Acute intermittent porphyria: Management

INTRODUCTION — Acute intermittent porphyria (AIP, Swedish porphyria, pyrroloporphyria, intermittent acute porphyria) is an autosomal dominant disorder of low penetrance resulting from a partial deficiency of porphobilinogen deaminase (PBGD, also known as hydroxymethylbilane synthase [HMBS], previously called uroporphyrinogen I synthase), the third enzyme in the heme biosynthetic pathway (figure 1).

Symptoms in AIP are chiefly due to effects on the visceral, peripheral, autonomic, and central nervous systems. They usually occur as intermittent attacks that can be life-threatening due to severe neurologic complications (eg, seizures, paresis). Symptoms may become chronic especially after many attacks.

The management of patients with attacks of AIP can be challenging because the disease manifestations are diverse and potentially severe. Timely intervention can resolve and prevent attacks; any other condition (eg, infection, medication exposure) that may have triggered the acute attack must also be addressed. Close long-term monitoring for complications is also needed.

The management of AIP is reviewed here, including treatment of acute attacks, prevention, and long-term monitoring for complications. The clinical manifestations and diagnosis of AIP and a general overview of the porphyrias are presented separately. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis" and "Porphyrias: Overview of classification and evaluation".)

OVERVIEW OF APPROACH — The goals of therapy for an acute attack of AIP (and any other acute neurovisceral porphyria, referred to collectively as acute hepatic porphyrias or AHPs) are to abate the attack as rapidly as possible with specific therapy and to provide symptomatic and supportive treatment until the attack abates.

Attacks are usually severe and require hospitalization, which facilitates intravenous hemin administration, treatment of pain and other symptoms, and monitoring of respiration, electrolytes, and nutritional status [1,2].

●Suspected versus established diagnosis – Individuals with suspected acute porphyria (eg, a new presentation consistent with AIP without a previous diagnosis) should be tested to confirm the presence of acute porphyria, by finding a substantial elevation of urinary porphobilinogen (PBG), before primary porphyria treatment is initiated, if possible. However, testing for elevated PBG may not be immediately available. (See 'Confirming that a patient has acute porphyria as a new or prior diagnosis' below.)

Urine total porphyrins should also be measured because PBG elevation does not occur in ADP and is less sustained in HCP and VP than in AIP. However, urine porphyrin elevations are nonspecific, and therefore porphyrins should not be ordered without also ordering PBG when acute porphyria is suspected. (See "Porphyrias: Overview of classification and evaluation", section on 'Initial testing for suspected AHP (urinary PBG and total porphyrins)'.)

•If PBG is elevated, it is not necessary to determine the specific type of acute porphyria the patient has before starting primary therapy with hemin, and therapy should not be delayed while awaiting the results of testing to distinguish among the acute porphyrias, as illustrated in the left side of the algorithm (algorithm 1) and discussed in more detail separately. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis".)

•If PBG and porphyrin results are not immediately available, the testing laboratory should be contacted and asked to expedite testing and to estimate when the results will be reported.

The initial results may be qualitative or expressed per liter; however, the laboratory should also be asked to report the final result as mg or micromol of PBG per gram or mmol of creatinine rather than per liter. A very high PBG result expressed per liter is diagnostic, but a normal value per liter does not exclude the possibility of a dilute urine sample and a falsely "normal" PBG concentration. PBG is expected to be in the range of 10 to 200 mg per gram of creatinine with an attack of AIP but may be less elevated in hereditary coproporphyria and variegate porphyria. Interpreting PBG results in terms of fold increases above normal is not recommended because upper limits of normal vary greatly between laboratories due to differences in methodology.

While the PBG and porphyrin results are pending, the pharmacy should be informed that a suspected case of acute porphyria may need urgent treatment with hemin.

A decision to start treatment with hemin when acute porphyria is suspected but the PBG result is not yet available may be justified if there are severe neurologic findings that are otherwise unexplained (eg, advancing paresis). Treatment with glucose should be initiated if the PBG result and/or hemin is not immediately available. Communication with the testing laboratory should continue until the result is reported. It is hoped that onsite rapid PBG testing will become more widely available in the future, to allow for more rapid diagnosis (or exclusion) of acute porphyria in patients with suggestive but nonspecific symptoms such as unexplained abdominal pain.

The choice of testing laboratory is important. Major send-out laboratories are reliable with regard to measuring urinary PBG and porphyrins. However, laboratories often report results as concentrations (per L) and may need to be asked to report results per g or mmol of creatinine.

•Testing for porphyria is appropriate even when the index of suspicion is not high, for example as part of a workup for unexplained symptoms such as abdominal pain in patients presenting to emergency units, primary clinicians or specialty clinics. In such instances, finding substantial elevations in urine PBG and porphyrin levels may be unexpected, if porphyria was part of a diagnostic evaluation but was not strongly suspected. Such results should be acted upon as soon as possible after results are reported, to facilitate specific treatment and avoid progression of signs and symptoms.

•For a patient with a previously well-established diagnosis of AIP (or other acute porphyria), the diagnosis of an acute attack is made clinically. Although testing for PBG elevation with each attack is recommended, therapy should not be delayed while awaiting the results of this testing. (See 'Evaluation before treatment of an attack' below.)

It is important to be sure that a previously established diagnosis is well-founded, which requires review of the evidence for the prior diagnosis, including documentation of a prior substantial elevation in PBG. Biochemical documentation of the type of acute porphyria and identification of the underlying familial genetic variant is considered standard of care. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'DNA testing'.)

●Porphyria-specific therapy – Hemin and carbohydrate (glucose) loading are used to abate acute attacks. They are considered specific therapies that downregulate hepatic delta-aminolevulinic acid synthase 1 (ALAS1), the rate-limiting enzyme for heme biosynthesis in the liver. (ALAS1 is the ubiquitous form of ALAS found in liver and other tissues, whereas ALAS2 is the erythroid form found only in erythrocyte precursors.) Hemin has a more potent effect and is used for severe attacks; glucose loading is sometimes used for mild attacks (eg, those that do not require hospitalization, opioid analgesia, or other intravenous medication; and are not accompanied by nausea and vomiting, motor neuropathy, paresis, seizures, agitation, delirium, psychosis, ileus that prevents oral intake, or hyponatremia). However, for most mild attacks, we suggest hemin because these attacks can progress and become more severe during glucose treatment. Glucose loading is used temporarily if hemin is not immediately available. (See 'Acute attack: Primary treatment (hemin)' below.)

●Supportive and symptomatic care – Symptomatic therapy and treatment of paralysis, seizures, and other potential disease manifestations can be initiated even before a diagnosis of porphyria is confirmed. Severe neurologic manifestations, including paralysis and seizures, are potentially life-threatening and must be addressed immediately. (See 'Acute attack: Management of symptoms and complications' below.)

Drugs harmful in porphyria should be avoided if possible until porphyria is excluded by a normal PBG result. (See 'Avoidance of exacerbating factors' below.)

Bedside spirometry should be available in all severe attacks to detect early respiratory impairment, and hemin should be continued until neurologic function recovers. (See 'Paresis and paralysis' below.)

Magnetic resonance imaging (MRI) for evaluation of seizures and other central nervous system symptoms may reveal findings consistent with posterior reversible encephalopathy syndrome (PRES). (See 'Seizures' below.)

