Acute Intermittent Porphyria - Pathogenesis, Clinical Features, and Diagnosis - UpToDate

26.08.
2021 Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis - UpToDate
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Acute intermittent porphyria: Pathogenesis, clinical

features, and diagnosis
Authors: Gagan K Sood, MD, Karl E Anderson, MD, FACP
Section Editor: Robert T Means, Jr, MD, MACP
Deputy Editor: Jennifer S Tirnauer, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2021. | This topic last updated: Jun 19, 2020.
INTRODUCTION
Acute intermittent porphyria (AIP; also called Swedish porphyria, pyrroloporphyria,

intermittent acute porphyria) is an acute neurovisceral porphyria resulting from a partial
deficiency of the heme biosynthetic enzyme porphobilinogen deaminase (PBGD). It is an
autosomal dominant disorder with low penetrance; development of symptoms is affected by
a variety of exacerbating factors.
Despite its well-characterized molecular genetics, the diagnosis of AIP is challenging.

Symptoms are often vague and nonspecific; the other possible causes of neurologic findings
and abdominal pain are numerous; and acute porphyria is often not considered because it is
rare. Clues from the family history may be absent, because penetrance of AIP is low and
symptoms are not present in the majority of family members with a disease-causing
mutation. Even if acute porphyria is considered, many clinicians are unfamiliar with
appropriate testing and interpretation of test results. As a consequence, diagnosis and life-
saving treatment are often delayed.
The pathogenesis, clinical manifestations, and diagnosis of AIP will be reviewed here.
Management of AIP and a general overview of the porphyrias are presented separately. (See
"Acute intermittent porphyria: Management" and "Porphyrias: An overview".)
PATHOGENESIS
Porphyrias are caused by alterations in the enzymes of heme biosynthesis. Heme is essential
in the function of many hemoproteins, including hemoglobin and hepatic cytochrome P450
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26.08.2021 Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis - UpToDate
enzymes. The liver rather than the bone marrow is the source of overproduction of heme
pathway intermediates in patients with hepatic porphyrias such as AIP; and the central,
peripheral, autonomic, and enteric nervous systems are affected when levels of these
intermediates are elevated in the circulation, suggesting neurotoxic effects of one or more
intermediates. Some neurologic manifestations may result from heme depletion in neuronal
cells, although this remains unproven. (See 'Neurologic dysfunction' below.)
Gene mutation — AIP is caused by heterozygosity for a mutation in the gene encoding

porphobilinogen deaminase (PBGD), also called hydroxymethylbilane synthase (HMBS) and
previously referred to as uroporphyrinogen I synthase. Inheritance is autosomal dominant
with low penetrance. More than 400 PBGD gene mutations have been recognized in AIP, all
of which lead to severe loss of PBGD enzymatic activity from the mutant allele. Virtually all
remaining PBGD activity is due to expression from the unaffected allele.
There is no convincing evidence for genotype-phenotype correlation in AIP (ie, particular

mutations do not predict disease severity). Rather, disease severity is highly variable, even
within families that share the same mutation. Disease severity is affected by a variety of
environmental and other factors that act primarily by increasing expression of an enzyme
upstream of PBGD/HMBS in the heme biosynthetic pathway, delta-aminolevulinic acid
synthase (ALAS1). This enzyme controls the rate of heme biosynthesis in the liver. (See
'Enzymatic defect' below and 'Exacerbating factors' below.)
The PBGD gene is transcribed as two separate splice variants, one erythroid-specific
(expressed only in erythroid precursor cells), the other a housekeeping form expressed in all
cell types, including hepatocytes and to a minor extent erythroid cells ( figure 1). The two
isoforms are produced through alternative splicing of two distinct primary mRNA transcripts
arising from two different promoters for the same gene [1,2]. The housekeeping promoter
(upstream of exon 1) is active in all tissues, while the erythroid-specific promotor (upstream
of exon 2) is only active in erythroid cells. Sequences in the erythroid promoter are
recognized by erythroid-specific trans-acting factors, such as GATA-1 and NF-E2 [3].
In AIP, the PBGD mutation always affects hepatic PBGD (ie, the housekeeping form of the
enzyme). The erythroid enzyme is generally affected as well because the mutations generally
occur in a region of the gene used for transcribing both housekeeping and erythroid forms,
although a resulting deficiency of the erythroid enzyme is not important in causing the
disease. Disease-causing mutations in some families (eg, splice-site mutations in exon 1,
base transitions in intron 1) result in decreased PBGD expression in non-erythroid tissues
including the liver, but not in erythroid cells, because transcription of the gene in erythroid
cells starts downstream of the site of the mutation [4]. In these AIP families, erythrocyte
PBGD activity is within the normal range in all those who have inherited the familial
mutation. (See 'Confirmatory testing' below.)

Enzymatic defect — AIP mutations in PBGD/HMBS cause the disease because they decrease
the activity of the PBGD/HMBS enzyme in the liver. This cytosolic enzyme catalyzes the third
step in heme biosynthesis, whereby four molecules of porphobilinogen (PBG; a five-
membered pyrrole ring) are sequentially condensed to form hydroxymethylbilane (HMB; a
linear tetrapyrrole) ( figure 2). HMB is unstable and is rapidly metabolized by the fourth
enzyme in the pathway to uroporphyrinogen III.
The PBGD enzyme is found in two forms: an erythroid-specific form that is synthesized only
in red blood cell (RBC) precursors in the bone marrow, and a housekeeping (ubiquitous)
form found in the liver and other tissues [1,2,5,6]. Residual amounts of the erythroid-specific
enzyme decline as circulating RBCs age, so an increased proportion of younger RBCs can
increase the measured activity of erythrocyte PBGD activity. Decreased activity of the hepatic
(housekeeping) form of PBGD, rather than the erythroid form, is responsible for AIP.
The role of the liver in the mechanism of neuronal damage is supported by findings from
liver transplantation: patients with AIP have marked clinical improvement after liver
transplantation. However, if a liver from a patient with AIP is provided to a patient with
another disorder such as liver cancer, the recipient typically develops neurovisceral
symptoms and elevated PBG [7].
Despite the causative role of PBGD/HMBS mutation in AIP, symptomatic AIP does not develop
in the majority of individuals with the mutation, who have asymptomatic (latent) AIP
throughout life (ie, PBGD/HMBS mutation is necessary but not sufficient for symptomatic
disease). Studies of genomic databases suggest that the penetrance may be as low as 1
percent [8]. AIP also becomes latent in some patients with a history of symptomatic disease
once exacerbating factors responsible for their attacks are recognized and eliminated. A
minority of heterozygotes have recurrent attacks even after known exacerbating factors are
addressed.
In addition to reduced PBGD activity, symptomatic AIP requires a marked induction of the
housekeeping (ubiquitous) form of the first enzyme in the heme biosynthetic pathway, delta-
aminolevulinic acid (ALA) synthase (ALAS1), which is upstream of PBGD ( figure 2). ALAS1 is
the rate-limiting enzyme for heme synthesis in the liver. Marked ALAS1 induction leads to
increased production and accumulation of ALA and PBG, which are potentially toxic
intermediates. (See 'Laboratory and imaging findings' below.)
ALAS1 synthesis is normally regulated by a pool of "free" heme in hepatocytes that is not yet
committed to hemoprotein synthesis. An increase in this "free" heme pool represses the
synthesis of ALAS1. Most of the heme synthesized in liver is used to make hepatic
cytochrome P450 enzymes (CYPs), which are abundant and turn over rapidly. Thus, the pool
of "free" or regulatory heme in hepatocytes is depleted by substances that induce CYP
synthesis. CYP inducers and reduced food intake can also induce ALAS1 directly.
ALAS1 synthesis is induced by the following:
● Depletion of the regulatory hepatic "free" heme pool, which in AIP is further favored by
a partial deficiency of PBGD.
● Some drugs, xenobiotics, and sex hormones (especially progesterone) that may induce
synthesis of ALAS1 and CYPs [9,10]. (See 'Medications' below and 'Sex hormones' below.)
● Caloric and carbohydrate restriction. (See 'Nutrition, glucose metabolism, and stress'
below.)
● Metabolic stress, which may induce hepatic heme oxygenase and accelerate heme
destruction and depletion of the regulatory heme pool, although this mechanism is not
proven in AIP. (See 'Nutrition, glucose metabolism, and stress' below.)
Many of these factors contribute in an additive fashion to cause ALAS1 induction and
increased levels of ALA and PBG, leading to exacerbations of AIP.
The PBGD enzyme has a unique cofactor, a dipyrromethane, that binds to its catalytic site,
upon which four additional pyrroles are assembled, forming a linear hexapyrrole; after
formation of the hexapyrrole, HMB is released [11,12]. It is possible, although unproven, that
high concentrations of PBG that accumulate during exacerbations of AIP may inhibit the
interaction of this cofactor with the enzyme and further reduce hepatic PBGD activity.
ALA and PBG are colorless. However, PBG degrades to form porphobilin, a brownish product
excreted in urine. In addition to ALA and PBG, urinary porphyrins are also increased in AIP.
Their formation may be enzymatic or non-enzymatic. At high concentrations in urine, PBG
molecules can randomly associate non-enzymatically to form a mixture of uroporphyrin
isomers. However, there is evidence that porphyrins in AIP are predominantly isomer III,
which are formed enzymatically, perhaps from ALA transported to tissues other than the
liver [13,14]. Porphobilin, a degradation product of PBG, and increased porphyrins account
for the reddish-brown urine seen during acute attacks. (See 'Bladder dysfunction/red urine'
below.)
Neurologic dysfunction — Neurologic dysfunction is responsible for the symptoms of AIP.

