Long-term management and treatment of acute intermittent porphyria with recurring attacks using pharmacological prophylaxis

Abstract

Background:

There is no definitive guidance on whether patients with acute intermittent porphyria (AIP) with recurrent attacks need pharmacological prophylactic treatment.

Methods:

The management strategies for patients with frequent (defined as ≥4 annualized attack rate (AAR) and less frequent attacks (<4 AAR), including treatment for acute attacks and duration of prophylaxis (weekly heme arginate 3 mg/kg body weight and/or investigational drug, givosiran), were summarized. The AAR for the following periods were presented: the first 2 years after diagnosis, before/after prophylaxis, and the most recent 2 years.

Results:

A total of 29 patients with AIP were included, 19 (34.5%) had <4 AAR and 10 (65.6%) had ≥4 AAR in the first 2 years after diagnosis. All patients experienced reduced attacks during the treatment course, 23 (79.3%) were attack-free during the most recent 2 years. Among the 9 patients who received prophylaxis (7 heme arginate; 1 givosiran, 1 heme arginate followed by givosiran), 5 (55.6%) were attack-free in the most recent 2-year period and prophylaxis was discontinued because there had been no attacks for >1 year. For patients without prophylaxis (n = 20), 18 (90.0%) were attack-free in the most recent 2-year period and 15 (75.0%) experienced attacks only in the first 2 years after diagnosis.

Conclusions:

Prophylaxis could be considered for patients with AIP with ≥4 biochemically confirmed attacks/year after routine treatment of 1–2 years, during which the severity and frequency of attacks should be closely monitored to determine the necessity of pharmacologic prophylaxis. More studies are needed to reach a consensus on the use of pharmacological prophylaxis and treatment of AIP.

INTRODUCTION

Acute intermittent porphyria (AIP) is an autosomal dominant hereditary disease resulting from pathogenic variants of the hydroxymethylbilane synthase (HMBS) or porphobilinogen deaminase (PBGD) gene.^1–3 The disease penetrance of AIP is low despite the estimated high prevalence of pathogenic HMBS variants, particularly in Caucasians.⁴ HMBS variants may lead to the overproduction and accumulation of porphyrin precursors δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) in heterozygotes,² who may present with diffuse pain in the abdomen and elsewhere, motor paralysis, and neuropsychological symptoms during acute porphyric attacks.^1,5,6 Measurement of urinary ALA and PBG is essential for the initial diagnosis of AIP but may not be always required for identifying recurrent attacks.^1,2,7–10

Acute porphyria attacks are commonly managed with hemin or carbohydrate infusions and supportive care for symptoms.^1,5,10 After being correctly diagnosed, patients should be given disease education, including information on avoiding precipitating factors, and genetic counseling to screen for affected family members.^1,10,11 Unfortunately, some patients may experience recurrent attacks, which can be debilitating and even life-threatening. Prevention of recurrent attacks includes exogenous hormonal therapy for frequent premenstrual attacks (eg, Gonadotropin-releasing hormone (GnRH) analogs and low-dose oral contraceptives) in situations where lifestyle changes, such as cessation of smoking, use of alcohol, and having regular eating habits, are insufficient to prevent attacks.^1,10 Liver transplantation is also an option if the standard treatment is unsuccessful, contraindicated, or the quality of life is unbearable. Scheduled prophylactic i.v. hemin therapy and, more recently, givosiran (a small interfering RNA therapeutic targeting ALAS-1 mRNA to reduce overproduction and accumulation of porphyrin precursors and porphyrins)^10,12 can also be considered for patients with frequent recurrent attacks.