Supportive and symptomatic treatment often includes opioid analgesics, phenothiazines, antiemetics, anxiolytics, sedatives for sleep, antihypertensives, and electrolytes for correction of metabolic abnormalities. (See 'Acute attack: Management of symptoms and complications' below.)

Exacerbating factors that may be contributing to the attack should be corrected promptly if possible, including elimination of potentially exacerbating medications; carbohydrate and caloric repletion, especially after fasting or metabolic stress; and treatment of concomitant infections. Monitoring for electrolyte abnormalities that complicate attacks should continue until the attack has resolved. It is important to avoid medications known to exacerbate acute porphyria and choose alternatives known to be safe until the diagnosis of acute porphyria is confirmed or excluded. (See 'Acute attack: Management of symptoms and complications' below and 'Avoidance of exacerbating factors' below.)

In women, the relationship of the attack to the menstrual cycle or to administration of progestins should be noted. Cyclic attacks typically occur premenstrually, during the luteal phase when progesterone levels are elevated, and are frequent in some women with AIP. Measuring serum progesterone at the time of an attack may help to identify this relationship. Keeping a menstrual and attack calendar can help to identify future attacks as premenstrual. (See 'Avoidance of exacerbating factors' below.)

●Latent disease – AIP remains "latent" in most individuals who inherit a pathogenic PBGD mutation. The term "latent" is variously defined, but often refers to individuals who have an AIP mutation but have not experienced an attack and usually have no elevations in porphyrin precursors and porphyrins. Although some individuals become susceptible to attacks at some time after puberty, most are believed to remain asymptomatic throughout life without developing increases in PBG and porphyrins. Patients with past attacks who have been well for many years with normal levels of PBG and porphyrins may also be referred to as having "latent" disease.

Asymptomatic individuals with elevated PBG levels are termed "asymptomatic high excreters" [3]; they may be more likely to develop attacks than those who have never had PBG elevations. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Diagnosis'.)

Individuals with latent disease do not require treatment but should be counseled yearly regarding potential triggers and means to avoid them, and their doctors should be made aware that they are at some risk for developing symptoms. They may also be at risk for developing liver cancer, but the degree of risk remains to be defined. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Clinical manifestations'.)

EVALUATION BEFORE TREATMENT OF AN ATTACK — This should include:

●Confirmation that the patient has AIP (or one of the other acute porphyrias), either as a new or existing diagnosis. However, treatment is sometimes initiated based on strong clinical suspicion before a report of porphobilinogen (PBG) elevation is available. (See 'Overview of approach' above and 'Confirming that a patient has acute porphyria as a new or prior diagnosis' below.)

●Determination based on clinical evaluation that the current symptoms are due to porphyria and not another condition. Individuals with porphyria can develop other conditions that may or may not trigger an attack; clinical evaluation of any acute illness should consider such possibilities. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis" and 'Diagnosis of an acute attack in a patient with an established diagnosis of acute porphyria' below.)

Confirming that a patient has acute porphyria as a new or prior diagnosis — Confirmation of a porphyria diagnosis is based on the finding of an elevated urinary PBG currently or in the past (algorithm 1). PBG elevation (at present or in the past) should be established by a quantitative method before hemin therapy is started. Details related to communication with the testing laboratory are described above. (See 'Overview of approach' above.)

When kidney function is severely impaired, AIP can be recognized by measuring PBG in plasma or serum. However, few laboratories offer this test and results are not as rapidly available.

A substantial elevation of urinary PBG is specific for the three most common acute porphyrias (AIP, variegate porphyria [VP] and hereditary coproporphyria [HCP], in that order), and is not found in any other medical condition. Of these porphyrias, AIP is the most commonly symptomatic (algorithm 2). Importantly, PBG may be less elevated during attacks of HCP and VP compared with AIP, so screening should also include measurement of urinary porphyrins, which are expected to be markedly elevated during attacks of AIP, HCP, and VP (see "Hereditary coproporphyria" and "Variegate porphyria"). Frequent attacks become much less frequent in most patients during treatment with givosiran, but attacks that do occur may be accompanied by little or no PBG elevation, a phenomenon that is poorly understood.

Patients with ALA dehydratase porphyria (ADP) have elevations in urine ALA and coproporphyrin III but not PBG, and elevation in erythrocyte zinc protoporphyrin. Screening for acute porphyrias will identify patients with ADP if urine porphyrins are measured. (See "ALA dehydratase porphyria".)

If PBG is found to be substantially elevated, further diagnostic testing is required to determine whether the patient has AIP, HCP, or VP. Urine porphyrins are elevated in all acute porphyrias as well as other medical conditions, so this is a much less specific finding than PBG elevation. To differentiate these acute porphyrias, additional samples should be collected for further testing before initiating treatment, if possible, but this should not delay treatment, which is the same for all of the acute porphyrias. Additional details related to diagnostic confirmation include the following:

●A prior diagnosis of AIP or other acute porphyria cannot be assumed to be correct without review of the prior laboratory documentation. Even a longstanding diagnosis of porphyria may be incorrect. Prior reports of DNA documentation should be examined carefully, since an identified variant may or may not be pathogenic. If evidence for the prior diagnosis is not available, particularly for an acutely ill patient, a spot urine should be obtained and tested for PBG and porphyrins (normalized to spot urine creatinine in the same sample) as soon as possible.

●In ADP, the fourth acute porphyria, which is very rare, PBG is normal or minimally elevated. ADP is excluded as a cause of acute symptoms if urine porphyrins are normal. Cases of ADP may be identified initially by elevation in urinary total porphyrins and further documented by elevations in urinary delta-aminolevulinic acid (ALA) and coproporphyrin III and erythrocyte zinc protoporphyrin. ADP should be confirmed by genetic analysis and finding biallelic pathogenic variants in the ALAD gene. (See "ALA dehydratase porphyria".)

●The distinction among AIP, HCP, VP, and ADP by biochemical testing can take place simultaneously with treatment. However, samples for testing should be obtained before administration of hemin because treatment can decrease levels of PBG and porphyrins.

●Molecular testing can also differentiate among the acute porphyrias if a known disease-causing mutation is identified, but sometimes variants identified are of uncertain significance (VUS).

Further details of the diagnostic evaluation are presented separately. (See "Porphyrias: Overview of classification and evaluation", section on 'Initial testing for suspected AHP (urinary PBG and total porphyrins)' and "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Diagnostic evaluation'.)

Recommendations regarding United States laboratories that can be contacted for testing are listed at the website of the United Porphyrias Association (https://www.porphyria.org/). Porphyria testing by different laboratories lacks harmonization, making comparison of results between laboratories difficult.

Diagnosis of an acute attack in a patient with an established diagnosis of acute porphyria — The diagnosis of an attack in a patient with known acute porphyria is primarily clinical. It is based on comparing the clinical presentation with prior acute attacks and on excluding other possible causes of the presenting signs and symptoms.

Recurrent attacks are generally similar in quality for each patient, although the severity may vary, especially if a different triggering factor is contributing. A substantial elevation of PBG does not prove that symptoms are due to porphyria because PBG can be elevated in the absence of symptoms, especially AIP and in some patients with HCP or VP.