Symptoms may be due to a combination of central, peripheral, sensory, motor, and
autonomic nervous system abnormalities. (See 'Clinical manifestations' below and
"Pathogenesis of delayed gastric emptying", section on 'Enteric nervous system'.)
The exact mechanism of these nervous system abnormalities in all acute porphyrias is
unknown. The most favored explanation is that one or more heme pathway intermediates
that are overproduced by the liver, or products derived from them, are neurotoxic. Favorable
experience with liver transplantation in AIP, which corrects PBGD deficiency in the liver but
not in other tissues, supports an essential role for the liver in the neuropathic process
[15,16]. An alternative hypothesis is that deficiency of heme in neuronal cells causes

symptoms by limiting formation of heme-containing proteins important for neurologic

functioning; however, there is less evidence supporting a role for heme depletion in the
pathogenesis of the nervous system abnormalities.
Evidence supporting the role of ALA or an ALA derivative as the pathogenic intermediate in
AIP includes the following findings:
● Circulating levels of ALA are increased in a variety of conditions with similar neurologic
sequelae, including all four of the acute porphyrias ( table 1), lead poisoning, and
hereditary tyrosinemia type I.
● ALA can enter cells readily and be converted to porphyrins, which in turn may have toxic
potential [14].
● ALA is structurally similar to gamma-aminobutyric acid (GABA), the major inhibitory

neurotransmitter in the central nervous system, and can interact with GABA receptors
[17,18].
However, a study of ALA loading in a normal volunteer to levels seen in patients with AIP
during acute attacks did not show any adverse neurologic effects [19].
Suggestions that reduced formation of heme-containing proteins might have clinical

consequences in AIP come from the following observations, although there is little evidence
of this mechanism in humans:
● Heme is essential for mitochondrial electron transport used to make ATP, and lack of
heme might cause dysfunction of the axonal membrane Na+/K+ ATPase, adversely
affecting neuronal function [20].
● Decreased production of nitric oxide by the heme-containing enzyme nitric oxide

synthase might compromise cerebral and intestinal blood flow in AIP [21,22].
● Hepatic heme depletion in rats impairs the activity of the hepatic enzyme tryptophan
pyrrolase, which is associated with increased tryptophan levels in plasma and brain, and
increased synthesis of the neurotransmitter 5-hydroxytryptamine [23].
● Genetically engineered PBGD mutant mice (created by gene targeting) show impaired
motor function and ataxia, despite normal or only slightly increased ALA levels in plasma
and urine [24-26]. However, these mice are homozygous or compound heterozygous for
PBGD mutant alleles, in contrast to heterozygous AIP patients.
EXACERBATING FACTORS

The frequency and severity of AIP attacks is highly variable, even within a family in which
multiple members share the same gene mutation. This variability of disease severity is
thought to be linked to unknown modifying genetic factors and variable exposure to
exacerbating factors, most of which affect expression of hepatic ALAS1 and/or deplete the
regulatory pool of heme that normally represses ALAS1 expression. (See 'Pathogenesis'
above.)
In many cases, it is apparent that unknown modifying genes and external exacerbating
factors are additive. For example, in a study that evaluated acute attacks in 47 individuals
with acute porphyria receiving anesthetic agents (33 of whom had AIP), porphyric symptoms
were worsened by anesthesia in 9 of 14 patients who already had symptoms; in contrast,
none of the 37 patients who received an anesthetic during an asymptomatic period
developed symptoms due to the anesthetic [27].
Some patients continue to have attacks of AIP after known exacerbating factors are
addressed, indicating that disease-modifying genes or other inducers of ALAS1 remain to be
identified.
Medications — Medications are among the most important exacerbating factors for AIP. A
partial list of drugs known to be unsafe or safe in the acute porphyrias is provided in the
table ( table 2). Most of the unsafe agents (eg, barbiturates, phenytoin, most other
antiepileptics, rifampin) induce hepatic ALAS1 and hepatic cytochrome P450 enzymes (CYPs)
[11,28].
Clinicians considering medications in patients with AIP should consult frequently updated
sources for information regarding medication safety, such as the websites of the American
Porphyria Foundation (www.porphyriafoundation.com) and the European Porphyria
Network (www.porphyria-europe.com). Of note, the evidence for these listings is often
limited and sometimes controversial, and it is useful to consult an expert center for advice,
particularly for patients with frequent attacks.
Ethanol and smoking — Alcohol and smoking can exacerbate AIP.
● Ethanol and other alcohols induce ALAS1 and some hepatic P450 enzymes (CYPs) [29,30].
● Smoke from tobacco (and presumably other sources such as marijuana) is also a known
inducer of hepatic CYPs. An association between cigarette smoking and repeated attacks
of porphyria was found in surveys of patients with AIP in Britain (144 patients) and
Sweden (356 patients) [31,32].
Based on these observations and our clinical experience, we suggest that patients with AIP
avoid alcohol and smoking to reduce the frequency of attacks. (See "Acute intermittent
porphyria: Management", section on 'Avoidance of exacerbating factors'.)
Sex hormones — There is strong evidence for a role of sex hormones (eg, progesterone) in
precipitating AIP symptoms. The following observations support the role of sex hormones,
especially progesterone:
● AIP attacks begin after puberty, are more common in women, and sometimes correlate
with the luteal phase of the menstrual cycle, when progesterone levels are highest (
figure 3) [33].
● Progesterone, as well as some progesterone and testosterone metabolites, are potent

inducers of hepatic ALAS1 and CYPs [34].
● Estrogens have less effect on hepatic heme synthesis and have been implicated as
harmful mostly when used in association with progesterone or synthetic progestins.
● Pregnancy is usually well tolerated in women with AIP, even though progesterone levels
are high [35]. However, some women experience more frequent attacks, sometimes in
association with reduced caloric intake or the use of certain drugs (eg, metoclopramide
for the treatment of hyperemesis gravidarum) [36,37].
Nutrition, glucose metabolism, and stress — Starvation and/or reduced intake of calories

and/or carbohydrates can exacerbate AIP. Reduced caloric or carbohydrate intake lead to
increased ALAS1 expression, which is mediated by increases in the peroxisome proliferator-
activated receptor-gamma coactivator 1 alpha (PGC-1alpha) [38-41]. Starvation and
metabolic stress may also induce hepatic heme oxygenase, which may deplete hepatic heme
and thus contribute to ALAS1 induction [42].
The role of glucose in suppressing ALAS1 expression explains the exacerbation of AIP and
other acute porphyrias by reduced intakes of calories and carbohydrates, which may occur
during illness, surgery, or other stresses. In such circumstances, increases in ALA and PBG,
and symptoms of porphyria can be reversed by carbohydrate administration, reflecting
down-regulation of PGC-1alpha [28,38,43,44]. (See "Acute intermittent porphyria:
Management", section on 'Carbohydrate loading as a temporizing measure'.)
Psychological stress has also been implicated in causing AIP attacks, but the mechanisms
involved are not well defined.
Effects of diabetes mellitus on AIP symptoms have not been carefully studied. Case studies
suggest that high glucose levels in diabetics with AIP may decrease the frequency of attacks
and lower ALA and PBG levels [45]. Glucose administration is used in the treatment of acute
AIP attacks. (See "Acute intermittent porphyria: Management", section on 'Carbohydrate
loading as a temporizing measure'.)

EPIDEMIOLOGY
AIP is the most common of the acute porphyrias worldwide, with a roughly estimated
prevalence, probably including asymptomatic cases, of approximately 50 per million [11].
Interrogation of exomic and genomic databases has revealed an unexpectedly high
prevalence of pathogenic variants in apparently unaffected individuals (approximately 100-
fold more common than symptomatic individuals) [8]. These findings suggest that important
modifying genes or environmental factors remain unidentified. The incidence of
symptomatic AIP in all European countries participating in the European Porphyria Network
(EPNet) was estimated to be 0.13 new cases per year per million over a three-year period.
Assuming a disease duration of 45 years, prevalence was calculated to be 5.9 cases per
million [46].
AIP is an inherited autosomal dominant condition with low disease penetrance (many
individuals with the relevant genotype are clinically asymptomatic, referred to as having
latent disease). The frequency of PBGD/HMBS mutations in the general population (ie, latent
AIP) is unknown; however, the observation that many families with an AIP mutation have
only one member with symptomatic AIP has long suggested that latent AIP may be quite
common.
● Race/ethnicity – AIP occurs in all races but may be most common in northern
Europeans [11].
● Sex – Males and females are equally likely to inherit a PBGD gene mutation. However,
AIP is more likely to manifest in women than men, leading to a female predominance of
the disease.
● Age – AIP is a disease of adults. It typically presents in the third or fourth decades of life.
Acute attacks are exceedingly rare before puberty, and few well-documented instances
of AIP in children are described in the literature. In one series of 204 cases,
approximately 5 percent of patients retrospectively reported symptoms beginning
before age 14, but these were not biochemically confirmed at the time [47]. Rare
homozygous cases are manifest in children, but with a different clinical picture that
includes impaired neurologic development but not acute attacks [11].
The lack of major AIP symptoms before puberty was illustrated in a Swedish registry that
evaluated 61 healthy children aged 3 to 16 years, who were diagnosed with AIP based on
DNA testing rather than symptoms [48]. Clinical findings were evaluated prospectively for
approximately 2.5 years, during which time symptoms developed in only six children (10
percent). In these six cases, symptoms were generally mild and of short duration (eg,
abdominal pain or nausea for two or three days). None of the children had paresis or other

severe symptoms. Moreover, urinary levels of ALA and PBG were elevated only slightly or not
at all during these episodes. Since abdominal pain is reported in 10 to 20 percent of healthy
children, these findings may not be different from the general population. (See "Chronic
abdominal pain in children and adolescents: Approach to the evaluation", section on
'Epidemiology'.)
CLINICAL MANIFESTATIONS
The presentation of AIP is highly variable and the symptoms are nonspecific, which accounts
in part for delays in diagnosis. Most individuals with PBGD/HMBS mutations never develop
symptoms (ie, most individuals with a mutation have latent rather than manifest AIP). Of
note, the neurovisceral symptoms in AIP are indistinguishable from the symptoms of other
acute porphyrias. (See "Porphyrias: An overview" and 'Differential diagnosis' below.)
When symptoms of AIP are present, they usually occur as intermittent acute attacks that are
sometimes life-threatening [11,28]. The most common symptoms are gastrointestinal and
neurologic, and include pain in the abdomen, chest, back, and extremities ( table 3). These
symptoms are due to abnormalities of the peripheral, autonomic, and central nervous
systems. Symptoms typically resolve between attacks, although patients can develop chronic
symptoms, especially after many years of repeated attacks. (See 'Chronic manifestations'
below.)
AIP does not have cutaneous manifestations, with the rare exception of patients with
advanced renal failure, who may develop elevations in plasma porphyrins sufficient to
produce blistering lesions on light-exposed areas of skin ( table 1) [28,49].
Acute attacks — Manifest (symptomatic) AIP is characterized by acute attacks of

neurovisceral symptoms accompanied by elevations in urinary porphyrin precursors and
porphyrins. Attacks develop over hours to days and persist for days to weeks, depending
upon precipitating factors and treatment. An exacerbating factor is often apparent, but may
not be in patients with frequent recurrent attacks. The frequency of attacks is highly
individual for each patient. As noted above, these acute neurovisceral symptoms are
identical to other acute porphyrias.
Abdominal pain — Abdominal pain is the most common and often one of the earliest
symptoms in AIP, occurring in 85 to 95 percent of patients with acute attacks ( table 3)
[28]. It is usually severe, steady, and poorly localized. Sometimes there is associated
cramping. Also common are constipation, bloating, nausea, vomiting, and signs of ileus such
as abdominal distension and decreased bowel sounds. Diarrhea and increased bowel
sounds are sometimes seen.

