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Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis

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
Literature review current through: Jul 2022. | This topic last updated: Jun 01, 2022.

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), also called hydroxymethylbilane synthase (HMBS). The gene is most commonly referred to as HMBS. AIP is an autosomal dominant disorder with low penetrance; a variety of exacerbating factors and unknown modifying genes determine whether symptoms will occur.

Despite its well-characterized molecular genetics, the diagnosis of AIP is challenging. Symptoms are often vague and nonspecific; other causes of neurologic findings and abdominal pain are numerous; and acute porphyria is rare and frequently not included in the differential diagnosis. Clues from the family history may be absent, because symptoms are not present in the majority of family members with a pathogenic variant in the HMBS gene. Even if acute porphyria is considered, many clinicians are unfamiliar with appropriate testing that can readily establish or exclude this diagnosis. Also, testing offered by different laboratories lacks consistency and harmonization. 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 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.

The central, peripheral, and autonomic nervous systems are affected when levels of certain heme pathway 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.)

Genetics — AIP is caused by heterozygosity for a pathogenic variant 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 pathogenic variants in HMBS 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 (particular variants do not predict disease severity). Rather, disease severity is highly variable, even within families that share the same variant. Disease severity is affected by a variety of environmental and other factors that act primarily by increasing expression of an enzyme upstream of PBGD in the heme biosynthetic pathway, delta-aminolevulinic acid synthase (ALAS1). This enzyme controls the rate of heme biosynthesis in the liver. (See 'Enzyme deficiency' below and 'Exacerbating factors' below.)

The HMBS/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 HMBS/PBGD variant always affects hepatic PBGD (the housekeeping form of the enzyme). The erythroid enzyme is generally affected as well because a region of the gene used for transcribing both housekeeping and erythroid forms is usually affected, although a resulting deficiency of the erythroid enzyme is not important in causing the disease. Disease-causing variants in some families (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 variant. (See 'Confirmatory testing' below.)

Enzyme deficiency — Pathogenic variants in HMBS/PBGD cause AIP because they decrease hepatic PBGD activity. 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 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 liver is central to neuronal damage in AIP, as 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 HMBS/PBGD pathogenic variants, the majority of individuals with pathogenic variants do not develop symptomatic AIP and have asymptomatic (latent) AIP throughout life (a pathogenic variant in HMBS/PBGD 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 individuals with a history of symptomatic disease after exacerbating factors responsible for their attacks are recognized and eliminated.

Only a minority of individuals with pathogenic variants in HMBS/PBGD have recurrent attacks even after known exacerbating factors are addressed. These individuals are sometimes referred to as "recurrent attack patients"; over time, some may have unexplained improvement.

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 in the heme synthesis pathway (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 directly induce synthesis of hepatic ALAS1.

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 induce ALAS1 and increase levels of ALA and PBG, leading to exacerbations of AIP.

PBGD 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 in part 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 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 that occur 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 processes [15,16]. A less favored hypothesis is that deficiency of heme limits formation of cellular hemoproteins important for neuronal or vascular functioning.

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 mouse models of PBGD deficiency (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 pathogenic HMBS variants in contrast to AIP patients, who are heterozygous.

EXACERBATING FACTORS — The frequency and severity of AIP attacks is highly variable, even within a family in which multiple members share the same gene variant. 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 environmental 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 (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 (https://porphyriafoundation.org/) and the European Porphyria Network (www.porphyria-europe.com). 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 (especially progesterone) in precipitating AIP symptoms:

AIP attacks begin after puberty, are more common in females, 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 individuals with AIP, even though progesterone levels are high [35]. However, some people experience more frequent attacks, sometimes in association with reduced caloric intake or the use of certain drugs, such as metoclopramide for the treatment of hyperemesis gravidarum [36,37]. However, whether metoclopramide is harmful in AIP has become controversial.

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 intake 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 are not well defined.

Effects of diabetes mellitus on AIP symptoms have not been carefully studied. Case studies suggest that in patients with AIP and diabetes, high glucose levels 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 individuals, of approximately 50 per million [11].

Interrogation of exomic and genomic databases has revealed an unexpectedly high prevalence of pathogenic HMBS 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 pathogenic variants in HMBS/PBGD in the general population (latent AIP) is unknown; however, the observation that many families with an AIP variant 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 pathogenic HMBS variant. However, AIP is more likely to manifest in females, leading to a female predominance of active 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 presentations are seen in children, but the clinical picture differs from classic AIP, in that it 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 pathogenic variants in HMBS/PBGD never develop symptoms (most have latent rather than manifest AIP). (See 'Pathogenesis' above.)

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 kidney 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 present in patients with frequent recurrent attacks. The frequency of attacks is highly individual for each patient. 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 [50]. 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 (intravenous hemin); however, recovery may be require up to one to two years, and some permanent paralysis may remain in some individuals [51,52].

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 [53]. 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 [54]. (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) [21,55]. (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 [11,28,43,54,56]. 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 'Enzyme deficiency' above.)