In patients receiving givosiran, it is important to consider acute pancreatitis as a possible cause of abdominal pain or as a factor that contributed to developing an acute attack. (See 'Givosiran adverse effects' below.)

A more extensive discussion of the clinical manifestations of AIP, symptoms of an acute attack, and diagnostic testing is presented separately. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Acute attacks'.)

In patients with frequent attacks, documenting increased PBG levels with every attack is not necessary before starting treatment. However, subsequent reporting of PBG and porphyrin levels is useful for ongoing management for the following reasons:

●Monitoring the degree of PBG elevation with each attack is useful in long-term management of individual patients.

●Defining the degree of increase over the patient's baseline with each attack is also useful for ongoing assessment and management.

●Monitoring the course of the disease and attack patterns over time may be useful for predicting future attacks.

In women, the relationship of the attack to the menstrual cycle or to administration of progestins should be noted.

The following considerations are important in interpreting PBG results in patients with symptoms suggesting an acute attack of porphyria:

●A substantial increase in urinary PBG (eg, >10 mg/L or >10 mg/g creatinine) is highly sensitive and specific for acute porphyria and is sufficient for initiating treatment.

●Levels of PBG (and porphyrins and ALA) are often high in patients with acute porphyrias in the absence of symptoms, especially in those who have had prior attacks. Therefore, substantial elevations in their levels are diagnostic of an acute porphyria, but not of an acute attack.

●Levels of PBG, ALA, and porphyrins are likely to increase above baseline during an acute AIP attack, but the levels and degree of elevation between attacks may fluctuate considerably, and "baseline levels" (ie, those present when the patient is asymptomatic) are often difficult to establish [3].

ACUTE ATTACK: PRIMARY TREATMENT (HEMIN)

Hemin

Indications and mechanism of action — For all attacks of AIP (or other acute porphyrias), we recommend intravenous administration of hemin. This is especially true for attacks that are severe enough to require hospitalization, opioid analgesia, or other intravenous medication; or accompanied by nausea and vomiting, motor neuropathy, paresis, seizures, agitation, delirium, psychosis, ileus that prevents oral intake, or hyponatremia [1,4]. Even milder attacks often warrant treatment with hemin because they can rapidly become more severe without treatment.

This therapy should be administered without delay once a diagnosis of an acute attack of porphyria is established (ie, we do not perform an initial trial of glucose loading prior to starting hemin). However, if hemin is not immediately available on site, glucose loading should be used until hemin becomes available. Although hemin is costly, prompt administration can usually lead to rapid resolution of an attack, usually within four to five days. In contrast, glucose loading and general supportive measures should be considered only for mild attacks that are likely to resolve rapidly without hemin [1,4]. (See 'Carbohydrate loading as a temporizing measure' below.)

Our recommendation to administer hemin as initial treatment for most acute attacks differs from the product labeling for the lyophilized hematin preparation available in the United States (Panhematin), which recommends an initial trial of glucose loading prior to hemin administration [5]. Evidence that supports this approach is discussed below. We also recommend reconstituting Panhematin with albumin rather than sterile water. (See 'Supporting evidence' below.)

Intravenously administered hemin becomes partially bound to plasma hemopexin and mostly to albumin and is readily taken up by hepatocytes. It then enters and reconstitutes the regulatory "free" heme pool in hepatocytes (a hypothetical pool of heme not yet committed to form hemoproteins or to degradation by heme oxygenase) and represses synthesis of the first enzyme in the heme biosynthetic pathway, delta-aminolevulinic acid synthase 1 (ALAS1) (figure 1) [1,4,6]. ALAS1 activity controls the rate of synthesis of heme (and heme precursors) in the liver. Repression of ALAS1 by hemin treatment in turn decreases accumulation of heme precursors and their byproducts in patients with acute porphyrias, as documented by rapid and dramatic reductions in plasma and urinary porphobilinogen (PBG) and delta-aminolevulinic acid (ALA). (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Exacerbating factors'.)

Available hemin preparations — Hemin is the generic term for two formulations.

●Lyophilized hematin (ie, heme hydroxide; Panhematin) is available in the United States.

●Normosang (a concentrated solution of heme arginate) is available in Europe and South Africa.

Either formulation is available in some other countries. These are therapeutically equivalent for the treatment of AIP (equivalent repression of hepatic ALAS1). A source of confusion is that hemin is also the chemical term for heme liganded to chloride. Hemin chloride is a very stable form of heme but is not soluble at physiologic pH and therefore is not suitable for intravenous administration.

Details of administration — A typical hemin regimen is 3 to 4 mg/kg body weight given intravenously as a single daily dose until symptoms resolve, often after four days but sometimes longer. Dose-response studies are lacking. Although product labeling for Panhematin recommends a dose range of 1 to 4 mg/kg, doses less than 3 mg/kg are probably less effective. Conversely, administration more frequently than once per day is unlikely to improve efficacy and is not recommended. Treatment duration is extended to achieve a full response, such as in patients with advanced motor neuropathy. Hemin has been administered safely during pregnancy [1,7,8].

Product labeling recommends reconstitution of Panhematin with sterile water. However, it was discovered postmarketing that degradation products begin to form immediately upon reconstitution with sterile water, and these heme degradation products can bind to endothelial cells and clotting factors, causing infusion-site phlebitis and a transient anticoagulant effect [7-10]. Thus, a widely adopted and recommended practice to minimize these effects is stabilization of the product by reconstitution with 25 percent human albumin rather than sterile water [1,11,12]. Heme arginate is available in Europe and is more stable than Panhematin, but reconstitution of heme arginate with albumin is often recommended by authorities in Europe.

Supporting evidence — Hemin was first used in the early 1970s and has been commercially available since 1983 [13,14]. High-quality data from large randomized trials are lacking for hemin. Although a single small randomized trial did not establish efficacy, numerous case series and reports have reported effectiveness in hastening recovery from acute attacks, with a low risk of adverse events [1,4,7,8,15]. The following studies illustrate the efficacy of hemin in abating acute porphyria attacks:

●A trial that randomly assigned 12 patients with AIP to heme arginate or placebo found that administration of heme arginate was associated with trends toward reduction in length of hospital stay (8 versus 11 days) and decreased analgesic requirement (6425 versus 8150 mg of meperidine [pethidine]; comparable to 857 versus 1087 mg of morphine), although these were not statistically significant [16]. Therapy was well tolerated, with only mild phlebitis in five patients.

●A series of 22 patients with AIP who had 51 acute attacks, all treated promptly with heme arginate, reported rapid resolution of symptoms in all cases, with ability to discontinue opioids within approximately three days, and total hospitalization time of seven days or fewer; results that compared favorably with historical controls [7]. The only toxicity was moderate thrombophlebitis in one patient.

●A review of 136 patients hospitalized for AIP between 1940 and 1988 noted that the mortality rate was lower in the hemin era compared with the pre-hemin era, although this may have been attributable in part to other improvements in care (eg, improvements in supportive care) [17].

●Patients themselves report that hemin treatment is beneficial. For example, 108 patients with acute hepatic porphyrias studied by the Porphyrias Consortium reported that therapy with hemin was the most effective in treatment of acute attacks, resulting in improvements in abdominal pain and other symptoms in three-fourths of those treated [18]. On a patient-reported efficacy scale of 1 to 10, hemin was rated 7.9, whereas glucose was rated 4.4.