Because the pain and other symptoms are neurologic rather than infectious or
inflammatory, abdominal tenderness, rebound tenderness, fever, and leukocytosis are
usually minimal or absent during an acute attack. If present, these findings suggest an
inflammatory disease rather than a direct manifestation of AIP. However, the presence of an
inflammatory process does not exclude the possibility of an AIP attack; infection may be a
precipitating factor for an acute attack, and treatment for infection and AIP may be needed
simultaneously. (See "Acute intermittent porphyria: Management", section on 'Avoidance of
exacerbating factors'.)
Peripheral neuropathy — Sensory and motor neuropathy is common during acute AIP

attacks and may precede the abdominal pain. The presentation is variable and the onset
may be acute. Pain in the extremities, along with patchy numbness, paresthesias, and
dysesthesias, may occur. A peripheral motor neuropathy develops early in some attacks, but
is more often a later manifestation of a prolonged attack.
Motor weakness, when present, usually begins proximally in the upper extremities and may
progress to the lower extremities and distally. Especially with prolonged attacks, it may also
involve cranial nerves and lead to bulbar paralysis, respiratory impairment, and death.
Advanced motor neuropathy with quadriplegia and respiratory paralysis can occur and is
potentially reversible with appropriate treatment (eg, intravenous hemin); however, recovery
may be require up to one to two years, and some permanent paralysis may remain in some
individuals [50,51].
Autonomic and central nervous system involvement — The autonomic nervous

system is commonly affected in AIP, as manifested by abdominal pain and other
gastrointestinal symptoms. In addition, tachycardia is the most common physical sign,
occurring in approximately 80 percent of attacks [52]. Hypertension, sweating, restlessness,
and tremor also occur. Attacks are accompanied by marked elevations of catecholamines,
which may explain some of these symptoms. Involvement of the enteric nervous system is
also likely, but has not been studied directly.
Insomnia is often an early symptom of an AIP attack. Other acute neuropsychiatric

manifestations include anxiety, restlessness, agitation, hallucinations, hysteria,
disorientation, delirium, apathy, depression, phobias, and altered consciousness, ranging
from somnolence to coma.
Central nervous system (CNS) involvement can also cause seizures and posterior reversible
encephalopathy syndrome (PRES), also called reversible posterior leukoencephalopathy
syndrome, and involvement of the hypothalamus can result in the syndrome of
inappropriate antidiuretic hormone secretion (SIADH), which may also cause seizures from
hyponatremia [53]. (See "Pathophysiology and etiology of the syndrome of inappropriate
antidiuretic hormone secretion (SIADH)".)
The magnetic resonance imaging (MRI) changes characteristic of PRES may be due to
vasospasm ( image 1) [21,54]. (See "Reversible posterior leukoencephalopathy
syndrome".)
Bladder dysfunction/red urine — Neuropathic bladder dysfunction during an attack can

cause dysuria, hesitancy, urinary retention, and incontinence. Bladder distension may be
evident on physical examination.
Dark or reddish-brown urine is often an early symptom of an AIP attack ( picture 1); this
may be mistaken for hematuria [11,28,43,53,55]. The abnormal color is due to accumulation
of porphyrins and/or porphobilin in the urine. The abnormal urine coloration may lessen or
return to normal between attacks. (See 'Enzymatic defect' above.)
Urinalysis may show a clear, reddish color (or red-brown appearance said to resemble port
wine) and a negative dipstick (ie, no heme, leukocyte esterase, nitrite, glucose, or protein is
detected). Thus, elevated leukocytes or nitrite should prompt evaluation for a coexisting
urinary tract infection.
Laboratory and imaging findings — Results of tests commonly obtained during the

evaluation of acutely ill patients (eg, in an emergency department) are mostly normal in
patients presenting with attacks of AIP. The following findings may be seen during an acute
attack; none of these are specific for AIP (or other acute porphyrias):
● Hyponatremia is common; it is sometimes due to SIADH and sometimes to other

mechanisms such as gastrointestinal or renal sodium loss.
● Other less-specific electrolyte abnormalities may include hypomagnesemia and

hypercalcemia [28].
● Chronically elevated transaminases are common, but other liver function tests (eg,
bilirubin) are usually normal. (See 'Chronic manifestations' below.)
● Mild elevations in serum amylase and lipase may be seen during acute attacks; however,
substantial elevations of these pancreatic enzymes should suggest pancreatitis as an
alternative or concurrent diagnosis.
● Hematologic abnormalities are generally absent (eg, leukocytosis, anemia,

thrombocytopenia typically are not seen); their presence suggests an infection or other
disorder.
● Abdominal imaging may reveal small and/or large bowel distension due to ileus.
● Brain imaging may show reversible densities in white matter resembling posterior
reversible encephalopathy syndrome (PRES; also called reversible posterior

leukoencephalopathy syndrome), a syndrome of deranged cerebrovascular function.

(See 'Autonomic and central nervous system involvement' above and "Reversible
posterior leukoencephalopathy syndrome".)
In contrast to the above findings, elevations of urinary porphyrin precursors (ALA and
especially PBG) and porphyrins are always present during an acute attack of AIP (and
hereditary coproporphyria and variegate porphyria) ( table 4). These elevations are seen
during acute attacks, and often between frequently recurring attacks as well.
● Urine – During an acute attack, AIP is characterized by elevated urinary PBG, ALA, and
porphyrins, which consist mostly of uroporphyrin and coproporphyrin.
• PBG – Urinary PBG excretion is generally 20 to 200 mg/day during an attack,

markedly higher than the normal level of approximately 0 to 4 mg/day or per gram
of creatinine. A PBG concentration of 20 to 200 mg/L would be expected on the spot
urine assay during an acute attack, provided that the urine is not very dilute. It is
important to measure creatinine and express results per gram or mmol creatinine
before concluding that porphyria has been excluded.
• ALA – Urinary ALA is generally also markedly increased, but less so than PBG (when
measured in mg rather than mmol).
• Porphyrins – Total urinary porphyrin excretion exceeds 1000 mcg/day during an

acute attack, accompanied by markedly increased PBG. In contrast, elevated urinary
porphyrins with normal PBG and ALA is a nonspecific finding associated with some
other porphyrias, as well as many non-porphyric medical conditions such as liver
disease. Normal total urinary porphyrins with minor elevations in specific porphyrin
fractions is not considered to be consistent with AIP or any other porphyrias and
has no diagnostic significance. (See 'Differential diagnosis' below.)
● Plasma or serum – ALA and PBG are also elevated in plasma or serum during an acute
attack, but less so than in urine. Normal or only slightly increased plasma porphyrins,
and a peak porphyrin fluorescence at approximately 620 nm at neutral pH, may be
detected in AIP. Plasma porphyrins are more likely to be increased in hereditary
coproporphyria (HCP) and especially variegate porphyria (VP).
● Stool – Normal or only slightly increased fecal porphyrin levels are seen in AIP, but are
markedly increase in active cases of HCP and VP.
● Red blood cells (RBCs) – Decreased erythrocyte porphobilinogen deaminase (PBGD)

activity is seen in approximately 90 percent of patients; this finding is also seen during
asymptomatic periods.

The analysis of these precursors and porphyrin patterns, and our approach to their testing
in symptomatic patients, is presented below. (See 'Symptomatic patients' below.)
Of note, while AIP and the two other common acute porphyrias, HCP and VP, are
characterized by elevated urinary ALA and PBG, the final acute porphyria, ALA dehydratase
porphyria (ADP), is characterized by elevated urinary ALA and porphyrins, without
significant PBG elevation.
Chronic manifestations — Most patients have complete interval resolution of their AIP

symptoms between attacks. However, some patients develop chronic symptoms, especially
after multiple recurrent attacks.
● Pain requiring opioid analgesics may persist chronically. Patients with severe chronic
pain can require long-term opioids and this can be effective if well-managed by a pain
specialist. Treatment arrangements should be in place for recurrent attacks when these
occur. (See "Evaluation of chronic non-cancer pain in adults" and "Approach to the
management of chronic non-cancer pain in adults".)
● Depression and anxiety can be severe and associated with an increased risk for suicide,
especially in patients with chronic pain; psychiatric monitoring may be required [28,56].
(See "Screening for depression in adults".)
● Persistent elevations in serum transaminases are especially common in patients who

have had repeated disease exacerbations; it is not clear if there is an increased risk for
developing cirrhosis [32,57].
● A substantially increased risk of hepatocellular carcinoma occurs, especially after age 50;
this risk does not necessarily correlate with the presence of cirrhosis [58-66]. Monitoring
for hepatocellular cancer is discussed separately. (See "Surveillance for hepatocellular
carcinoma in adults", section on 'Our approach to surveillance' and "Acute intermittent
porphyria: Management", section on 'Monitoring for disease complications'.)
● Persistent hypertension may occur and be associated with development of chronic renal
disease [32,67,68]. Renal histology may reveal interstitial disease rather than findings
attributable to hypertension [69]. A number of patients have required dialysis or renal
transplantation, which have generally been well tolerated [70]. Evidence from a 2017
study suggests that a common variant of peptide transporter 2 (PEPT2), which encodes a
transporter for ALA in the kidney, may predispose to development of renal disease in
AIP [71].
DIAGNOSTIC EVALUATION

A high index of suspicion for acute porphyria is desirable because the presenting findings
are nonspecific and can be quite variable; early diagnosis and treatment of symptomatic AIP
can avert long-term and life-threatening complications.
Porphyria should be considered early in the evaluation of patients with unexplained

abdominal pain and/or neuropsychiatric symptoms even when acute porphyria is not the
most likely diagnosis (ie, even when the index of suspicion is not yet high).
While every patient with an acute episode of abdominal pain should not be screened for
acute porphyria, testing is appropriate after an initial workup for more common causes is
unrevealing. (See 'Clinical manifestations' above and "Evaluation of the adult with abdominal
pain".)
● Urinary ALA, PBG, and porphyrin excretion is increased during attacks and may decline
between attacks; however, levels often remain elevated between frequent exacerbations
and are sometimes elevated in those who have never had symptoms. Individuals with
elevated urinary heme intermediates who have never had symptoms are sometimes
referred to as "asymptomatic high excreters." (See 'Diagnosis' below.)
● ALA and PBG are less elevated in HCP and VP than in AIP and may decline more quickly
with attack resolution. In ALA dehydratase porphyria (ADP), the rarest type of porphyria,
PBG was normal or modestly elevated, with marked elevations in ALA and porphyrins
(mostly coproporphyrin III) in all documented cases. (See "ALA dehydratase porphyria".)
● Low erythrocyte PBGD activity is found in approximately 90 percent of patients with AIP
regardless of acute symptoms. (See 'PBGD activity (erythrocytes)' below.)
In addition to the importance of considering AIP, early testing for elevated PBG using spot
urine is also important because PBG testing is not available in-house at most medical
centers, and there will likely be delay in obtaining a result from an outside laboratory. The
laboratory should be asked to expedite PBG testing. Urinary PBG testing is very sensitive and
specific for AIP, hereditary coproporphyria, and variegate porphyria when done in the
setting of acute symptoms.
Overview of the evaluation — AIP (or other acute porphyria) should be suspected in an

