 1) the acute or inducible porphyrias and 2) the mainly inherited inborn errors of metabolism character-
chronic cutaneous porphyrias. The acute hepatic porphyrias
ized by defects in heme biosynthesis. Porphyrias have
are further classified into acute intermittent porphyria
varied presentation, with a broad spectrum of clinical
(AIP), hereditary coproporphyria, variegate porphyria,
and porphyria due to severe deficiency of delta- manifestations that may be confused with other medical
aminolevulinic acid (ALA) dehydratase (ALADP). Discus- conditions.
sion: AIP is the most common, and ALADP is the least Porphyrias are classified into two major categories:
common acute porphyria. The clinical presentations of 1) the acute or inducible porphyrias, and 2) the chronic
acute porphyrias are nonspecific. There are no pathogno- cutaneous porphyrias (1). There are two main ways of
monic signs or symptoms. The most frequent presenting classifying the porphyrias; one is based upon clinical
symptom is abdominal pain, but pain in the chest, back, or manifestations of the disease, and the other on the prin-
lower extremities may also occur. Hyponatremia is the cipal site of metabolic defect (Table 1). The discussion
most common electrolyte abnormality during acute attacks, herein will be primarily limited to the evaluation and
and hypomagnesemia is also common. Both are risk factors
management of acute porphyrias, which are the major
for development of seizures, which occur in  20–30% of
forms likely to present to emergency departments
acute attacks. Conclusion: Once suspected, the diagnosis of
porphyria can be rapidly established by checking random (EDs) and to be seen by emergency physicians. The
urinary porphobilinogen. Initial management of acute acute hepatic porphyrias are four in number: acute
porphyria includes discontinuation of all potentially harmful intermittent porphyria (AIP), hereditary coproporphy-
drugs and management of symptoms. Acute attacks should ria (HCP), variegate porphyria (VP), and porphyria
be treated emergently with intravenous heme and glucose due to severe deficiency of delta-aminolevulinic acid
to avoid considerable morbidity and mortality. Acute (ALA) dehydratase (ALADP) (1). Fortunately, most
attacks last a few days, and the majority of patients are of the patients with acute porphyria, with possible
asymptomatic between attacks. Prognosis is good if exception of the very rare recessive form of ALADP,
the condition is recognized early and treated aggres- are asymptomatic most of the time. Acute porphyria
sively. Ó 2015 Elsevier Inc.
symptoms rarely, if ever, occur prior to puberty, and
, Keywords—acute porphyria; abdominal pain; haem most patients remain asymptomatic throughout their
metabolism; Panhematin; autosomal dominant lives.

RECEIVED: 8 September 2014; FINAL SUBMISSION RECEIVED: 31 March 2015;

ACCEPTED: 18 April 2015

305
306 S. Besur et al.

Table 1. Usual Schemes for Classification of the Porphyrias

Chromosomal
Porphyrias Inheritance Gene Affected Location Comments

According to the clinical

manifestations of disease
Acute or inducible porphyrias
ALADP AR ALAD [PBGS] 9q34 Very rare severe disease in infancy
AIP AD PBGD [HMBS] 11q23.3 Most severe form
HCP AD CPOX 3q12 May also have cutaneous feature
VP AD PPOX 1q22 May also have cutaneous feature
Cutaneous chronic porphyrias
CEP AR URO3S 10q26.1–q26.2 Rare, usually manifests in infancy/
childhood
HEP AR UROD 1p34.1 Rare, usually manifests in infancy/
childhood
PCT (Type I) Acquired None known None known Disease of adults
PCT (Type II) AR UROD 1p34.1 Requires additional defects
EPP AR FECH 18q21.31 Common: onset in infancy
XLPP X-linked ALAS 1 Xp11.21 Gain of function mutations
According to the principal site of
metabolic defect
Acute hepatic porphyrias
ALADP AR ALAD [PBGS] 9q34 Very rare severe disease in infancy
AIP AD PBGD [HMBS] 11q23.3 Most severe form
HCP AD CPOX 3q12 May also have cutaneous features
VP AD PPOX 1q22 May also have cutaneous features
Chronic hepatic porphyrias
HEP AR UROD 1p34.1 Usually manifests in infancy
PCT (Type I) Acquired None known None known Disease of adults
PCT (Type II) AR UROD 1p34.1 Requires additional defects
Erythropoietic porphyrias
CEP AR URO3S 10q26.1–q26.2 Rare, usually manifests in infancy/
childhood
EPP AR UROD 18q21.31 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 two forms of ALA synthase, the ubiquitous house-
life-threatening manifestations and not to indicate dura- keeping form 1 and the erythroid-specific form 2.
tion of disease. All acute porphyrias produce similar neu- These two forms are products of separate genes and
rovisceral manifestations regardless of associated are under quite different regulation. ALA synthase-1
enzymatic defects, and hence, should be managed in a can be upregulated markedly by transcriptional and
similar way. It is important early on to consider the diag- posttranscriptional mechanisms, and an ‘‘uncon-
nosis and perform the appropriate biochemical and ge- trolled’’ upregulation of this enzyme in the liver is
netic tests to either establish or to exclude diagnosis of the biochemical sine qua non of acute porphyric
acute porphyria. attacks. Upregulation of ALA synthase-1 occurs due
to three main known causes:
DISCUSSION
1. Lipophilic drugs and chemicals interact with nu-
Heme Biosynthesis clear receptors that, in turn, increase activation of
drug-response elements in the upstream enhancer
Acute porphyria is due to the deficiency of a specific of ALA synthase-1 (2).
enzyme involved in heme synthesis. The normal pathway 2. Deficiency of glucose or other gluconeogenic com-
of heme synthesis is shown in Figure 1. pounds that normally suppress gene expression of
The first step is condensation of glycine and succi- ALA synthase (the so-called ‘‘glucose effect’’) (3).
nyl CoA to form delta-aminolevulinic acid (ALA), 3. Deficiency of heme, the end product of the heme
catalyzed by the mitochondrial enzyme ALA synthase, pathway shown in Figure 1, which not only re-
the rate controlling step in heme synthesis. There are presses transcription of the ALA synthase-1 gene,
Acute Porphyrias 307