Adverse effects — Side effects of hemin other than infusion-site phlebitis are uncommon. Infusion-site phlebitis from Panhematin can be diminished by reconstitution with albumin rather than sterile water. (See 'Details of administration' above.)

Fever, aches, malaise, hemolysis, anaphylaxis, and circulatory collapse have been reported; excessive dosing of hemin caused reversible renal damage (acute tubular necrosis) in one case and acute liver failure requiring liver transplantation in another [19-22]. Hemin therapy is expensive, but its use can shorten hospitalization and reduce medical costs. Intravenous hemin is best given into a large-bore central vein with high blood flow by way of a peripherally inserted central catheter (PICC line) or other central venous catheter to reduce the risk of phlebitis.

Iron overload can develop after multiple hemin treatments. We monitor serum ferritin in patients who receive multiple hemin infusions (eg, at baseline and after 10 to 15 doses of hemin). Serum ferritin is also followed to detect iron deficiency, which is common in women with or without AIP, and in patients with repeated hospitalizations and frequent blood sampling. Of note, hemin administration can acutely raise serum ferritin as part of a subclinical acute phase response, and this may not be an indication of iron overload. When assessing iron status, ferritin should be measured as long as possible (preferably at least one month) after the most recent hemin administration. (See 'Monitoring for disease complications' below.)

Carbohydrate loading as a temporizing measure — Carbohydrate loading with intravenous glucose should be used if hemin is not immediately available (ie, as a temporizing measure) but is not a substitute for hemin. Glucose and other carbohydrates reduce excretion of porphyrin precursors by downregulating hepatic delta-aminolevulinic acid synthase 1 (ALAS1), an effect mediated by decreases in the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-alpha). However, the effects of glucose are weak compared with those of hemin. (See 'Supporting evidence' above and "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Nutrition, glucose metabolism, and stress'.)

Carbohydrate loading may be given as oral glucose polymer solutions, if tolerated, in amounts of at least 300 grams daily. However, during attacks, most patients have nausea, vomiting, and poor gut motility and are unable to take in sizable oral doses of glucose or other carbohydrates. Thus, in most cases, intravenous glucose needs to be given. A typical regimen is 300 to 400 grams per 24 hours, usually administered as a 10 percent solution [1]. This can be given for mild attacks for several days until improvement occurs or for more severe attacks until hemin becomes available.

Glucose administration is generally well tolerated. Of note, however, the effects of several liters of free water administered daily with intravenous glucose may increase the risk of hyponatremia. A parenteral nutrition (hyperalimentation) regimen may be used for malnourished patients or those with prolonged limitation of oral intake due to continuing symptoms. Hyperglycemia may also occur in some patients; glucose levels should be monitored and insulin may be given with glucose to prevent marked hyperglycemia in patients with glucose intolerance.

Therapies we do not use — Although other treatments have been suggested, none should be considered a substitute for hemin. As an example, cimetidine is a known inhibitor of hepatic cytochrome P450 enzymes (CYPs) and prevents hepatic porphyria in normal rodents caused by chemicals (eg, allylisopropylacetamide [AIA], which causes porphyria only after metabolic activation by hepatic CYPs) [23]. Chemicals requiring CYP activation are rarely if ever implicated in attacks of human AIP. Cimetidine has not been studied in rodents with targeted porphobilinogen deaminase (PBGD) mutations. Uncontrolled observations in small numbers of patients were suggested to show that intravenous cimetidine leads to resolution of attacks [24]; however, these reports do not exclude spontaneous improvement, which can occur without treatment with hemin [24]. Therefore, use of cimetidine in AIP lacks both rationale and clinical evidence, and it should not be considered a suitable, less expensive substitute for hemin.

Hemodialysis has also been suggested for treating acute attacks if hemin is not immediately available [25]. However, convincing evidence that hemodialysis leads to clinical or biochemical improvement is lacking. Plasmapheresis is also not regarded as effective [26].

ACUTE ATTACK: MANAGEMENT OF SYMPTOMS AND COMPLICATIONS — Neurologic and psychiatric manifestations of an acute attack are treated symptomatically using drugs that are considered safe in acute porphyrias, until specific therapy with hemin and/or glucose resolves the attack (table 1).

Pain — Pain in AIP is due to direct neuropathic effects of the disease during attacks; pain may become chronic. Pain is usually severe enough to require opioid analgesics during an attack. Parenteral administration of opioids such as morphine, hydromorphone, or fentanyl is often required during attacks when pain is severe and prolonged and oral intake of medications is not possible due to nausea, vomiting, and/or ileus. Meperidine is not recommended due to risk of precipitating seizures. Nonsteroidal antiinflammatory drugs (NSAIDs) are generally inadequate and can cause adverse effects on the gastrointestinal tract and kidneys. Most NSAIDs are probably safe in acute porphyrias, but some authoritative listings disagree. Acetaminophen is a safe alternative for mild pain. Chronic opioid treatment for chronic pain is sometimes necessary; this is best guided by a pain specialist.

Autonomic symptoms — Tachycardia and hypertension can be caused by effects of AIP on the autonomic nervous system. These can be treated with beta-adrenergic blocking agents; caution is warranted because tachycardia is sometimes due to hypovolemia or incipient cardiac failure [27].

Nausea and vomiting — Nausea and vomiting often accompany abdominal pain and may be caused by visceral neuropathy, ileus, or central nervous system effects of acute porphyria. Nausea and vomiting can interfere with dietary intake, which in turn can worsen the acute attack. Thus, these symptoms should be treated with antiemetics, along with intravenous fluids and carbohydrate supplementation for patients who are unable to maintain adequate oral hydration and caloric intake. Phenothiazine derivatives, such as prochlorperazine or promethazine, or serotonin (5-HT3) receptor antagonists such as ondansetron are safe to use in the acute porphyrias. (See "Characteristics of antiemetic drugs", section on 'Phenothiazines' and "Characteristics of antiemetic drugs", section on 'Serotonin receptor antagonists'.)

Cardiac telemetry may be appropriate during administration of 5-HT3 receptor antagonists (eg, ondansetron) or other drugs that can prolong the corrected QT interval (QTc) during hospitalization for acute attacks, although an increased risk of these adverse effects has not been reported in acute porphyrias. (See "Characteristics of antiemetic drugs", section on '5-HT3 receptor antagonists'.)

Anxiety and insomnia — Anxiety and insomnia may be due to a variety of central nervous system effects. These symptoms can be treated with short-acting benzodiazepines (table 2) in low doses [1]. (See "Pharmacotherapy for insomnia in adults", section on 'Benzodiazepine hypnotics'.)

Paresis and paralysis — Weakness caused by motor neuron dysfunction is especially common during severe and prolonged attacks; neuromuscular respiratory failure may also occur.