adult with otherwise unexplained neurovisceral symptoms, such as abdominal pain;
vomiting; constipation; muscle weakness; psychiatric symptoms; or pain in the limbs, head,
neck, or chest ( table 3). Previous similar and recurrent symptoms may have occurred.
Importantly, a negative family history is not helpful in excluding the diagnosis of AIP,
because symptomatic disease may skip generations; in some families, only a single
individual who carries the AIP disease mutation has manifestations of AIP. Ethnicity is also
not helpful because AIP occurs in all races. Imaging is not useful for diagnosing AIP, but it

may be performed during the evaluation to look for other causes of the clinical findings. (See
'Differential diagnosis' below.)
The diagnostic approach depends on whether the patient is symptomatic at the time of
testing. Symptomatic patients are tested for elevations of urinary porphobilinogen (PBG) and
total porphyrins; if PBG is clearly elevated, the patient can be diagnosed with acute
porphyria, and treatment can (and often should) be initiated without waiting for additional
testing to determine the specific type of acute porphyria. However, samples for this
subsequent testing should be obtained at the time of the acute attack (ie, before therapy is
initiated) because samples obtained before treatment have the greatest likelihood of
providing a clear diagnosis.
Major features of the diagnostic evaluation include the following ( algorithm 1):
● Establish presence of acute porphyria and start therapy – A patient with acute
symptoms who is not previously known to have acute porphyria should have urinary
PBG tested with as little delay as possible. Urinary porphyrins are also measured on the
initial spot urine sample.
A substantial elevation of urinary porphobilinogen PBG (eg, >10 mg/L or >10 mg/g
creatinine) is sufficient to establish the presence of acute porphyria; importantly, this is
the only result required to initiate treatment, which is the same for all of the three
most common acute porphyrias (AIP, hereditary coproporphyria [HCP], and variegate
porphyria [VP]). If urinary PBG is substantially elevated, treatment should not be delayed
while awaiting the results of further testing to determine the specific type of porphyria,
especially in acutely ill patients ( algorithm 1). Details of PBG testing are discussed in
more detail below. (See 'Test urinary PBG and initiate treatment if positive' below.)
Subsequent biochemical testing can be done after treatment is started, preferably using
samples obtained before treatment is started. Of note, this subsequent analysis may
take days or weeks, depending on available laboratory resources.
● Determine the type of acute porphyria – Once the patient is determined to have a
substantial PBG elevation, the specific diagnosis of AIP, HCP, or VP can be established by
biochemical testing of urine (for ALA, PBG, and porphyrins), plasma and stool (for
porphyrins). In order to ensure the most accurate results, samples should be collected
before treatment is initiated because therapy (especially with hemin) reduces the levels
of these intermediates ( table 4). In practice, urinary PBG and some or all of this
additional biochemical testing is often ordered simultaneously before treatment with
hemin. Measuring creatinine on the same sample is important, since a very dilute urine
sample may give a falsely low PBG value, and this is obviated by expressing results as

per gram of creatinine. (See 'Test urinary PBG and initiate treatment if positive' below
and 'Obtain plasma and stool samples during the acute attack' below.)
● Obtain confirmatory testing – An approximately half-normal level of erythrocyte PBG

deaminase (PBGD) activity is found in approximately 90 percent of patients with AIP. In
patients with biochemical testing consistent with AIP, we perform DNA testing for PBGD
gene mutations, to confirm the diagnosis and to allow DNA testing of asymptomatic
family members ( table 5). (See 'Confirmatory testing' below.)
● Evaluate asymptomatic family members – Asymptomatic blood relatives of an

individual with a known AIP mutation can be evaluated by DNA testing, which is more
reliable for detecting latent cases than measuring erythrocyte PBG deaminase (PBGD)
activity. Identified AIP gene carriers can then take precautions to avoid exacerbating
factors. (See 'Asymptomatic patients' below.)
● Diagnose subsequent attacks clinically – We obtain a spot urine sample before hemin
treatment for measurement of PBG and creatinine, in order to monitor disease severity
by documenting the degree of PBG elevation for each attack. This information is useful
for the management of patients who have recurring attacks after known exacerbating
factors have been addressed, a setting in which management may be especially
challenging. It is also useful to measure "baseline" PBG levels between attacks for
comparison. However, in individuals with a known diagnosis of AIP, subsequent acute
attacks are often similar to past attacks, and the diagnosis of an acute attack is
confirmed clinically (ie, based on symptoms rather than biochemical testing). Treatment
of an acute attack in a patient with known AIP should not be delayed while awaiting the
results of PBG levels. (See "Acute intermittent porphyria: Management", section on
'Diagnosis of an acute attack in a patient with an established diagnosis of acute
porphyria'.)
This testing is described in more detail in the following sections.
Symptomatic patients
Test urinary PBG and initiate treatment if positive — Screening of a patient with

suspected acute porphyria is done with a spot (random) urine sample, which should be
assessed for PBG and total porphyrins ( algorithm 1). Measurement of urine creatinine is
also important, because a very dilute sample (eg, obtained after initial hydration with oral or
intravenous fluids) may show a misleadingly low PBG concentration even during an acute
attack.
Urine is tested first because PBG is increased in urine in all of the three most common acute
porphyrias, and a substantial increase (eg, >10 mg/L or >10 mg/g creatinine) is highly

sensitive and specific for an acute porphyria and is sufficient for initiating treatment,
regardless of the results of subsequent testing to determine which of the acute porphyrias is
present [28]. In a patient with renal failure, PBG can be measured in plasma or serum
instead of urine [28,49]. A sample obtained at the time of the acute attack and before
therapy is the most reliable for this testing because levels are highest during attacks, and
therapy (especially with hemin) can lower production and levels of these intermediates.
Porphyrins are also measured on the urine sample, but if the PBG is substantially elevated, a
porphyrin result and other results are not required to initiate treatment. Measuring
porphyrins also enables diagnosis of ADP and individuals with HCP and VP in whom PBG
elevation resolves rapidly. (See "Acute intermittent porphyria: Management", section on
'Overview of approach' and 'Obtain plasma and stool samples during the acute attack'
below.)
● Urinary PBG should be measured on a spot urine sample, which avoids delays from
collecting a 24-hour urine. Unfortunately, an inexpensive kit for rapid, semiquantitative
determination is no longer marketed. Therefore, it is necessary to have a rapid method
for urine PBG measurement available on-site, or to ask referral laboratories how rapidly
a quantitative result can be obtained and to expedite performance and reporting of the
test. The value of a rapid result is in the ability to initiate immediate treatment with
hemin based on a positive result, or to provide strong evidence against AIP, HCP, and VP
if the result is negative. Delays in therapy for critically ill patients may occur when a
rapid test result is not available.
Regardless of results from the rapid test, we perform quantitative PBG and porphyrin
measurements (send out tests at most institutions) using the same sample. The original
spot urine (or an aliquot) should be submitted to a laboratory that will carry out both
determinations, normalized to creatinine, on one sample.
● Send-out testing for PBG and porphyrins may be the only option when screening for
acute porphyrias, and results may take one to two weeks. The laboratory should be
made aware of the urgency of testing. Measurement of ALA and porphyrin fractionation
are requested if PBG or total porphyrins are elevated [28]. Substantial urinary PBG
elevation is sufficient to initiate therapy with hemin.
Laboratories that measure PBG by mass spectrometry generally have a substantially

lower upper limit of normal than those using ion exchange chromatography. This makes
it difficult to generalize about expected increases relative to this limit, and absolute
values provide more readily interpreted information. Regardless of the method or the
upper limit of normal, values <5 mg/day or <5 mg/g creatinine are likely to be
insignificant elevations.

Elevated urinary porphyrins not accompanied by PBG elevation is a nonspecific finding; is

not diagnostic for acute porphyria; and, while this may be seen during recovery of an attack
of HCP or VP, such patients rarely require urgent treatment with hemin. ALA is elevated, but
less-so than PBG, in the three most common acute porphyrias (AIP, HCP, and VP). Urine ALA
is markedly increased in ALA dehydratase porphyria (ADP), as well as other disorders in
which ALAD activity is diminished such as lead poisoning. Results of this extended urine
testing are interpreted along with results of plasma and stool porphyrin testing ( table 5).
Importantly, however, this additional testing is not required to exclude AIP, HCP, and VP if
urinary PBG and total porphyrins were normal at or near the time of symptoms and before
treatment with hemin. (See 'Obtain plasma and stool samples during the acute attack' below
and 'Differential diagnosis' below.)
If initial urine testing is negative but concern for AIP remains (eg, samples obtained after
partial symptom resolution or treatment initiation), urine testing can be repeated when
symptoms recur. Depending on the degree of suspicion for AIP and other acute porphyrias,
biochemical testing can also be done during asymptomatic periods; in this setting, testing
must be more comprehensive. DNA testing is also becoming a more widely available option.
(See 'Asymptomatic patients' below.)
Obtain plasma and stool samples during the acute attack — Additional testing of
plasma and stool porphyrins, preferably before treatment, is required to distinguish among
AIP and the other acute porphyrias (HCP, VP, ADP); this is done when a symptomatic patient
is found to have a substantial increase in urine PBG and/or porphyrins. These tests are
available from all major commercial laboratories. Characteristic patterns for AIP and other
porphyrias are presented in the table ( table 4).
Spot samples obtained at the time of acute symptoms (before treatment) are most reliable;
however, obtaining these samples should not delay treatment in a patient who is acutely ill
and has a substantial elevation in urinary PBG and/or ALA (or a history of these findings).
Results from a spot fecal sample obtained one to two days after starting treatment are likely
to be accurate, depending on intestinal transport time. If samples were not obtained during
the acute attack, these can be obtained during a subsequent attack; alternatively,
comprehensive biochemical testing with or without DNA testing can be done during
asymptomatic periods. (See 'Asymptomatic patients' below.)
Results consistent with AIP include the following:
● Plasma or serum – AIP is characterized by increased plasma or serum ALA and PBG,
especially during exacerbations, but less so than urine, along with normal or slightly
elevated total plasma porphyrins ( table 4 and table 5). Plasma may show a
fluorescence emission peak at 620 nm when diluted at neutral pH. In contrast, VP has

elevated plasma porphyrins, with a diagnostic fluorescence emission peak at

approximately 626 nm at neutral pH.
● Stool – AIP is characterized by normal or slightly increased stool porphyrins. In contrast,