Urinalysis may show a clear, reddish color (or red-brown appearance said to resemble port wine) and a negative dipstick (negative for heme, leukocyte esterase, nitrite, glucose, and protein). 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 (such as 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 bilirubin is usually normal. (See 'Chronic manifestations' below.)

Mild elevations in serum amylase and lipase may be seen during acute attacks; however, substantial elevations of these enzymes should suggest pancreatitis as an alternative or concurrent diagnosis.

Hematologic abnormalities are generally absent (there typically is no leukocytosis, anemia, or thrombocytopenia); presence of these abnormalities 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.

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 of 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 with 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). A peak porphyrin fluorescence at approximately 626 nm at neutral pH is highly specific for VP. (See "Variegate porphyria", section on 'Diagnosis'.)

Stool – Normal or only slightly increased fecal porphyrin levels are seen in AIP, but levels are markedly increased 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 with AIP; 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.)

While AIP and the two other common acute porphyrias, HCP and VP, are characterized by elevated urinary ALA and PBG, the fourth and most rare acute porphyria, ALA dehydratase porphyria (ADP), is characterized by elevated urinary ALA and porphyrins, without significant PBG elevation. (See "ALA dehydratase porphyria".)

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. Skin biopsy may demonstrate small fiber neuropathy [50]. 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 [28,57]. (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 [32,58].

A substantially increased risk of liver cancer (hepatocellular carcinoma or cholangiocarcinoma) occurs, especially after age 50; this risk does not necessarily correlate with the presence of cirrhosis [59-69]. Monitoring for liver 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 kidney disease [32,70,71]. Kidney histology may reveal interstitial disease rather than findings attributable to hypertension [72]. A number of patients have required dialysis or kidney transplant, which have generally been well tolerated [73]. A common variant in the PEPT2 gene, which encodes peptide transporter 2, a transporter for ALA in the kidney, may predispose to development of kidney disease in AIP [74].

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 delta-aminolevulinic acid (ALA), porphobilinogen (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 hereditary coproporphyria (HCP) and variegate porphyria (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".)

For first-line testing (screening) for AIP and other acute porphyrias, it is recommended to measure PBG and total porphyrins using a spot/random urine, with results normalized to creatinine. Measuring ALA is not essential, since all conditions that elevate ALA will also elevate urine porphyrins.

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 a 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, HCP, and VP 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 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 (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 (>10 mg/L or >10 mg/g creatinine) is sufficient to establish the presence of acute porphyria; this is the only result required to initiate treatment, which is the same for all of the three most common acute porphyrias (AIP, HCP, and 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. 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). 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 pathogenic variants in the PBGD gene 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 HMBS variant can be evaluated by DNA testing, which is more reliable for detecting latent cases than measuring erythrocyte PBGD activity. Identified asymptomatic heterozygotes 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, 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 (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 (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 (>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 kidney 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 ALA dehydratase porphyria (ADP) and identification of individuals with HCP and VP, in whom PBG elevation resolves rapidly [75]. (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 [28,75]. 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 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 (such as with 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 has also become 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 (see 'Differential diagnosis' below):

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 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 past 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. Genetic analysis for pathogenic variants in HMBS/PBGD may also be performed and has become widely 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 pathogenic variant in the HMBS/PBGD gene has been identified in a family member. In this setting, DNA testing specifically for the known familial variant should be pursued 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 variant 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 variant are at risk for porphyria attacks and may benefit from avoiding factors that could trigger an attack (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 HMBS/PBGD variant has not been identified, evaluation of the index patient (the family member with acute porphyria) should be pursued first to determine the type of porphyria and the specific gene variant, if possible.

Individuals identified to have a pathogenic variant in HMBS/PBGD should be counseled on preventive measures to avoid developing symptoms. (See "Acute intermittent porphyria: Management", section on 'Avoidance of exacerbating factors'.)

Children – Children of individuals who have a pathogenic variant in HMBS/PBGD should be tested for the variant. The advantage of identifying asymptomatic children who have inherited the familial variant and have a risk of developing symptoms after puberty is that they can take 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", section on 'Ethical, legal, and psychosocial issues'.)

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 HMBS/PBGD gene variants. 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 HMBS/PBGD variant, in which case targeted genetic analysis is most appropriate. If there is a family history of porphyria but a familial HMBS/PBGD variant is not identified by DNA testing (in the family and/or the patient), other porphyria genetic testing should be pursued, including the coproporphyrinogen oxidase (CPOX) gene, affected in HCP, and the protoporphyrin oxidase (PPOX) gene, affected in VP (table 5).

DNA testing is occasionally negative in the case of variants 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 DNA testing if possible.

PBGD deficiency can be identified in a fetus by measuring the enzyme activity or by identifying the parental variant using DNA testing in amniotic fluid cells. However, this is seldom done and usually not indicated, because the great majority of individuals with HMBS/PBGD variants 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 [28,75].

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. (See 'Overview of the evaluation' above.)