Bedside spirometry should be available to detect early respiratory impairment in patients with severe attacks of porphyria. A falling vital capacity should prompt close monitoring of partial pressure of oxygen (pO₂) and partial pressure of carbon dioxide (pCO₂) (typically in an intensive care unit [ICU]) to determine the need for ventilatory support. Typically, ICU care is appropriate in patients with respiratory impairment from any cause (eg, when forced vital capacity [FVC] is <50 percent of predicted or maximal inspiratory pressure [MIP] is less negative than -30 cm H₂O). (See "Respiratory muscle weakness due to neuromuscular disease: Clinical manifestations and evaluation".)

Options available for ventilatory support are discussed in detail separately. (See "Respiratory muscle weakness due to neuromuscular disease: Management".)

Hemin treatment is indicated in any patient with porphyric motor neuropathy. If started soon after the symptoms appear, this can lead to rapid improvement, beginning within hours or days. Patients with advanced motor neuropathy in whom the initial diagnosis of porphyria and treatment were delayed will recover more slowly and at an unpredictable rate.

There are no established guidelines for continued hemin treatment in such patients, but hemin can be continued at least until neurologic improvement is evident and other acute symptoms of the attack have cleared. Hemin may be given less frequently as improvement occurs (frequency reduced to every second day or twice weekly). Less frequent dosing may be adjusted to maintain a normal or modestly elevated level of urine or plasma porphobilinogen (PBG) as determined by serial measurements. Patients have been treated for weeks to months without adverse effects as neurologic function gradually improves, although experience is extremely limited.

Neurologic recovery from severe attacks can continue for one to two years or longer. Some patients are left with some motor weakness, such as foot or wrist drop or hand weakness. Close follow-up is important to avoid or promptly treat recurrent attacks because these are detrimental to continued recovery from previous paresis.

There are few additional options for treatment of advanced motor neuropathy that does not respond to hemin.

Seizures — Seizures can be caused by direct central neurologic dysfunction due to porphyria itself or by hyponatremia, often resulting from hypothalamic involvement and the syndrome of inappropriate antidiuretic hormone secretion (SIADH). SIADH is a diagnosis made when the total blood volume is increased, which may not always be the case in individuals with AIP who have seizures from hyponatremia. Hyponatremia and hypomagnesemia should be carefully corrected if present. (See "Overview of the treatment of hyponatremia in adults" and "Hypomagnesemia: Evaluation and treatment".)

●Seizures are treated as acute, provoked events (eg, with treatment of the underlying cause [AIP or hyponatremia], supportive care, and establishment of intravenous access); a benzodiazepine or levetiracetam is used, as is generally recommended, if a seizure lasts longer than two minutes. (See "Evaluation and management of the first seizure in adults", section on 'Acute symptomatic seizures' and "Evaluation and management of the first seizure in adults", section on 'Early postseizure management'.)

●Additional antiepileptic medications may be required if seizures do not resolve rapidly (eg, within 5 to 10 minutes). (See "Convulsive status epilepticus in adults: Management".)

●Chronic antiepileptic therapy is rarely needed but is appropriate when epilepsy is a concomitant condition. (See "Overview of the management of epilepsy in adults".)

If an antiepileptic medication is required, early involvement of a porphyria expert and a consulting neurologist is important, as well as the use of resources listing safe and unsafe drugs (table 1). Almost all anticonvulsant medications have at least some potential for exacerbating acute porphyrias. Gabapentin (eg, Neurontin, Gralise), pregabalin, and levetiracetam (Keppra) are safe, and clonazepam is probably less harmful than phenytoin, barbiturates, or valproic acid [28,29].

PREVENTION OF ATTACKS

Avoidance of exacerbating factors — Reducing or eliminating exacerbating factors plays an important role both in treating the acute attack and in preventing future attacks [30]. Often multiple predictable inciting factors have contributed to an attack and must be addressed.

Potentially harmful medications and lifestyle factors include the following:

●Medications – Drugs known to be harmful in patients with AIP should be discontinued whenever possible during the acute attack (table 1). It is strongly recommended that clinicians consult the websites of the Porphyria Drug List (https://www.porphyriadrugs.com/) and the Norwegian Porphyria Center (NAPOS) (https://www.drugs-porphyria.org/), which are frequently updated; list many drugs, including those that are not classified with certainty; and provide evidence for these classifications. It should be kept in mind that classifications of drugs (eg, as safe, probably safe, probably unsafe, or unsafe) are often based on incomplete evidence and are sometimes controversial.

These websites should be consulted to avoid prescribing harmful drugs in treating intercurrent illnesses or symptoms (table 1) [31,32]. (See 'Acute attack: Management of symptoms and complications' above and "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Medications' and "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Exacerbating factors'.)

●Smoking and alcohol – We counsel patients to avoid or discontinue smoking, including use of marijuana, and to avoid alcohol intake. Smoking and alcohol intake can both exacerbate AIP (and other acute porphyrias) via induction of hepatic cytochrome P450 enzymes (CYPs), which in turn can deplete the regulatory pool of hepatic heme; they can also directly induce delta-aminolevulinic acid synthase (ALAS1), leading to increased synthesis of toxic heme precursors. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis" and "Porphyrias: Overview of classification and evaluation" and "Overview of smoking cessation management in adults".)

●Diet – Consultation with a dietitian may identify dietary factors responsible for precipitating attacks and help maintain a well-balanced diet somewhat high in carbohydrates (eg, as 60 to 70 percent of total calories). Additional dietary carbohydrates and/or calories are unlikely to be helpful and may lead to excessive weight gain. If used, weight loss diets should provide gradual weight loss and should be used during periods of clinical stability. Precipitation of acute porphyria symptoms after weight loss surgery has been reported; although it has been applied safely in some patients, we prefer to avoid this method of weight loss [33]. (See "Dietary assessment in adults".)

●Treatment and prevention of infections and other intercurrent illnesses – Infection or other illnesses can cause metabolic stress that may exacerbate AIP. Prompt treatment of any infections or other illnesses, including safe antibiotics, adequate hydration, and correction of any associated metabolic abnormalities, is essential.

Infections such as urinary tract infections or pneumonia may trigger attacks of porphyria. Abdominal infections and other conditions (eg, appendicitis, pancreatitis, diverticulitis) may present similarly to AIP attacks. Fever and leukocytosis are likely to be caused by infection or inflammation rather than AIP. When symptoms are due to both an infection and an acute attack, the infection should be treated simultaneously with specific AIP treatment (hemin). (See "Evaluation of the adult with abdominal pain" and "Causes of abdominal pain in adults".)

Vaccinations are as important in individuals with AIP as in those without AIP. We ensure that all appropriate vaccinations are administered to prevent infections that might trigger an attack. Specific recommendations are presented in detail separately. (See "Standard immunizations for nonpregnant adults".)

●Attention to iron stores – Anemia is not a feature of AIP; however, iron deficiency is common in women during their reproductive years and should be corrected because of the theoretical concern that iron deficiency might further impair heme synthesis. It may be advantageous to monitor serum ferritin and assure adequacy of iron stores as indicated by a level above approximately 20 ng/mL. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and "Treatment of iron deficiency anemia in adults".)

●Suppression of menstrual cycle-related attacks – Frequently recurring attacks confined to the luteal phase of the menstrual cycle can be prevented with a gonadotropin-releasing hormone (GnRH) analogue to suppress ovulation [34-38]. If treatment is effective after several months, additional therapies should be included to prevent bone loss. Options include low-dose estradiol, preferably by the transdermal route; a bisphosphonate; or switching to a low-dose estrogen-progestin contraceptive. (See "Hormonal contraception for menstrual suppression" and "Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists", section on 'GnRH with add-back therapy'.)