HCP has markedly elevated coproporphyrin III, and VP has markedly elevated
coproporphyrin III and protoporphyrin in stool ( table 4 and table 5).
While these biochemical findings are consistent with AIP, they are not specific. As examples:
● Elevated urinary or plasma ALA is also seen with HCP, VP, ADP, lead poisoning, and
hereditary tyrosinemia type 1
● Elevated urinary or plasma PBG is seen with HCP and VP
● Elevated urinary or plasma porphyrins are seen with HCP, VP, ADP, cutaneous
porphyrias, and some other medical conditions (eg, liver disease)
● A plasma fluorescence peak at approximately 626 nm is specific for VP, but a peak at 620
nm is seen with other types of blistering cutaneous porphyrias
Patients with biochemical findings consistent with AIP should have erythrocyte PBG
deaminase (PBGD) testing and preferably DNA testing to confirm the diagnosis of AIP and
enable screening of relatives. (See 'Confirmatory testing' below.)
The following findings suggest that another condition (another acute porphyria or another
medical condition) is present rather than AIP:
● Increases in urinary porphyrins in the setting of normal ALA and PBG may occur in HCP
and VP, in which ALA and PBG increases are smaller in magnitude and briefer in duration
than with AIP. Elevated urinary porphyrins without elevated plasma or fecal porphyrins
(ie, nonspecific porphyrinuria) may occur in other medical conditions, especially
hepatobiliary disease, and is not consistent with any of the acute porphyrias.
● Marked elevation in fecal porphyrins is characteristic of HCP and VP rather than AIP, and
in very rare porphyrias such as congenital erythropoietic porphyria.
● A plasma fluorescence peak at approximately 626 nm is consistent with VP.
Further details regarding distinction of AIP from other porphyrias are presented below. (See
'Differential diagnosis' below.)
Asymptomatic patients
● Adults – Asymptomatic adults may be tested for AIP for two major reasons.
• An individual may have had symptoms suggestive of acute porphyria but did not
have appropriate diagnostic testing during the symptomatic episode(s). In

individuals who are asymptomatic at the time of testing, measurement of urinary

PBG, ALA, and total porphyrins may be useful if positive, but results are less likely to
be positive than at the time of symptoms. If results are negative, further evaluation
depends on clinical suspicion and elimination of other possible causes of the
symptoms, and may include plasma porphyrins, fecal porphyrins, and erythrocyte
PBGD activity; gene sequencing may also be performed, and is becoming more
readily available ( table 5). (See 'Test urinary PBG and initiate treatment if positive'
above and 'Obtain plasma and stool samples during the acute attack' above and
'Confirmatory testing' below.)
• An individual may be asymptomatic but learn that a porphobilinogen

deaminase/hydroxymethylbilane synthase (PBGD/HMBS) gene mutation has been
identified in a family member. In this setting, DNA testing specifically for the known
familial mutation should be used because it is more cost effective, sensitive, and
specific than the biochemical testing described above for patients with acute
symptoms. Individuals found to carry the familial mutation should have urinary PBG
measured, since substantial elevation indicates a higher risk for becoming
symptomatic. (See 'Confirmatory testing' below.)
Asymptomatic individuals who carry the familial mutation are at risk for porphyria
attacks and may benefit from avoiding factors that could trigger an attack (eg,
certain medications, ethanol, smoking, fasting). (See 'Exacerbating factors' above.)
If they do develop symptoms of AIP, the cause is likely to be recognized sooner

because they are already known to have latent AIP rather than simply a family
history of the disease.
If there is a family history of porphyria but a familial PBGD/HMBS mutation has not
been identified, evaluation of the index patient (ie, the family member with acute
porphyria) should be pursued first to determine the type of porphyria and the
mutation, if possible.
Individuals identified to have a PBGD/HMBS mutation should be counseled on

preventive measures to avoid developing symptoms. (See "Acute intermittent
porphyria: Management", section on 'Avoidance of exacerbating factors'.)
● Children – Children of AIP gene carriers who have a defined mutation should have DNA
testing. The advantage of identifying asymptomatic children who have inherited the
familial mutation is that the risk of developing symptoms is present soon after puberty,
and identification of a mutation can facilitate precautions to prevent attacks and/or
diagnose and treat attacks promptly. (See "Acute intermittent porphyria: Management",
section on 'Avoidance of exacerbating factors'.)

The decision to test is largely up to the parents, after considering the benefit of early
diagnosis, the potential risks of discrimination regarding insurance and occupational
opportunities, and the cost of DNA testing. Because the danger of attacks is low during
childhood, such testing can be postponed until near puberty at the discretion of the
parents. Ethical issues related to genetic testing of children are reviewed in more detail
separately. (See "Genetic testing".)
Confirmatory testing — Confirmation of the diagnosis if AIP is done by measuring the

activity of PBGD (the deficient enzyme in AIP) in erythrocytes or preferably DNA testing for
PBGD/HMBS mutations. Testing is done in individuals with the following findings:
● Characteristic patterns of ALA, PBG, and porphyrin excretion in urine, plasma or serum,
and stool ( table 4).
● A history of symptoms suggestive of AIP without appropriate diagnostic testing at the

time of acute symptoms, especially if diagnoses other than porphyria have been
eliminated.
● A family history of AIP or a known familial PBGD/HMBS mutation, in which case targeted
mutation analysis is most appropriate. If there is a family history of porphyria but a
familial PBGD/HMBS mutation is not identified by DNA testing (in the family and/or the
patient), other porphyria gene mutations should be pursued (eg, coproporphyrinogen
oxidase [CPOX] for HCP; protoporphyrin oxidase [PPOX] for VP) ( table 5).
DNA testing is especially useful, but may be more costly. DNA testing is occasionally negative
in the case of mutations in non-coding regions of the gene. Large deletions may not be
recognized by gene sequencing. Thus, we prefer to test both for erythrocyte PBGD enzyme
activity and gene mutations if possible.
Of note, PBGD deficiency can be identified in a fetus by measuring the enzyme activity or by
identifying the parental DNA mutation in amniotic fluid cells. However, this is seldom done
and usually not indicated, because the great majority of individuals with PBGD/HMBS
mutations remain asymptomatic during their lifetime, and those who do become
symptomatic typically do so after puberty; moreover, effective treatment is available for any
attacks that may develop [28].
Importantly, findings from confirmatory testing by DNA studies or measuring erythrocyte

PBGD activity cannot be used to distinguish between latent and active AIP or to identify an
acute attack.
PBGD activity (erythrocytes) — PBGD activity is measured in erythrocytes because

PBGD/HMBS mutations typically affect enzymatic activity of both the ubiquitous and
erythrocyte-specific forms of PBGD, and erythrocytes are the most accessible source for
measuring cytosolic heme pathway enzymes. PBGD activity testing is less expensive and
more widely available than DNA testing.
Erythrocyte PBGD activity is approximately half-normal in most patients with AIP. Decreased
PBGD activity in the appropriate clinical setting is helpful in confirming the diagnosis of AIP.
However, PBGD activity is less accurate than DNA testing, for the following reasons:
● There is overlap between the wide ranges of activity for this enzyme in individuals with
and without AIP.
● Some PBGD mutations cause enzymatic activity to be deficient only in non-erythroid

tissues. (See 'Gene mutation' above.)
● Erythrocyte PBGD activity is highly dependent upon red blood cell (RBC) age, and an
increase in the proportion of younger RBCs in the circulation (which may not always
have the appearance of reticulocytes) can raise the activity into the normal range in
patients who have AIP and a concurrent condition (sometimes inapparent) such as
hemolytic anemia or hepatic disease [72-74]. (See 'Enzymatic defect' above.)
PBGD activity testing is also useful in rare AIP families without an identified mutation,
because some mutations are not detected by gene sequencing (eg, large deletions or
mutations in regulatory regions), although this is rare.
DNA testing — A pathogenic variant (mutation) in the PBGD/HMBS gene is identified by

DNA testing (also called molecular testing or mutation analysis). A listing of available
resources for DNA testing is provided on the Genetic Testing Registry website. Identification
of a pathogenic mutation not only confirms the diagnosis of AIP, but most importantly
enables accurate identification of other gene carriers in a family. If DNA testing reveals a
pathogenic PBGD/HMBS mutation in an individual who has never had symptoms and with a
normal PBG level, we refer to this as latent AIP. (See 'Diagnosis' below.)
Finding a specific mutation in an index patient with proven AIP is highly recommended
before other family members are screened using DNA studies (as is the case for other acute
porphyrias as well). Rarely, a mutation is not found in a biochemically proven index case, and
biochemical screening must be relied upon for screening in such families.
It should be noted also that, as in other genetic conditions, it is not always clear if an
identified DNA sequence variant is pathogenic or benign [8]. Because such variants have
importance for both patients and their relatives, it is important to establish a biochemical
diagnosis in an affected individual, and to know if the gene (in this case PBGD/HMBS) was
fully sequenced to exclude other variants in that individual.

Diagnosis — We distinguish between manifest AIP (a disease) and latent AIP (a carrier state
with the potential to develop disease). These terms should be clearly defined when used in
clinical settings and publications.
● Manifest AIP – The diagnosis of AIP is generally made by measuring deficient PBGD
activity in erythrocytes and/or identifying a PBGD/HMBS mutation in an individual with
symptoms and biochemical findings consistent with AIP (ie, neurovisceral symptoms and
substantially elevated urinary PBG, with little or no elevation in plasma and fecal
porphyrins) ( algorithm 1 and table 5). Both tests are not required for diagnosis. If
only one confirmatory test can be done, DNA testing is more reliable. At least 95 percent
of individuals with AIP will have a mutation in the PBGD/HMBS gene, and approximately
90 percent will have deficient activity of erythrocyte PBGD.
● Latent AIP – The diagnosis of latent AIP is made by identifying a DNA mutation affecting
PBGD activity in an individual without symptoms of AIP. The term "latent" is sometimes
used for heterozygotes who have never had symptoms or PBG elevation and sometimes
for individuals who had manifest AIP in the past but no symptoms for many years, with
or without continued PBG elevation.
Some individuals with a PBGD/HMBS mutation who have never had symptoms may have
elevations in PBG that can be substantial; these are also considered clinically latent, and
these individuals are sometimes referred to as "asymptomatic high excreters." The latter
term may also include asymptomatic individuals with persistently high levels of PBG
who had symptoms of AIP in the past.
As noted above, an individual without AIP may have low erythrocyte PBGD activity; this
is because the normal range and the range for AIP are wide and overlap. If such an
individual has no PBGD/HMBS mutation and normal levels of PBG, the diagnosis of latent
AIP is not warranted. (See 'PBGD activity (erythrocytes)' above.)
DIFFERENTIAL DIAGNOSIS
The major considerations in the differential diagnosis of AIP are other causes of abdominal
pain; other causes of neuropathic or neuropsychiatric symptoms; other causes of liver
disease/abnormal liver function tests; and other porphyrias. Like AIP, these conditions may
present with nonspecific symptoms. Unlike AIP, non-porphyric conditions are associated with
normal urinary PBG. Isolated elevation of urine porphyrins (ie, without increased ALA and/or
PBG) is more suggestive of a non-porphyric condition rather than AIP; HCP and VP remain
possible because urinary ALA and PBG can normalize rapidly in these conditions, which are
excluded by further biochemical testing [75].