Figure 1. Heme biosynthetic pathway showing the sites of enzyme defects in the porphyrias and the major biochemical abnor-
malities 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 = porpho-
bilinogen; PROTO = protophyrin; URO = uroporphyrin; ZN = zinc.

but also blocks translocation of the enzyme into progesterone), and other intercurrent illnesses or stress
mitochondria and decreases the stability of its (Table 2). More extensive lists of drugs that may
mRNA and enhances breakdown of the inactive trigger acute attacks are available at the following
mitochondrial enzyme by Lon protease (4–6). Web sites: American Porphyria Foundation (www.
porphyriafoundation.com/drug-database), the European
Pathogenesis of Acute Attacks Porphyria Initiative Web site (www.porphyriaeurope.
org), and the Porphyria South Africa Web site (www.
The enzyme deficiencies in AIP, HC, and VP are only par- porphyria.uct.ac.za).
tial (50% of the normal), as opposed to ALA dehydratase These trigger factors cause increased demand for he-
deficiency (< 5% of the normal). patic heme or reduce heme concentration, resulting in
The ALA dehydratase enzyme normally has high ac- increased synthesis of ALA synthase (shown in
tivity in the heme biosynthetic pathway. Hence, a more Figure 1), causing accumulation of proximal intermedi-
severe deficiency in inactive enzyme is necessary to cause ate products. The exact mechanism for the neurologic
clinical manifestations. These enzymatic defects predis- damage in acute porphyrias is not completely under-
pose affected individuals to be susceptible to acute at- stood. However, the preponderance of evidence favors
tacks of porphyria. Some of the common triggers for the idea that ALA (or perhaps, a metabolite of ALA)
acute attacks include prolonged severe fasting or die- is the chief neurotoxin (6,7). The principal group
ting, alcohol, drugs (barbiturates, hydantoins, rifampin, affected is women in their child-bearing years (20–45
progestins, endogenous steroid hormones, especially years of age). The attacks are often cyclical, linked to
308 S. Besur et al.

Table 2. Factors Known to Trigger or Exacerbate Acute Hyponatremia is a common electrolyte abnormality
Porphyric Attacks
that occurs during acute attacks. Although the hyponatre-
Porphyrias mia, which may be severe (serum Na < 125 mEq/L), has
been ascribed to syndrome of inappropriate antidiuretic
Drugs and chemicals, especially: hormone secretion (SIADH), blood volumes have been
Excess alcohol
Barbiturates found to be reduced (16). Therefore, all criteria for
Estrogens SIADH may not be met. Other contributing factors may
Hydantoins include vomiting and resuscitation with high-volume
Progestagens
Sulfonamides dextrose. Skin manifestations do not occur in acute inter-
All drugs that are suicide substrates or potent inducers of mittent porphyria, with the exception of patients with
cytochrome P450 end-stage renal disease, who may develop blistering
Dieting; fasting; deficiency of carbohydrate intake
(gastric bypass surgery) skin lesions (17). Cutaneous manifestations may occur
Exhaustion—emotional or physical in active hereditary coproporphyria (HCP) or VP due to
Intercurrent acute illnesses accumulation of coproporphyrins or harderoporphyrin.
Cigarette smoking