PBGD activity (erythrocytes) — PBGD activity is measured in erythrocytes because HMBS/PBGD variants 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 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 HMBS/PBGD variants cause enzymatic activity to be deficient only in non-erythroid tissues. (See 'Genetics' 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 liver disease [76-78]. (See 'Enzyme deficiency' above.)

PBGD activity testing is also useful in rare AIP families without an identified variant, because some variants (large deletions or mutations affecting regulatory regions) are not detected by gene sequencing, although this is rare.

DNA testing — A pathogenic variant (mutation) in the HMBS/PBGD 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 variant 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 HMBS/PBGD variant 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 variant 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 variant 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 [8,75]. 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 HMBS/PBGD) 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 an HMBS/PBGD variant in an individual with symptoms and biochemical findings consistent with AIP (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 pathogenic variant in the HMBS/PBGD gene, and approximately 90 percent will have deficient activity of erythrocyte PBGD.

Latent AIP – The diagnosis of latent AIP is made by identifying a variant affecting PBGD activity in an individual without symptoms of AIP. The term "latent" is sometimes used for heterozygous individuals who have never had symptoms or PBG elevation and sometimes used 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 HMBS/PBGD variant 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 HMBS/PBGD variant 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 [75,79].

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, hepatobiliary disease may be associated with elevations in urinary porphyrins, and lead poisoning and hereditary tyrosinemia type 1 may cause elevated ALA and porphyrins. (See "Evaluation of the adult with abdominal pain" and "Causes of abdominal pain in adults".)

An individual with porphyria may present with another cause of abdominal pain (appendicitis, diverticulitis, inflammatory or ischemic bowel disease, biliary or kidney/ureteral 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).

Neuropathy – Neuropathies can have a variety of clinical presentations and etiologies. Unlike AIP (or other acute porphyrias), other causes of neuropathy, such as 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".)

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".)

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".)

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".)

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

Pathogenesis – 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 autosomal dominant with low penetrance (most patients never have symptoms). Acute attacks are usually associated with one or more exacerbating factors, such as medications (table 2), smoking, progesterone, reduced caloric or carbohydrate intake (especially fasting), and stress. (See 'Epidemiology' above and 'Pathogenesis' above and 'Exacerbating factors' above.)

Presentation – Manifestations are identical in all acute porphyrias and involve sensory, motor, and autonomic nervous system abnormalities including abdominal pain, vomiting, constipation, and extremity weakness and pain (table 3). Hypertension, hyponatremia, seizures, quadriplegia, or respiratory paralysis may be life-threatening. (See 'Clinical manifestations' above.)

Evaluation – AIP (or other acute porphyria) should be suspected in an adult with unexplained neurovisceral symptoms. Diagnostic delays are common, so previous similar and recurrent symptoms should increase suspicion. A negative family history does not exclude the diagnosis, because symptomatic disease may skip generations. (See 'Overview of the evaluation' above.)

For a previously undiagnosed patient with acute symptoms consistent with acute porphyria, first-line testing should be measurement of urine porphobilinogen (PBG) and total porphyrins (algorithm 1). The most useful results are obtained from samples obtained during the acute attack before treatment is initiated. (See 'Symptomatic patients' above.)

Urinary PBG – Urinary PBG and total porphyrins are ordered first; if these results are normal, no further testing is needed. Urinary PBG elevation is highly sensitive and specific for the three most common acute porphyrias (AIP, hereditary coproporphyria [HCP], and variegate porphyria [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 porphyrias, but is often not available.

In contrast, elevated urinary porphyrins are nonspecific and may be seen in other medical conditions but are useful for detecting 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'.)

Second-line testing – After finding a substantial elevation in urinary PBG, additional diagnostic testing distinguishes AIP from other porphyrias. This testing also determines whether elevation of urine porphyrins, a nonspecific finding, is due to acute porphyria or not. Preferably, samples obtained before treatment with hemin are used. Testing includes urinary ALA and porphyrins 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). 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.)

Diagnostic confirmation – The diagnosis of AIP is confirmed by decreased erythrocyte PBGD and/or a pathogenic variant in the HMBS/PBGD gene. Biochemical plus genetic confirmation is preferred. (See 'Confirmatory testing' above and 'Diagnosis' above.)

Relatives – Asymptomatic first-degree relatives are diagnosed by DNA testing. Measuring erythrocyte PBGD activity is less expensive and less reliable. An individual with a pathogenic variant in HMBS/PBGD but no symptoms is referred to as having latent AIP. (See 'Asymptomatic patients' above and 'Diagnosis' above and 'Epidemiology' above.)

Differential – Major considerations are other causes of abdominal pain, neuropathy (Guillain-Barré syndrome), neuropsychiatric symptoms or seizures, liver disease, other acute porphyrias (ADP, HCP, VP), and, rarely, cutaneous porphyrias (table 1). (See 'Differential diagnosis' above and "Porphyrias: An overview", section on 'Acute hepatic porphyrias (AHP; exemplified by AIP)'.)

Treatment – (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.

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Topic 7096 Version 32.0

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