The definition of recurrent AIP attack described in the literature is by frequency and nature, which can range from an event that requires hospitalization, emergency medical services, or requiring hemin infusions at home, with or without well-documented biochemical confirmation.^3,7,12,13. The frequency used in different studies also slightly differs (3 or more,^14,15 4 or more,^16–18 and more than 4¹⁰ symptomatic porphyria episodes per year requiring medical attention). Some studies have recommended considering weekly prophylactic heme therapy in patients with frequent recurrent attacks (defined as ≥3 attacks requiring treatment in the last 12 mo),¹⁹ and more recently chronic use of givosiran was suggested to restrict to patients who are well-documented biochemically and with a history of ≥3 acute attacks in the past year.^1,10,12,15

Now that a number of strategies for prophylaxis are available, it is important to evaluate patient selection and timing of initiation when considering each strategy. The socioeconomic impacts and potential safety issues associated with pharmacological prophylaxis for AIP have been an ongoing interest of researchers.^6,14,20 However, currently, there is no clear guidance for starting pharmacological prophylaxis.

In the present study, we aim to retrospectively review the long-term management of patients with AIP. The findings will be used to guide our AIP management practice and provide clues as to whether pharmacological prophylactic treatment should be considered, as well as the time of initiation and discontinuation.

METHODS

Study design

In this retrospective study, the medical records of patients with AIP who received care at Chung Gung Memorial Hospital (CGMH) were reviewed. Information related to AIP care and management strategies and treatment outcomes were collected.

Study subjects

All patients who had been diagnosed with AIP and received outpatient clinic follow-up at CGMH were eligible for this study. Written consent was waived due to the retrospective nature of the study. No potentially identifiable human images or data are presented in this study. The study protocol received approval from the ethics committee of CGMH before study initiation (IRB: 201900074B0 and 202000914B0), and the study was carried out following the Declaration of Helsinki.

Extracted information

Patient demographics and clinical characteristics including triggering factors, menopausal status, management provided during acute attacks, and use of pharmacologic prophylaxis, detailed records of all porphyria attacks were collected from the initial presentation to September 2022. Records of urinary ALA and PBG were also collected, if available. The number of attacks was converted as annualized attack rate (AAR) for the following periods: (1) the first 2 years of AIP diagnosis; (2) before initiating prophylaxis (for patients receiving prophylaxis); (3) 1–2 years after menopause (for women in menopause); and (4) the most recent 2-year follow-up. Age of onset, current age, years of experiencing attacks, and duration of prophylaxis use were summarized.

Definition of attack

In this study, frequent recurrent attack was defined as ≥4 clinically and/or biochemically confirmed severe AAR in the previous year. A severe AIP porphyric attack was defined as a symptomatic attack having severe abdominal pain requiring an ER visit, requiring human heme infusion at the hospital and a narcotic agent for pain control, and an elevation of PBG/ALA, if available. Patients with mild porphyric attacks of abdominal pain, which could be treated with i.v. glucose administration and/or pain killer with non-narcotic agents, and extra HA infusion was not necessary, were not considered as having severe attacks in this study.

Prophylactic treatment

Prophylactic treatment was recommended to patients with ≥4 clinically and/or biochemically confirmed severe AAR in the previous year after the routine treatment of 1–2 years. Patients who met these criteria received i.v. HA (3 mg/kg body weight) weekly. Two patients (case 8 and 25) received givosiran because they participated in the phase 3 trial (from June 2018 to May 2021).^12,21,22

Statistical analysis

The demographic and clinical characteristics of the study population are summarized for each participant. All data analysis was performed using Microsoft Excel (Microsoft, Redmond, WA)

RESULTS

A total of 29 patients with AIP received care at CGMH. The patient demographics, disease characteristics, and historical number of attacks before diagnosis are presented in Table 1. Two of the patients were male and the current age of the study cohort ranged from 22 to 80 years old. The age of symptom onset was between 16 and 39 years old, and patients had experienced from 1 attack to more than 6 attacks per year before diagnosis. The time from onset of symptoms of AIP to diagnosis was between less than 1 month and 32 years. The diagnosis of AIP was confirmed in all patients genetically, and the most prevalent HMBS mutation was c.77G>A, which was present in 5 of the 29 patients (Table 1).

TABLE 1.