● Other causes of abdominal pain – Abdominal pain can occur in numerous clinical
settings. Acute porphyrias should be considered after initial evaluation excludes other
more common causes of abdominal pain. Unlike AIP (or other acute porphyrias), other
causes of abdominal pain do not cause elevations of urinary PBG. However, other causes
of abdominal pain may be associated with elevations in urinary porphyrins (eg,
hepatobiliary disease) or ALA and porphyrins (eg, lead poisoning and hereditary
tyrosinemia type 1). (See "Evaluation of the adult with abdominal pain" and "Causes of
abdominal pain in adults".)
Importantly, an individual with porphyria may present with another cause of abdominal
pain (eg, appendicitis, diverticulitis, inflammatory or ischemic bowel disease, biliary or
renal stones), and these conditions can also precipitate an acute porphyria attack.
Therefore, an elevated PBG does not exclude other causes of abdominal pain, and the
presence of another cause of abdominal pain does not exclude AIP (or other acute
porphyria).
● Other causes of neuropathy – Neuropathies can have a variety of clinical presentations

and etiologies. Unlike AIP (or other acute porphyrias), other causes of neuropathy (eg,
Guillain-Barré syndrome, which can mimic AIP) do not cause elevations of urinary PBG.
However, lead poisoning causes neuropathy and elevations of urinary ALA and
porphyrins. (See "Overview of polyneuropathy" and "Overview of hereditary
neuropathies".)
● Other causes of neuropsychiatric symptoms – Neuropsychiatric symptoms can

include anxiety, agitation, insomnia, hallucinations, seizures. There are many potential
causes, including neurodegenerative disease, alcohol and drug use, infectious,
autoimmune and paraneoplastic encephalitides, psychiatric illness, and psychotropic
medications. Like AIP, some of these other conditions may be associated with
hyponatremia from the syndrome of inappropriate ADH secretion (SIADH), and
abnormalities on neuroimaging may be seen. Unlike AIP (or other acute porphyrias),
these other causes of neuropsychiatric symptoms do not cause elevations of urinary
PBG. (See "Approach to the patient with visual hallucinations".)
● Other causes of seizures – Seizures may occur in a setting of acute medical illness
including hypoglycemia, hypocalcemia, uremia, and drug or alcohol intake. Unlike AIP
(or other acute porphyrias), these other causes of seizures do not cause elevations in
PBG. (See "Evaluation and management of the first seizure in adults".)
● Liver disease/abnormal liver function tests – Liver disease due to any cause may be
associated with elevated urinary porphyrin excretion, especially coproporphyrin. This
occurs because coproporphyrin is normally excreted in both bile and urine, and urinary
excretion of coproporphyrin increases when hepatobiliary function is impaired. Patients
with liver disease may also have slight elevations in ALA. Unlike AIP (or other acute
porphyrias), liver disease is not associated with elevated urinary PBG. (See "Approach to
the patient with abnormal liver biochemical and function tests".)
● Other acute porphyrias – Like AIP, other acute porphyrias can cause acute
neurovisceral attacks characterized by abdominal, neuropsychiatric symptoms, and
increases in urinary PBG, ALA, and porphyrins. Unlike AIP, other acute porphyrias,
namely HCP, VP, and ADP, have different patterns of porphyrin precursors and
porphyrins in urine, plasma or serum, and stool ( table 5 and table 4). VP, and less
commonly HCP, may also have blistering skin manifestations ( table 1); however, the
absence of skin manifestations does not exclude HCP or VP. (See "Porphyrias: An
overview".)
Importantly, as noted above, it is not necessary to differentiate AIP from other acute
porphyrias before treatment is started, because all acute porphyrias are treated in the
same manner during an acute attack; however, samples needed for distinguishing
among acute porphyrias should be collected before treatment if possible. (See
'Diagnostic evaluation' above.)
• HCP – Hereditary coproporphyria (HCP) is an acute porphyria like AIP; both HCP and
AIP are characterized by elevated urinary PBG, especially during an acute attack.
However, PBG elevation in HCP may be less marked and more transient than in AIP.
Unlike AIP, HCP can have blistering photosensitivity, although this is rare. Unlike AIP,
HCP is characterized by substantially increased fecal porphyrins, with predominance
of coproporphyrin III. (See "Hereditary coproporphyria".)
• VP – Variegate porphyria (VP) is an acute porphyria like AIP; both VP and AIP are
characterized by elevated urinary PBG, especially during an acute attack. PBG
elevation may be less marked and more transient in VP than in AIP. Unlike AIP, VP
also commonly causes blistering photosensitivity. VP is characterized by
substantially increased fecal porphyrins, with a predominance of coproporphyrin III
and protoporphyrin; in VP, plasma porphyrins are increased with a characteristic
peak fluorescence at approximately 626 nm when plasma is diluted at neutral pH,
which distinguishes VP from all other types of porphyria. (See "Variegate
porphyria".)
• ADP – Delta-aminolevulinic acid dehydratase (ALAD) porphyria (ADP) is an acute

porphyria like AIP. ADP is extremely rare. Unlike AIP (or HCP or VP), ADP is
characterized by elevated urinary ALA rather than PBG, as well as markedly
increased urinary coproporphyrin III and erythrocyte zinc protoporphyrin. All
documented cases of ADP have been in males, which is unexplained. (See "ALA
dehydratase porphyria".)
● Cutaneous porphyrias – Rarely, cutaneous porphyrias, which do not cause

neurovisceral symptoms but do cause increased porphyrin levels, may be misdiagnosed
as AIP in a patient who presents with coincidental abdominal pain or neurological
symptoms that are unrelated to the cutaneous porphyria. Unlike AIP (or HCP or VP), the
exclusively cutaneous porphyrias are associated with normal urinary PBG (
algorithm 2 and algorithm 3) and have diagnostic patterns of porphyrins in urine,
plasma, erythrocytes, and stool. (See "Congenital erythropoietic porphyria" and
"Erythropoietic protoporphyria and X-linked protoporphyria" and "Porphyria cutanea
tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and
diagnosis".)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Porphyria".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Acute intermittent porphyria (The Basics)")
SUMMARY AND RECOMMENDATIONS
● AIP is the most common of the four acute (neurovisceral) porphyrias ( table 1). It is
caused by an inherited deficiency of porphobilinogen deaminase (PBGD; also called
hydroxymethylbilane synthase [HMBS]), the third enzyme in the heme biosynthetic
pathway ( figure 2). AIP is an autosomal dominant disease with low penetrance (ie,

most patients who inherit the mutation never have symptoms). (See 'Epidemiology'
above and 'Pathogenesis' above.)
● Acute attacks of AIP are usually associated with one or more exacerbating factors, such
as medications ( table 2), smoking, sex hormones (eg, progesterone), reduced caloric
or carbohydrate intake (especially fasting), and stress. Unknown modifying genetic
factors are undoubtedly important in determining disease severity. (See 'Exacerbating
factors' above.)
● Clinical manifestations of AIP are due to neurologic dysfunction, which may include a
combination of sensory, motor, enteric and autonomic nervous system abnormalities.
The resulting neurovisceral symptoms can include abdominal pain, vomiting,
constipation, and extremity weakness and pain ( table 3). Hypertension,
hyponatremia, seizures, quadriplegia, or respiratory paralysis may be life-threatening,
requiring prompt diagnosis and treatment. The neurovisceral symptoms of AIP are
identical to other acute porphyrias. (See 'Clinical manifestations' above.)
● AIP (or other acute porphyria) should be suspected in an adult of any ethnic background
with otherwise unexplained neurovisceral symptoms, especially if previous similar and
recurrent symptoms have been reported. A negative family history is not helpful in
excluding the diagnosis of AIP, because symptomatic disease may skip generations.
Delays in diagnosis are common. (See 'Overview of the evaluation' above.)
● For a previously undiagnosed patient with acute symptoms consistent with AIP (or other
acute porphyria), we use a stepwise approach to diagnostic testing ( algorithm 1). The
most useful results are obtained from samples obtained during the acute attack before
treatment is initiated. (See 'Symptomatic patients' above.)
• Urinary porphobilinogen (PBG) and total porphyrin testing is ordered first; if these
results are normal, no further testing is needed to exclude AIP or other acute
hepatic porphyrias (hereditary coproporphyria [HCP], variegate porphyria [VP, or
delta-aminolevulinic acid dehydratase porphyria [ADP]) as the cause of concurrent
or recent symptoms.
• Urinary PBG elevation is highly sensitive and specific for the three most common
acute porphyrias (AIP, HCP, and VP) and is sufficient for initiating treatment, which is
the same for all acute porphyrias. Rapid testing for elevated urinary PBG greatly
facilitates prompt diagnosis or exclusion of these three porphyrias, especially in the
presence of symptoms. Elevation in urinary porphyrins, on the other hand, is
nonspecific and may be seen in other medical conditions, but this finding is useful
for detecting cases of HCP and VP, in which PBG may be only transiently elevated,
and to identify the fourth acute porphyria (ADP), which is extremely rare and which

elevates ALA and coproporphyrin III but not PBG. (See 'Test urinary PBG and initiate
treatment if positive' above and "Acute intermittent porphyria: Management",
section on 'Overview of approach'.)
• After finding a substantial elevation in urinary PBG, additional diagnostic testing is

done, preferably from samples obtained before treatment with hemin, to
distinguish among AIP, HCP, and VP. This testing includes urinary ALA and
porphyrins (if not already done), and plasma and stool porphyrins. Urinary
porphyrins are fractionated if the total urinary porphyrins are elevated. These tests
are likely to have long turnaround times (weeks) at most centers. If PBG is
substantially elevated, plasma and stool samples can be obtained and sent for
porphyrin measurements while treatment with hemin is started. (See 'Obtain
plasma and stool samples during the acute attack' above.)
• The diagnosis of AIP is confirmed by a finding of decreased erythrocyte PBG

deaminase (PBGD) activity and/or a mutation in the PBGD gene, also called
hydroxymethylbilane synthase (HMBS). We prefer to perform both confirmatory
tests if possible. (See 'Confirmatory testing' above and 'Diagnosis' above.)
● Asymptomatic family members and children of PBGD/HMBS mutation carriers are

diagnosed by DNA testing. Measuring erythrocyte PBGD activity is less expensive and
less reliable. An individual with a gene mutation but no symptoms is referred to as
having latent AIP; this is much more common than symptomatic AIP. (See 'Asymptomatic
patients' above and 'Diagnosis' above and 'Epidemiology' above.)
● Major considerations in the differential diagnosis of AIP are other causes of abdominal
pain; other causes of neuropathy (eg, Guillain-Barré syndrome); other causes of
neuropsychiatric symptoms or seizures; liver disease; other acute porphyrias (ADP, HCP,
VP); and, rarely, non-acute cutaneous porphyrias presenting with a concurrent condition
causing abdominal pain or neuropathy ( table 1). (See 'Differential diagnosis' above
and "Porphyrias: An overview", section on 'Acute hepatic porphyrias (AHP; exemplified
by AIP)'.)
● Treatment of AIP is discussed separately. (See "Acute intermittent porphyria:

Management".)
ACKNOWLEDGMENT
We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019.
The editors at UpToDate gratefully acknowledge Dr. Schrier's role as Section Editor on this

topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his
dedicated and longstanding involvement with the UpToDate program.
The UpToDate editorial staff also acknowledges extensive contributions of Donald H

Mahoney, Jr, MD to earlier versions of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
Topic 7096 Version 30.0

GRAPHICS
PBGD gene alternative splicing: Housekeeping and erythroid-specific

variants
Organization of the PBGD gene and alternative splicing to produce housekeeping and erythroid-
specific transcripts. Exons are shown as solid rectangles; Alu repeat elements are shown by
pentagons. The promotor for the housekeeping transcript is upstream of exon 1, and the
promotor for the erythroid transcript is immediately upstream of exon 2. ATG-H and ATG-
E represent the translation initiation codons for the housekeeping and erythroid forms,
respectively.
PBGD: porphobilinogen deaminase, also called hydroxymethylbilane synthase (HMBS).
Reproduced with permission from: Anderson KE, Sassa S, Bishop DF, Desnick RJ. Disorders of heme
biosynthesis: X-linked sideroblastic anemias and the porphyrias. In: The Metabolic and Molecular Basis of
Inherited Disease, 8th ed, Scriver CR, Beaudet AL, Sly WS, et al (Eds), McGraw-Hill, New York 2001. Copyright ©
2001 McGraw-Hill Education.
Graphic 96535 Version 2.0

Heme biosynthesis pathway showing chemical intermediates and sites of production (mitochon
Heme synthesis begins with the formation of delta-aminolevulinic acid (ALA) from glycine and succinyl-CoA by ALA synthase (AL
regulated by heme via feedback repression (dashed arrow at the top of the frame). Refer to UpToDate for a discussion of porph
CoA: coenzyme A.
Reproduced from: Anderson KE. The porphyrias. In: Zakim and Boyer's Hepatology: A Textbook of Liver Disease, 5th ed, Boyer TD, Wright TL, Man
permission of Elsevier Inc. All rights reserved.

Comparison of the major features of the four acute porphyrias
Deficient enzyme
Neurovisceral Blistering skin

(step in heme Inheritance
manifestations lesions
synthesis)
ALA dehydratase ALA dehydratase (2) Autosomal recessive Yes No

porphyria (ADP)
Acute intermittent PBG deaminase (3) Autosomal dominant, Yes No*

porphyria (AIP) variable penetrance
Hereditary Coproporphyrinogen Autosomal dominant, Yes Uncommon

coproporphyria (HCP) oxidase (6) variable penetrance
Variegate porphyria Protoporphyrinogen Autosomal dominant, Yes Common

(VP) oxidase (7) variable penetrance
Refer to UpToDate topics on porphyria for details.
ALA: 5-aminolevulinic acid (delta-aminolevulinic acid); PBG: porphobilinogen.
* A rare exception is patients with advanced renal failure, who may develop elevations in plasma porphyrins that produce blistering
skin lesions.

Examples of drugs known to be safe or unsafe in the acute porphyrias
Safe
Acetaminophen (paracetamol) Cephalosporins; refer to note Local anesthetics ¶ (eg, lidocaine,
Aminoglycosides Erythropoietin Δ bupivacaine)
Anesthetic (eg, propofol) Gabapentin Opioid analgesics ¶
Antiemetics* (ondansetron); refer to Glucocorticoids Penicillin and derivatives

note Histamine 2 receptor antagonists Δ (eg, Phenothiazines (eg, chlorpromazine,
Aspirin cimetidine, famotidine) prochlorperazine, promethazine)
Atropine Insulin Proton pump inhibitors (eg,

lansoprazole, omeprazole,
Benzodiazepines ¶ (eg, lorazepam, Levetiracetam
pantoprazole)
midazolam); refer to note
Vigabatrin
Unsafe
Alcohol Ethosuximide and methsuximide Primidone Δ
¶ Δ
Anesthetics (eg, etomidate, Griseofulvin Progesterone and synthetic
ketamine, thiopental) Hydralazine progestins Δ
Antipyrine (phenazone) Hydroxyzine Pyrazinamide Δ
Barbiturates Δ Meprobamate Δ Rifampin Δ
Carbamazepine Δ Nifedipine Spironolactone
Carisoprodol Δ Nitrofurantoin Sulfasalazine
Clonazepam (high doses) Oxcarbazepine Sulfonamide antibiotics Δ (including
Danazol Δ trimethoprim-sulfamethoxazole
Pentazocine
[cotrimoxazole])
Diclofenac Δ and possibly other Phenytoin Δ
NSAIDs Tamoxifen
Phenobarbital Δ
Efavirenz Topiramate
Ergot derivatives (including Valproic acid Δ

dihydroergotamine)
Estrogens Δ
This table includes examples of commonly used drugs known to be safe or unsafe in the acute porphyrias (ie, porphyrias
associated with acute neurovisceral attacks).
NOTE: This list is incomplete and includes drugs for which there is general agreement among experts. It is
recommended that clinicians consult the websites of the American Porphyria Foundation and the European Porphyria
Network, which are frequently updated; list many other drugs, including those that are not classified with certainty; and
provide evidence for these classifications. Because the evidence base is inadequate, expert assessments of the safety of
drugs in porphyria may differ. Refer to the UpToDate topics on individual porphyrias for more information.
NSAIDs: nonsteroidal antiinflammatory drugs.
* Serotonin 5HT3 antagonists are probably safe. Classification of metoclopramide is controversial but is generally a less effective
antiemetic.
¶ Not all agents within the same class will necessarily have the same risk. For example, though opioids are generally considered
safe, pentazocine may be unsafe. Benzodiazepines that are rapidly metabolized or administered in low doses are considered safe,
but the safety of high doses or prolonged use of long-acting agents is less certain. There are conflicting reports on the safety of
cephalosporins.
Δ In United States labeling for these drugs, porphyria is listed as a contraindication, warning, precaution, or adverse effect.
Erythropoietin is regarded as safe by other sources. Estrogens are unsafe for porphyria cutanea tarda but can be used with caution
in the acute porphyrias, especially in low doses or by the transdermal route.
Adapted from: Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias.
Ann Intern Med 2005; 142:439.

Menstrual cycle

Acute intermittent porphyria incidence of signs and symptoms
Abdominal pain 85 to 95%
Vomiting 43 to 88%
Constipation 48 to 84%
Muscle weakness 42 to 60%
Psychiatric symptoms 40 to 58%
Limb, head, neck, or chest pain 50 to 52%
Hypertension 36 to 54%
Tachycardia 28 to 80%
Convulsion 10 to 20%
Sensory loss 9 to 38%
Fever 9 to 37%
Respiratory paralysis 9 to 14%
Diarrhea 5 to 12%
AIP: acute intermittent porphyria.
From Annals of Internal Medicine, Anderson KE, Bloomer JR, Bonkovsky HL, et al, Recommendations for the diagnosis and treatment of the
acute porphyrias, Vol 142, Pg 439. Copyright © 2005 American College of Physicians. All Rights Reserved. Reprinted with the permission of
American College of Physicians, Inc.

Brain MRI images showing posterior reversible encephalopathy syndrome in AIP
(A, B) Brain MRI with axial FLAIR sequences showing hyperintensities scattered in the subcortical white
matter of the frontal and parietal lobes and prominent geographic subcortical hyperintensities in bilateral
occipital lobes.
(C, D) These FLAIR lesions recovered after one year. May be due to vasospasm.
MRI: magnetic resonance imaging; AIP: acute intermittent porphyria; PRES: posterior reversible encephalopathy
syndrome; FLAIR: fluid attenuated inversion recovery.
Reproduced with permission from: Kuo HC, Huang CC, Chu CC, et al. Neurological complications of acute intermittent
porphyria. Eur Neurol 2011; 66:247. Copyright © 2011 Karger Publishers, Basel, Switzerland. All rights reserved.

Urine in acute intermittent porphyria
Photograph of urine from a normal subject (left) and a subject with acute intermittent
porphyria (middle). The colors are compared with a dilute aqueous solution of red
wine (right).
AIP: acute intermittant porphyria
Provided by Shigeru Sassa, MD, PhD.

Excretion patterns for porphyrins, porphyrin precursors, and porphyrin metabolites; and de
ficient erythrocyte enzymes in the porphyrias
Type of Specific
Urine Stool Erythrocytes Plasma
porphyria porphyria
Acute neurovisceral ADP ALA, * Zinc ALA*

coproporphyrin protoporphyrin
III Markedly
decreased ALAD
activity
Acute neurovisceral AIP ALA, PBG, * Decreased PBGD ALA, PBG*

uroporphyrin, activity by [approximately
coproporphyrin approximately 620 nm] ¶
50% (most
cases)*
Acute neurovisceral, HCP ALA, PBG, Coproporphyrin III * Δ

rarely coproporphyrin [approximately
blistering cutaneous III 620 nm] ¶
Acute neurovisceral, VP ALA, PBG, Coproporphyrin III, * Porphyrin-

commonly blistering coproporphyrin protoporphyrin peptide
cutaneous III conjugate
[approximately
626 to 628 nm] ¶
Cutaneous, PCT and HEP Uroporphyrin, Heptacarboxyl Zinc Uroporphyrin,

blistering heptacarboxyl porphyrin, protoporphyrin heptacarboxyl
porphyrin isocoproporphyrins (markedly porphyrin
elevated in HEP, [approximately
normal or mildly 620 nm] ¶
elevated in PCT)
Cutaneous, CEP Uroporphyrin I; Coproporphyrin I Uroporphyrin I; Uroporphyrin I,

blistering coproporphyrin I coproporphyrin I coproporphyrin I
[approximately
620 nm] ¶
Cutaneous, EPP and XLP ◊ Protoporphyrin* Metal-free Protoporphyrin

nonblistering protoporphyrin § [approximately
634 nm] ¶
Refer to UpToDate topics on individual porphyrias for additional information.
ADP: delta-aminolevulinic acid (ALA) dehydratase porphyria; ALAD: ALA dehydratase; AIP: acute intermittent porphyria; PBG:
porphobilinogen; PBGD: porphobilinogen deaminase; HCP: hereditary coproporphyria; VP: variegate porphyria; PCT: porphyria
cutanea tarda; HEP: hepatoerythropoietic porphyria; CEP: congenital erythropoietic porphyria; EPP: erythropoietic protoporphyria;
XLP: X-linked protoporphyria.
* Porphyrin levels normal or slightly increased.
¶ Fluorescence emission peak of diluted plasma at neutral pH.
Δ Plasma porphyrins usually normal, but increased when blistering skin lesions develop.
◊ Urine porphyrins (especially coproporphyrin) increase only with hepatopathy.
§ Zinc protoporphyrin ≤15 percent of total in classic EPP, but 15 to 50% in variant form (XLP).
Provided by Karl Anderson, MD, FACP.