Laboratory Evaluation of Acute Porphyrias

menstrual cycles, highlighting the importance of endog-
enous steroids, especially progesterone, in pathogenesis. The clinical presentations of acute porphyrias are nonspe-
However, pregnant women typically do not suffer severe cific in the absence of pathognomonic signs or symptoms.
attacks despite increased levels of estrogen and proges- Random urinary porphobilinogen (PBG) is the most
terone (8). Rather, acute attacks have more of a ten- important rapid test for diagnosis of acute porphyria
dency to occur in the postpartum period, for still (part TR52001; PBG test kit, Thermo Scientific, Wal-
unknown reasons. tham, MA) (18).
Epidemiology The results from this test are usually available in < 10
min. Unfortunately, this test is currently not available in
In most countries, AIP is the most common and ALADP most hospitals or urgent care clinics.
is the least common acute porphyria. In the setting of a positive urinary PBG screening test,
All acute porphyrias are autosomal dominant, with the the diagnosis of acute porphyria should be confirmed by
exception of ALADP, which is an autosomal recessive measuring quantitative ALA, PBG, and total porphyrins
disorder (Table 1) (9,10). from the same urine sample that was used for the initial
rapid screening test. In anuric patients, diagnosis of acute
Clinical Features porphyria can be established by measuring serum PBG.
All patients with true manifestations of AIP will have
Abdominal pain and tachycardia are the most common markedly increased urinary ALA and PBG levels during
presenting symptoms and signs in acute porphyria. an attack (up to 25–100 mg of ALA and 50–200 mg PBG
Abdominal pain is usually colicky, affecting the lower per day; normal range 0–4 mg/day). An alternate diag-
abdomen and lasting hours to days. nosis such as HCP, VP, lead poisoning, or hereditary tyro-
It typically comes on gradually and escalates in sinemia should be considered if urinary ALA excretion
severity. Other frequent symptoms, signs, and their char- (in mg/g creatinine) exceeds that of PBG.
acteristics are listed in Table 3 (1315). Neurologic PBG in urine may be converted nonenzymatically to
manifestations of acute porphyrias are listed in uroporphyrin, and hence, although the defect in AIP
descending order of frequency in Table 3. Other neuro- lies in hepatic PBG deaminase, there may be increased
logical manifestations may include muscle weakness, dif- urinary uro- and coproporphyrin levels. Urine may turn
ficulty swallowing, other bulbar signs, confusion, pink or even dark red or black (due to porphyrin or por-
delirium, and seizures. Generalized weakness may some- phobilin formation) after exposure to air and light
times progress rapidly to quadriparesis and acute respira- (16,19–21).
tory insufficiency, especially if the correct diagnosis is The major increases in porphyrins and their precursors
missed and patients are treated with barbiturates or hy- that occur in biochemically manifest porphyrias are sum-
dantoins (e.g., for treatment of seizures). marized in Figure 1.
Many patients with acute porphyric attacks, when The second line of diagnostic evaluation includes
asked, will describe passing reddish to brownish urine. testing for plasma and urine fecal porphyrins, and
The urine may darken considerably if exposed to air, erythrocyte PBG deaminase levels, along with DNA
light, and warmth. Such findings should alert astute clini- genetic analysis for mutation in the relevant genes.
cians to think of the diagnosis. AIP can be differentiated from other porphyrias by
Acute Porphyrias 309