Patient demographics and characteristics at diagnosis

Patient case no.	Sex	Current age	Age at onset	PBGD gene mutation	Predicted protein change	Time from symptom onset to diagnosis	No. attacksa before diagnosis
1	Female	51–55	35	c.77G>A	p.Arg26His	3 y	>6/y
2	Female	46–50	22	c.77G>A	p.Arg26His	1.5 y	2
3	Female	56–60	34	c.1008_1019del; CAGCCTGGCCAA	p.Ile336fs, PTC358	7 y	2
4	Female	36–40	28	c.1008_1019del; CAGCCTGGCCAA	p.Ile336fs, PTC358	<1 mo	1
5	Female	36–40	20	c.1008_1019del; CAGCCTGGCCAA	p.Ile336fs, PTC358	1.5 y	>6/y
6	Female	51–55	30	c.973C>T	p.Arg325X	10 y	>6/y
7	Female	56–60	36	c.652G>A	p.Gly218Arg	5 mo	2
8	Female	26–30	16	c.652G>A	p.Gly218Arg	<1 mo	1
9	Female	46–50	21	c.662G>A; c.652-1G>A	p.Gly221Asp, Splicing aberration	3 mo	2
10	Female	41–45	19	c.662G>A; c.652-1G>A	p.Gly221Asp, Splicing aberration	<1 mo	1
11	female	31–35	16	c.346C>T	p.Arg116Trp	3 mo	3
12	Female	36–40	20	c.33+5G>A	Splicing aberration	3 mo	3
13	Female	51–55	39	c.88-4_88-16del AAGTCTCTACCCG	Splicing aberration	3 mo	2
14	Female	51–55	17	c.655_656insG	p.Ala219fs, PTC250	2 mo	2
15	Male	51–55	27	c.77G>A	p.Arg26His	10 y	4
16	Female	61–65	39	c.77G>A	p.Arg26His	21 y	2
17	Female	36–40	28	c.77G>A	p.Arg26His	<1 mo	1
18	Male	75–80	33	c.848G>A	p. Trp283X	32 y	4
19	Female	46–50	35	c.848G>A	p. Trp283X	4 y	3
20	Female	46–50	38	c.713T>C	p.Leu238Pro	2 y	2
21	Female	51–55	25	c.113delT	p.Val38fs, PTC42	2 mo	2
22	Female	46–50	27	c.113delT	p.Val38fs, PTC42	<1 mo	1
23	Female	46–50	27	c.88-4_88-16del AAGTCTCTACCCG	Splicing aberration	1 y	>6/y
24	Female	36–40	28	c.88-4_88-16del AAGTCTCTACCCG	Splicing aberration	<1 mo	1
25	Female	31–35	27	c.517C>T	p.Arg173Trp	4 mo	3
26	Female	26–30	23	c.673C>T	p.Arg225X	1 y	>6/y
27	Female	21–25	22	c.651G>C	p.Gln217His	9 mo	>6/y
28	Female	66–70	30	c.772-1G>C	Splicing aberration	3 mo	2
29	Female	56–60	33	c.446G>A	p.Arg149Pro	3 y	3

^aSent to the emergency room due to abdominal pain.

Abbreviation: PBGD, porphobilinogen deaminase.

The distribution of the annualized attacks in the first 2 years of diagnosis is presented in Figure 1A. Of all patients, 19 had <4 attacks, 5 experienced ≥4–6 attacks, and 5 experienced ≥7 attacks per year in the first 2 years of diagnosis. All patients received disease education, exacerbating factor evaluation (Supplemental Table S1, http://links.lww.com/HC9/A675), genetic counseling after diagnosis, and routine management for acute attacks (including daily HA (3–5 mg/kg) daily for 3–5 days and symptomatic treatment during acute attacks). All patients had substantially reduced frequencies of attacks after appropriate disease management; a total of 23 (79.3%) patients experienced no attack within the most recent 2 years. The majority of patients (78.3%, n = 18) who experienced no attacks within the most recent 2 years did not receive pharmacologic prophylaxis treatment (Figure 1B).