The mechanisms by which multiple factors can exacerbate AIP are discussed in more detail separately. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Exacerbating factors'.)

Givosiran — Givosiran (Givlaari) is a small interfering RNA (siRNA) therapeutic directed against hepatic ALAS1, the gene that is induced in individuals with active AIP and thereby contributes to the accumulation of the neurotoxic heme intermediates delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) [39]. Givosiran is approved by the US Food and Drug Administration for treatment of adults with acute hepatic porphyrias (AIP, hereditary coproporphyria [HCP], variegate porphyria [VP], and ALA dehydratase porphyria [ADP]) [40]. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'Gene silencing'.)

Indications for givosiran — For most adults with AIP (or other acute hepatic porphyria) who have frequent attacks (at least three to four attacks per year, or requiring hemin prophylaxis to prevent this frequency of attacks), we suggest givosiran. This is expected to markedly reduce the frequency of attacks, although long-term safety data are limited, as discussed below. Givosiran has not been studied for treatment of acute attacks, and hemin remains recommended for this purpose. (See 'Hemin' above.)

Administration of givosiran

●Dosing – Givosiran is administered as a subcutaneous injection once per month at a dose of 2.5 mg/kg. Medical support should be available to manage rare anaphylactic reactions. Concomitant use of drugs metabolized by cytochromes CYP1A2 and CYP2D6 (table 3) should be avoided or monitored. In patients with obesity, the dose may be limited to one vial (189 mg), since the drug is targeted to the liver and uptake in adipose tissue is unlikely.

●Monitoring

•All individuals treated with givosiran should have monitoring of liver function tests at baseline and periodically (eg, monthly) during treatment, at least for the first six months. Since long-term experience is limited, continued monitoring of liver function tests and other safety tests may be appropriate after the first six months. The drug should be discontinued if severe transaminase elevations (eg, more than five times the upper limit of normal) or increased bilirubin develop.

•Monitoring of kidney function and discontinuation if it worsens is also appropriate [41]. The efficacy and safety of givosiran in patients with pre-existing liver or kidney dysfunction has not been studied, and these individuals should have continued monthly monitoring during therapy.

•Givosiran can cause increased blood homocysteine levels, the significance of which is unclear. The package insert advises testing blood homocysteine levels before and during treatment and, if homocysteine is elevated, assessing levels of vitamin B12, folate, and vitamin B6 [42]. Supplementation of these vitamins if deficient has decreased plasma levels of homocysteine during treatment with givosiran [43,44].

●Expected response – Attacks may still occur at a reduced rate with givosiran, with or without elevation of urinary ALA and PBG, and unless another cause for symptoms is evident, individuals who develop acute attacks while receiving givosiran are treated with hemin (see 'Hemin' above). Chronic symptoms are also likely to persist and are treated as described below. (See 'Chronic symptoms' below.)

The need for continuing givosiran treatment should be reevaluated periodically, although the optimal duration of therapy before this reevaluation occurs and the optimal criteria for deciding to continue or discontinue therapy have not been determined. Reevaluation after one to two years of givosiran treatment seems reasonable until more data become available [43].

Evidence for efficacy of givosiran — The efficacy of givosiran in reducing the rate of AIP attacks was demonstrated in the following trials:

●The ENVISION trial, which randomly assigned 94 individuals 12 years or older with acute hepatic porphyria (AHP, of which 89 had AIP) who had at least four attacks yearly to receive monthly givosiran (2.5 mg/kg) or placebo for six months, found a dramatic reduction in the rate of acute attacks, defined as attacks requiring a medical visit, hospitalization, or home administration of hemin [45]. Individuals with significant kidney disease and liver disease were excluded. Compared with controls, who had an annualized attack rate of 12.5, individuals assigned to givosiran had only 3.2 annualized attacks, and one-half of the individuals in the givosiran group had no attacks at all. Daily pain scores were also improved, hemin use was decreased, and biochemical testing showed reductions in urinary ALA and PBG. These benefits occurred rapidly and were sustained for the duration of the trial. In an open-label extension period, 93 patients received givosiran 2.5 or 1.25 mg/kg for six months or more before transitioning to 2.5 mg/kg, and improvement and less requirement for hemin treatment were sustained [46].

●Two earlier dose-finding trials reported similar findings and helped to establish the 2.5 mg/kg dose, which reduced ALAS1 levels and urinary ALA and PBG by a mean of 86, 91, and 96 percent, respectively [47].

Similar benefits are anticipated in individuals with other AHPs based on the similar role of ALAS1 in acute attacks.

Givosiran adverse effects — In the ENVISION trial, adverse effects included rash, nausea, decreased glomerular filtration rate, and increased hepatic transaminases; one individual with increased transaminases discontinued therapy and one temporarily stopped therapy and resumed at a lower dose without recurrence [45].

Acute pancreatitis has been reported in patients treated with givosiran, leading to a revision of the package insert to note this possible adverse effect [48].

It is especially important to consider acute pancreatitis as an alternative or additional cause of abdominal pain. Pancreatitis, like any other illness, may contribute to the development of an acute attack. Evaluation is discussed separately. (See "Clinical manifestations and diagnosis of acute pancreatitis".)

Prophylactic hemin — Prophylactic hemin is sometimes an effective option for preventing frequent attacks of acute porphyrias [49]. This is especially true if givosiran is not available or poorly tolerated.

A GnRH is another alternative if attacks are in the luteal phase of the menstrual cycle. (See 'Avoidance of exacerbating factors' above.)

Hemin can be administered once or twice weekly. The decision to initiate prophylactic hemin is made on a case-by-case basis depending on attack frequency and severity. For example, prophylactic hemin might be appropriate in a patient who has at least monthly severe, non-cyclic attacks despite the preventive measures outlined above. An indwelling port may be necessary to assure venous access. (See 'Hemin' above.)

Liver transplantation — Transplantation of a normal liver in patients disabled by recurrent attacks of AIP has been highly effective in most cases without advanced motor neuropathy [50-52]. This may be an option for severely affected patients whose disease is not responsive to other treatment. However, quadriplegic patients may not be good candidates for such major surgery. Reasonable indications for liver transplantation include frequent hospitalizations, unresponsiveness to hemin or givosiran, and poor quality of life. However, it is often difficult to weigh the risks and benefits of liver transplantation because of the unpredictable natural course of the disease, which may progress or improve. These factors also complicate the decision regarding the timing of transplantation. Primary liver cancer is another indication for liver transplantation in AIP and other acute hepatic porphyrias. Combined liver-kidney transplantation should be considered in patients with neuropathic manifestations who also have developed advanced renal disease [53].

Conventional scoring systems (eg, model for end-stage liver disease [MELD] score) for assessing priority for liver transplantation are not applicable to patients with AIP because they usually do not have advanced parenchymal liver damage even when neuropathic manifestations are severe. Patients with AIP and severe neuropathic symptoms who are being considered for liver transplant receive exception points for expedited waitlist priority on deceased donor transplant lists. Living related donor liver transplant is another option.