Table 3. Common Presenting Symptoms and Signs of Acute Porphyria

Frequencies of Symptoms
Symptoms and Signs and Signs (%) Comment

Gastrointestinal
Abdominal pain 85–95 Usually unremitting (for hours or longer) and poorly localized but
can be cramping.
Vomiting 43–88 Neurologic in origin and rarely accompanied by peritoneal signs,
fever, or leukocytosis.
Constipation 48–84 Nausea and vomiting often accompany abdominal pain. May be
accompanied by bladder paresis.
Diarrhea 5–12
Neurologic
Pain in extremities, back 50–70 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.
Paresis 42–68 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.
Respiratory paralysis 9–20 Preceded by progressive peripheral motor neuropathy and
paresis.
Mental symptoms 40–58 May range from minor behavioral changes to agitation, confusion,
hallucinations, and depression.
Convulsions 10–20 A central neurologic manifestation of porphyria or due to
hyponatremia, which often results from syndrome of
inappropriate antidiuretic hormone secretion or sodium
depletion.
Cardiovascular
Tachycardia 64–85
Systemic arterial hypertension 36–55 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. How- Nonspecific elevations in urine porphyrins are seen in
ever, this alone cannot be relied upon for diagnosis patients with hepato-biliary disease and lead toxicity.
of AIP because various factors like gene mutations Alcohol and P-450-inducing drugs may also increase
(5%) causing selective PBG deaminase deficiencies in urinary porphyrin excretion. Fecal porphyrins may be
liver, with normal levels in erythrocytes or increase increased in those with gastrointestinal bleeding or in
in erythrocyte levels due to concomitant hemolytic patients who consume large amounts of red meat.
anemia, may lead to false-negative results. Molecular Increased erythrocyte porphyrins, especially zinc proto-
methods and DNA analysis for gene mutations to iden- porphyrin, may be seen in patients with iron deficiency
tify gene-encoding PBG deaminase is not only helpful and lead.
in confirming AIP, but also assists in identifying other
gene carriers in the family. DNA analysis assists in the Management
diagnosis when a specific mutation within a family or
geographic area is already known. Lists of updated Patients with well-documented acute porphyria who pre-
mutations are available at the human gene mutation sent to the ED with typical clinical features and without
database (http://www.hgmd.cf.ac.uk/ac/index.php). high fever, white cell count, or peritoneal signs should
In the United States, genetic testing for all forms of be treated immediately with high carbohydrate intake
porphyria is available through the laboratory of R.J. Des- (at least 300 g/day), narcotic analgesics, and phenothia-
nick, MD, PhD, department of genetics and genomics, zines.
Icahn School of Medicine at Mt. Sinai, New York, NY. Panhematin, preferably reconstituted in human
A recommended approach to make a correct diagnosis serum albumin, should be administered as quickly
of acute porphyria and to distinguish among the several as it can be prepared, at a dose of 3 mg hematin/kg
types accurately is outlined in Figure 2. Misdiagnosis is body weight/day, by way of central, high-flow vein
common, often due to poor lab technique, inappropriate (12,22). They should be monitored at least hourly for
work-up, or lack of clinical experience. Laboratory data the first 6–8 h. If they show signs or symptoms of
must be reviewed and confirmed irrespective of the progressive confusion, delirium, or weakness, they
degree of clinical suspicion. should be admitted to the intensive care unit.
310 S. Besur et al.

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 Panhematin is supplied as a lyophilized powder cake
discontinuation of all potentially harmful drugs and in amber vials. It can be reconstituted either with sterile
management of symptoms. Many commonly used water or albumin. When reconstituted with sterile water,
drugs can worsen symptoms or even may have it should be administered quickly (within 1 h) due to the
deleterious effects. Hence, it is imperative that inherent instability of aqueous solutions. Heme therapy
providers consult the Web sites of the American can result in obliterative thrombophlebitis and coagulop-
Porphyria Foundation (www.porphyriafoundation. athy. Most authorities recommend that it be reconstituted
com) and the European Porphyria Network (EPNET: with albumin (132 mL of 25% human serum albumin) as
www.porphyria-europe.com), to avoid drugs that are per recommendations of the United States Porphyria
harmful to the patient. Consortium. Reconstitution with albumin improves sta-
Tachycardia, hypertension secondary to sympathetic bility (at least 24 h) and reduces side effects (12,22).
hyperactivity, can be managed with beta-blockers in the Adverse effects of repeated courses of heme may
absence of other contraindications. Chlorpromazine or include iron overload and, perhaps, development of
ondansetron are the preferred antiemetics. tachyphylaxis when used frequently and for long
Treatment of seizures includes gradual correction of periods. Patients should be screened for iron overload
hyponatremia, hypomagnesemia, and anticonvulsants. when heme therapy is used frequently or for long
Gabapentin and vigabatrin can be safely used. Pain is periods (> 3 years). Fortunately, the incidence of iron
treated with narcotic analgesics. The other measures overload, even among patients receiving prophylactic
include providing at least 300 g carbohydrate per day repeated infusions of heme, is low (23,24). Orthotopic
(enterally or parenterally), hydration, and correction of liver transplantation should be considered in patients
electrolyte abnormalities. At least 3 L of 10% glucose so- who have frequent, nearly continuous and unremitting
lution is given daily for mild attacks or while awaiting attacks. Rapid and complete resolution of symptoms
heme therapy (see below) to become available. and biochemical abnormalities has been seen in patients
The aim of the definitive treatment of an acute attack is who undergo transplantation (2527).
to reduce the activity of ALAS-1, and this is best achieved
by administering intravenous heme. This results in rapid Prevention
reduction of ALA and PBG. Typically, about 4–5 days of
treatment with heme is required to resolve symptoms af- Patients are encouraged to wear a medical alert bracelet,
ter an acute attack. and gene-defect carriers should be counseled to avoid
Acute Porphyrias 311

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