Algorithm for diagnosis of acute porphyria and use of hemin in patients with symptoms sugges
attack
Urine PBG may be tested by a screening method on-site (semiquantitative result, if available) or measured in a specialized labo
available in days to weeks). If available, a rapid method is extremely helpful because treatment can be initiated based on a pos
makes the diagnosis of an acute porphyria very unlikely. However, all symptomatic patients with suspected acute porphyria sho
porphyrins, and creatinine measured from the same sample. Because the results of quantitative testing are not known for days
total porphyrins on the same urine sample. Urine creatinine is measured to allow normalization (results expressed per gram of
topics on acute porphyrias for further details of diagnosis and treatment, and patterns of plasma and fecal porphyrin elevation
PBG: porphobilinogen; AIP: acute intermittent porphyria; HCP: hereditary coproporphyria; VP: variegate porphyria; ALA: delta-aminolev
ADP: ALAD porphyria.
* We perform genetic testing for the relevant porphyria following diagnosis; this may be used for further confirmation of the diagnosis
relatives and identification of new mutations. Genetic testing is required to confirm a diagnosis of ADP.

Diagnostic testing for active porphyrias
Additional
Concurrent or Types of
testing (if Enzyme and DNA
recent clinical Initial testing porphyria
initial results tests
manifestations identified
are positive)
Acute neurovisceral Spot urine PBG and Spot urine ALA, Delta-aminolevulinic Erythrocyte ALAD
total porphyrins PBG, and total acid dehydratase Sequence ALAD gene
(normalized with urine porphyrins porphyria (ADP)
creatinine) (quantitative,
Acute intermittent Erythrocyte PBGD
normalized with urine
porphyria (AIP) Sequence PBGD gene
creatinine)
Plasma porphyrins* Hereditary Sequence CPOX gene
Erythrocyte coproporphyria (HCP)
porphyrins ¶ Variegate porphyria Sequence PPOX gene
Fecal porphyrins (VP)
Blistering Total porphyrins Erythrocyte total Porphyria cutanea Erythrocyte UROD

photosensitivity (plasma*, serum, or porphyrins tarda (PCT) Sequence UROD
spot urine), with Urinary ALA and PBG gene Δ
fractionation if
Fecal total porphyrins Hepatoerythropoietic Erythrocyte UROD
elevated
porphyria (HEP) Sequence UROD gene
HCP Sequence CPOX gene
VP Sequence PPOX gene
Congenital Erythrocyte UROS

erythropoietic Sequence UROS gene
porphyria (CEP)
Nonblistering Total erythrocyte Erythrocyte metal-free Erythropoietic Sequence FECH gene

photosensitivity porphyrins ¶ and zinc protoporphyria (EPP)
protoporphyrin;
plasma total X-linked Sequence ALAS2 gene
porphyrins and protoporphyria (XLP)
fluorescence scan
First-line testing for symptomatic patients is guided by clinical features (ie, neurovisceral, cutaneous chronic blistering, or
cutaneous acute nonblistering). All spot urine measurements should be normalized with spot urine creatinine. If initial
testing is positive, further comprehensive testing follows to identify the type of acute porphyria. Enzyme measurements
may be used but are not available for all porphyrias. DNA testing usually follows establishment of a biochemical diagnosis.
Refer to UpToDate topics on overview of porphyria and specific porphyrias for additional details and testing in
asymptomatic patients.
PBG: porphobilinogen; ALA: delta-aminolevulinic acid; ADP: delta-aminolevulinic acid dehydratase porphyria; ALAD: delta-
aminolevulinic acid dehydratase; PBGD: porphobilinogen deaminase; CPOX: coproporphyrinogen oxidase; PPOX: protoporphyrin
oxidase; UROD: uroporphyrinogen decarboxylase; UROS: uroporphyrinogen III synthase; FECH: ferrochelatase; ALAS2: delta-
aminolevulinate synthase-2.
* Plasma porphyrins should include measurement of the total, fractionation if the total is elevated, and determination of the
fluorescence peak wavelength at neutral pH.
¶ It is important to verify that the method used by the laboratory measures all erythrocyte porphyrins and not just zinc
protoporphyrin.
Δ UROD mutations are neither required nor specific for a diagnosis of PCT. UROD mutations are found in approximately 20% of
patients with PCT and therefore are helpful if present. The presence of a UROD mutation is a predisposing factor but not sufficient
to cause PCT.

Algorithm for distinguishing chronic blistering cutaneous porphyrias
This algorithm outlines an approach to the patient with suspected cutaneous porphyria and chronic blistering photosensitivity.
porphyrias are generally very elevated (eg, 10 times the upper limit of normal). Fractionation of porphyrins is accompanied by d
wavelength at neutral pH. Separate algorithms are available for the patient with suspected cutaneous porphyria with acute no
suspected acute (neurovisceral) porphyria. Refer to UpToDate topics on individual porphyrias for further discussions of the clin
PCT: porphyria cutanea tarda; HCP: hereditary coproporphyria; VP: variegate porphyria; CEP: congenital erythropoietic porphyria; HEP: h
aminolevulinic acid; PBG: porphobilinogen; UROD: uroporphyrinogen decarboxylase; CPOX: coproporphyrinogen oxidase; PPOX: protopo
* We perform gene sequencing of the relevant gene for all cutaneous porphyrias diagnosed biochemically; this may be used for further
mutations, and genetic counseling. For PCT, UROD gene sequencing often does not reveal a mutation; the presence of a heterozygous U
other biochemically proven cases of porphyria, mutation of the associated gene is expected, and if no mutation is identified, this sugge
regulatory gene.

Algorithm for distinguishing non-blistering cutaneous porphyrias
This algorithm outlines an approach to the patient with suspected cutaneous porphyria and non-
blistering photosentivity. Separate algorithms are available for the patient with suspected cutanous
porphyria with blistering photosentitivity, and the patient with suspected acute (neurovisceral) porphyria.
Refer to UpToDate topics on individual porphyrias for further discussions of the clinical manifestations
and diagnostic evaluation. Refer to content on photosensitivity disorders for other diagnostic
considerations.
EPP: erythropoietic protoporphyria; XLP: X-linked protoporphyria; FECH: ferrochelatase; ALAS2: delta-
aminolevulinic acid synthase, erythroid form.
* We perform gene sequencing of the relevant gene for any patient with protoporphyria (FECH gene in EPP, ALAS2
gene in XLP). This is used for further diagnostic confirmation and especially for genetic testing and counseling of
family members.


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Acute intermittent porphyria: Pathogenesis, clinical

Acute intermittent porphyria (AIP; also called Swedish porphyria, pyrroloporphyria,

Despite its well-characterized molecular genetics, the diagnosis of AIP is challenging.

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Gene mutation — AIP is caused by heterozygosity for a mutation in the gene encoding

There is no convincing evidence for genotype-phenotype correlation in AIP (ie, particular

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ALAS1 synthesis is induced by the following:

Neurologic dysfunction — Neurologic dysfunction is responsible for the symptoms of AIP.

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symptoms by limiting formation of heme-containing proteins important for neurologic

● ALA is structurally similar to gamma-aminobutyric acid (GABA), the major inhibitory

Suggestions that reduced formation of heme-containing proteins might have clinical

● Decreased production of nitric oxide by the heme-containing enzyme nitric oxide

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Ethanol and smoking — Alcohol and smoking can exacerbate AIP.

● Progesterone, as well as some progesterone and testosterone metabolites, are potent

Nutrition, glucose metabolism, and stress — Starvation and/or reduced intake of calories

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Acute attacks — Manifest (symptomatic) AIP is characterized by acute attacks of

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Peripheral neuropathy — Sensory and motor neuropathy is common during acute AIP

Autonomic and central nervous system involvement — The autonomic nervous

Insomnia is often an early symptom of an AIP attack. Other acute neuropsychiatric

Bladder dysfunction/red urine — Neuropathic bladder dysfunction during an attack can

Laboratory and imaging findings — Results of tests commonly obtained during the

● Hyponatremia is common; it is sometimes due to SIADH and sometimes to other

● Other less-specific electrolyte abnormalities may include hypomagnesemia and

● Hematologic abnormalities are generally absent (eg, leukocytosis, anemia,

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leukoencephalopathy syndrome), a syndrome of deranged cerebrovascular function.

• PBG – Urinary PBG excretion is generally 20 to 200 mg/day during an attack,

• Porphyrins – Total urinary porphyrin excretion exceeds 1000 mcg/day during an

● Red blood cells (RBCs) – Decreased erythrocyte porphobilinogen deaminase (PBGD)

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Chronic manifestations — Most patients have complete interval resolution of their AIP

● Persistent elevations in serum transaminases are especially common in patients who

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Porphyria should be considered early in the evaluation of patients with unexplained

Overview of the evaluation — AIP (or other acute porphyria) should be suspected in an

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● Obtain confirmatory testing – An approximately half-normal level of erythrocyte PBG

● Evaluate asymptomatic family members – Asymptomatic blood relatives of an

This testing is described in more detail in the following sections.

Test urinary PBG and initiate treatment if positive — Screening of a patient with

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Laboratories that measure PBG by mass spectrometry generally have a substantially

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Elevated urinary porphyrins not accompanied by PBG elevation is a nonspecific finding; is

Results consistent with AIP include the following:

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elevated plasma porphyrins, with a diagnostic fluorescence emission peak at

● Stool – AIP is characterized by normal or slightly increased stool porphyrins. In contrast,

● A plasma fluorescence peak at approximately 626 nm is consistent with VP.

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individuals who are asymptomatic at the time of testing, measurement of urinary

• An individual may be asymptomatic but learn that a porphobilinogen

If they do develop symptoms of AIP, the cause is likely to be recognized sooner

Individuals identified to have a PBGD/HMBS mutation should be counseled on