If a living related donor is pursued, the donor should undergo comprehensive evaluation including targeted genetic screening to exclude latent AIP, which would disqualify them as a donor. Recurrence of AIP in the recipient has been reported due to the same mutation being present in the asymptomatic sibling donor that was not recognized prior to transplantation [54].

Investigational approaches

●PBGD mRNA infusion – A mouse model has been used to investigate infusion of the mRNA for human PBGD/HMBS (which encodes the enzyme missing in AIP) encapsulated in lipid nanoparticles [55]. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Pathogenesis'.)

●PBGD gene therapy – Preclinical studies have investigated the feasibility of gene therapy in an AIP mouse model. A clinical trial in AIP found that gene therapy failed to reduce frequent attacks or reduce levels of porphyrin precursors; however, efforts to improve the efficacy of gene therapy vectors are ongoing [56,57].

Additional details about the mechanisms and techniques for RNA interference (RNAi)-based therapies and gene therapy are discussed in more detail separately. (See "Overview of gene therapy, gene editing, and gene silencing".)

CHRONIC SYMPTOMS — Despite the terminology of acute porphyria, symptoms can be persistent and chronic [1]. In some patients, residual paresis may be present after recovery from severe attacks; other patients may have chronic pain without paresis. Our prospective series of 112 patients with recurrent attacks of acute hepatic porphyria (104 [93 percent] with AIP) documented a median of six attacks per year (range, 0 to 52) [58]. Symptoms occurred on a daily basis in 52 (46 percent); one-third had at least 10 attacks per year; and three-fourths of the attacks were severe enough to require treatment in a health care facility. Common symptoms included pain in the abdomen, arms, legs, and back, as well as nausea, tiredness, and anxiety. The severe and chronic symptoms experienced by some individuals with AIP highlights the need for disease-modifying therapies in this disease.

The pathogenesis of chronic pain and other symptoms in AIP is poorly understood; in some cases, these symptoms may represent longstanding and possibly permanent neuropathic effects of repeated attacks that were not promptly treated. Many individuals with chronic symptoms have persistent elevations of biomarkers (ALA and PBG) in between attacks [58].

Nearly one-half of the patients in the prospective series were receiving prophylactic hemin, and more than one-half required opioid analgesics [58]. However, in contrast to acute attacks, subacute or chronic symptoms are unlikely to respond to acute administration of hemin. Because hemin is rapidly metabolized to biliverdin and bilirubin by hepatic heme oxygenase and biliverdin reductase, it represses hepatic delta-aminolevulinic acid synthase (ALAS1) for only a few days after intravenous administration.

A trial of hemin or givosiran may be warranted in patients with subacute symptoms, but chronic pain and other symptoms are treated symptomatically, often with consultation with a pain management specialist.

The possible use of liver transplantation should be evaluated before development of chronic complications such as extensive paresis, if possible. (See 'Liver transplantation' above.)

Patients may benefit and contribute to development of new treatments by participating in clinical trials. Information can be obtained from the Porphyrias Consortium in the United States (https://www.rarediseasesnetwork.org/cms/porphyrias), or the International Porphyria Network (IPNET; https://porphyrianet.org/en/content/worldwide-network).

MONITORING FOR DISEASE COMPLICATIONS — Patients with AIP are at increased risk for developing systemic arterial hypertension, chronic renal failure, and hepatocellular carcinoma [30]. Iron stores may be decreased from menstrual blood loss (as in women without AIP) or increased from frequent hemin therapy.

Along with standard medical care, we recommend screening for the following:

●Hypertension and renal damage – We monitor blood pressure and screen for hypertension according to standard practices. If present, hypertension should be controlled, nephrotoxic drugs avoided, and renal function monitored (serum creatinine and blood urea nitrogen [BUN], and urinalysis) (see "Overview of hypertension in adults"). Interestingly, renal damage may be related to genetic variation in peptide transporter 2, which transports delta-aminolevulinic acid (ALA) [59].

●Liver cancer – Patients with acute porphyrias, and especially those with continued elevations of ALA and porphobilinogen (PBG) and over age 50, should be screened by hepatic imaging (ultrasound) at six-month intervals for early detection of liver cancer, either hepatocellular carcinoma (HCC) or cholangiocarcinoma, due to the increased incidence especially after age 50; a prospective study of 62 patients found that screening increased survival [1,30,60,61]. These tumors often develop without elevation of serum alpha fetoprotein (AFP). The risk may also be increased in patients with latent forms of acute porphyrias [62]. (See "Surveillance for hepatocellular carcinoma in adults".)

Most patients who have developed HCC are described as not having cirrhosis. This may be understandable, given the finding of biallelic pathogenic variants in the HMBS gene in liver cancers that develop in individuals with AIP [63]. This suggests that HMBS is a tumor suppressor gene, and that these tumors result from somatic mutations in individuals who have a preexisting inherited HMBS variant.

Longitudinal information about the liver is very limited in the acute hepatic porphyrias. Some patients with AIP have persistent transaminase elevations that require evaluation of their etiology and continued monitoring.

●Decreased or increased iron stores – Monitoring of serum ferritin is useful to assure adequacy of iron stores as indicated by a level above approximately 40 ng/mL and for early detection of iron overload in patients treated repeatedly with hemin (eg, at baseline and every 6 to 12 months or after 10 to 15 doses). Ferritin may increase acutely after hemin infusions; thus, ferritin testing should be delayed until at least a month after the last hemin treatment. MRI or liver biopsy may also be indicated to establish the presence or absence of iron overload.

Phlebotomy may be necessary if iron overload is documented; some patients tolerate removal of 450 mL of blood every two to four weeks, as is done for other iron overload disorders. Alternatively, small-volume phlebotomies before hemin infusions may be effective in reducing iron overload; however, increased ferritin levels within a month of the last hemin dose may be due to an acute phase response rather than iron overload. Experience with chelation therapy is limited, and chelation is avoided because iron chelators can reduce iron availability for hepatic heme synthesis in rodents, suggesting they might exacerbate AIP.

PREGNANCY — Most women with AIP do not consider the disease to be a barrier to having children because pregnancy is usually well tolerated, despite elevations in circulating progesterone [30].

However, some women have more frequent attacks during pregnancy, and some women experience increased symptoms in the postpartum period. Attacks during pregnancy and postpartum are treated with hemin in the same manner as in the absence of pregnancy. Experience has shown that hemin is safe and effective during pregnancy. Interruption of pregnancy should never be considered as a necessity in the management of AIP [64].

Experience with givosiran during pregnancy is lacking.

The role of genetic testing in family members is discussed in detail separately. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Asymptomatic patients' and "Genetic testing".)

PROGNOSIS — Data are scarce regarding the prognosis of individuals with AIP and other acute porphyrias due to the rarity of the condition. In addition, individuals with the mildest clinical phenotypes may never be diagnosed with AIP, leading to an inaccurate overestimation of morbidity and mortality. Longitudinal natural history studies to better define prognosis are now underway by the Porphyrias Consortium in the United States and by the International Porphyria Network (IPNET).

Mortality is increased in patients with severe clinical manifestations. This was demonstrated in a retrospective review of 136 patients with AIP severe enough to require hospitalization, which found a standardized mortality ratio of 3.2 (95% CI 2.4-4.0) [17]. During almost 50 years of observation, approximately one-third of the patients died. Common causes of death included complications of the initial or a subsequent acute attack (eg, complications of respiratory paralysis), which accounted for 20 and 38 percent of deaths, respectively. Suicide was also common (five patients). The standardized mortality ratio remained high after exclusion of the 10 patients who died during the initial acute attack (2.6, 95% CI 1.8-3.4). This study spanned the introduction of hemin therapy, after which survival was better than before hemin but still less than the general population. Age at diagnosis and sex were not predictive of mortality, nor were levels of porphyrin precursor excretion.

However, patients can have a good prognosis, especially if their disease remains latent or when the diagnosis is made in a timely fashion, acute attacks are managed rapidly, and future attacks prevented. (See 'Prevention of attacks' above.)

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 5^th to 6^th 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 10^th to 12^th 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 topic (see "Patient education: Acute intermittent porphyria (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview of management – The goal of therapy for an acute attack of acute intermittent porphyria (AIP) is to abate the attack as rapidly as possible and to provide appropriate supportive and symptomatic care. Hospitalization is usually required. (See 'Overview of approach' above.)

•Confirm porphyria – Treatment of an acute attack requires confirmation of acute porphyria, based on the finding of elevated urinary porphobilinogen (PBG), either presently or in the past, but it does not require diagnosis of the specific type of acute porphyria (algorithm 1). The need for rapid reporting of a PBG result should be discussed with the participating laboratory if acute porphyria is strongly suspected but not previously diagnosed. (See 'Evaluation before treatment of an attack' above.)

•Determine subtype simultaneously with treatment – Testing to differentiate AIP and other acute porphyrias that elevate PBG (hereditary coproporphyria [HCP] and variegate porphyria [VP]) can continue simultaneously with treatment, using samples collected before treatment is begun.

Urine total porphyrins are markedly elevated in all acute porphyrias during attacks and should also be measured in addition to PBG when screening for acute porphyrias.

•Patient with known porphyria, confirm an attack clinically – In a patient known to have an acute porphyria based on prior testing, an acute attack is largely established clinically. (See 'Diagnosis of an acute attack in a patient with an established diagnosis of acute porphyria' above.)

●Acute attack

•Severe – For an attack of AIP (or other acute porphyria) severe enough to require hospitalization, opioid analgesia, or other intravenous medication, or that is accompanied by paresis, seizures, agitation, delirium, psychosis, or hyponatremia, we recommend intravenous hemin rather than carbohydrate loading (Grade 1B). Hemin should be administered without delay once an acute attack is diagnosed. Carbohydrate loading should be used as a temporizing measure while awaiting the availability of hemin. (See 'Acute attack: Primary treatment (hemin)' above.)

•Mild – We also suggest hemin rather than carbohydrate loading for AIP attacks with mild pain not requiring opioids, without severe manifestations (Grade 2C). However, an initial trial of carbohydrate loading is sometimes effective.

•Dosing – A typical hemin regimen is Panhematin, 3 to 4 mg/kg reconstituted with 25 percent human albumin given intravenously as a single daily dose for four days. Treatment is continued until symptoms resolve. Typical carbohydrate regimens include oral glucose polymer solution, up to 300 grams daily; or 10 percent intravenous glucose, 300 to 400 grams per 24 hours. (See 'Carbohydrate loading as a temporizing measure' above.)

●Complications

•Paralysis – Quadriparesis and respiratory paralysis are potentially life-threatening and must be addressed immediately, with mechanical ventilation as needed. Bedside spirometry should be available to detect early respiratory impairment, and hemin should be continued until neurologic function recovers. (See 'Paresis and paralysis' above.)

•Seizures – Seizures may be due to hyponatremia or porphyria itself. Many anticonvulsant medications have at least some potential for exacerbating acute porphyrias. Gabapentin and levetiracetam are safe, and clonazepam may be less harmful than phenytoin, barbiturates, or valproic acid. (See 'Seizures' above.)

•Pain – Pain is the most prominent symptom and almost always requires opioid analgesics. Nausea and vomiting, agitation, hallucinations, anxiety, insomnia, tachycardia, and hypertension also require therapy. (See 'Acute attack: Management of symptoms and complications' above.)

●Triggers – Some patients with AIP have identifiable triggers for attacks; these should be avoided and/or minimized whenever possible. Patients should avoid smoking, alcohol, and harmful medications (table 1). Lists of safe and unsafe drugs are available on websites of the Porphyria Drug List (https://www.porphyriadrugs.com/) and the Norwegian Porphyria Center (NAPOS) (https://www.drugs-porphyria.org/). Additional strategies include maintenance of a well-balanced diet somewhat high in carbohydrates, correction of iron deficiency as detected by monitoring serum ferritin, and prompt treatment of intercurrent infections or other illnesses. (See 'Avoidance of exacerbating factors' above.)

●Givosiran – For adults who have frequent attacks (eg, four or more per year) despite avoiding triggers, we suggest givosiran (Grade 2B). (See 'Indications for givosiran' above and 'Evidence for efficacy of givosiran' above.)

Dosing is a once-monthly subcutaneous injection. Liver and kidney function should be monitored closely, especially in individuals with underlying liver or kidney disease. Acute attacks in individuals receiving givosiran are treated with hemin. (See 'Administration of givosiran' above.)

●Other prevention – Other prophylactic approaches include gonadotropin-releasing hormone (GnRH) analogues in women with frequent luteal phase attacks, prophylactic hemin at approximately weekly intervals for non-cyclic attacks, or liver transplantation for severe intractable manifestations. Decisions about these therapies are made on a case-by-case basis. Additional approaches are under investigation. (See 'Prevention of attacks' above.)

●Chronic pain – A pain management specialist is often helpful for control of chronic pain, especially if opioids are required long term. (See 'Chronic symptoms' above.)

●Long-term complications – Patients with AIP are at risk for developing chronic kidney disease, hepatocellular carcinoma or cholangiocarcinoma, iron deficiency from menstrual blood loss (as in females without AIP) or iron overload from frequent hemin. Recommended monitoring includes aminotransferases and ferritin levels. Hypertension should be controlled and nephrotoxic drugs avoided. Patients over age 50 should have hepatic imaging for hepatocellular carcinoma. Reasonable indications for liver transplantation include frequent hospitalizations, disease unresponsive to medical therapies, and poor quality of life. (See 'Monitoring for disease complications' above.)

●Pregnancy – Pregnancy is generally well tolerated, but some individuals experience more attacks during pregnancy. Attacks during pregnancy are treated promptly with hemin, similar to nonpregnant individuals. Experience with givosiran during pregnancy is lacking. (See 'Pregnancy' above and 'Prognosis' above.)

●Diagnosis – The pathogenesis, clinical manifestations, and diagnosis of AIP are presented separately. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis" and "Porphyrias: Overview of classification and evaluation".)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges Stanley L Schrier, MD, who contributed as Section Editor on earlier versions of this topic review and was a founding Editor-in-Chief for UpToDate in Hematology.

The UpToDate editorial staff also acknowledges extensive contributions of Donald H Mahoney, Jr, MD, to earlier versions of this topic review.