FIGURE 1.

Annualized number of attacks during: (A) The first 2 years after diagnosis (n = 29). (B) the most recent 2 years (n = 28). A total of 9 patients received prophylactic treatment for the management of recurrent attacks, and 20 received routine care without being given prophylaxis. One patient did not receive prophylaxis for personal reasons, and she passed away due to septic shock and frequent severe attacks.

The long-term management, treatment outcome, and follow-up of patients with frequent attacks (≥4 AAR, n = 10) or less frequent attacks (< 4 AAR, n = 19) during the first 2 years after diagnosis are summarized in Table 2 and Table 3, respectively. All patients with frequent attacks required HA treatment for acute attacks (Table 2); 10 out of 19 patients with less frequent attacks (52.6%) did not use HA for acute attacks (including 3 patients treated with glucose infusions because HA was not available before 2002 in Taiwan) and 9 of these patients experienced no further attack within 2 years after diagnosis (Table 3).

TABLE 2.

Long-term management of porphyric attacks^a and treatment outcome for patients with AIP experiencing frequent^b attacks

	Initial presentation		Routine treatment			Prophylaxis
Case no.	Neurologic porphyriac	ICU stay	AAR (1st 2 y)	Treatment for acute attacks	AAR (before prophylaxis)	Drug	Year of AIP before prophylaxis	Duration of prophylaxis (year)	AAR after prophylaxis	Year since discontinuation	AAR after menopause	AAR (recent 2 y)
1	Mild PNP	—	>6	HA	>6	HA	12	9	4	>1	No attack	No attack
6	Severe painful PNP	—	5.5	HA	6.45	HA	2	5	0.75	ongoing	Frequent	1
7	—	—	6.5	HA	6.5	HA	2	15	2	>1	1	No attack
8	—	—	10	HA	HA:12, G:38d	HA, G	2	HA:4, G:3	HA:1.3, G: 10d	Ongoing	NA	9
11	—	—	6	HA	6	HA	1	5	0.8	>10	NA	No attack
12	Coma due to severe hyponatremia	+	5	HA	5	HA	2	16	2.1	Ongoing	NA	0.5
23	Mild PNP	—	12.5	HA	12.5	HA	2	7	11d	ongoing	NA	10.5d
25	-	—	5	HA	4.3	G	2	3.25	1.7d	>1e	NA	No attack
29	-	—	8	HA	8	HA	2	10+	<2	>1	No attack	No attack
27	Severe painful PNP, seizure	+	10	HA	>6f	—	—	—	—	—	—	—

Note: +, yes; —, no.

^aAttacks requiring hospitalization for heme arginate infusion for porphyric attacks.

^bDefined as 4 or more clinically and/or biochemically confirmed attacks per year under routine treatment for 1–2 years after AIP diagnosis.

^cSymptoms/signs of the central or peripheral nervous system.

^dFrequent mild porphyric attacks with abdominal pain, which could be treated with i.v. glucose administration and/or pain killer with non-narcotic agents, and extra heme arginate infusion was not required.

^eDiscontinued givosiran due to pregnancy and remission after delivery.

^fPatient passed away in 2006 due to septic shock and frequent severe attacks of >6 per year.

Abbreviations: AAR, annualized attack rate; AIP, acute intermittent porphyria; G, monthly subcutaneous injection with givosiran; HA, weekly i.v. infusion with heme arginate (3–5 mg/kg) for prophylaxis or daily heme arginate (3–5 mg/kg) during acute attacks; ICU, intensive care unit; NA, not applicable, not in menopause; PNP, polyneuropathy.

TABLE 3.

Long-term follow-up for patients with AIP without frequent attack^a

	Initial presentation		Routine treatment
Case no.	Neurologic porphyriab	ICU stay	AAR in the first 2 y after diagnosis	Treatment for attacks	AAR 3rd year after diagnosis till September 2022	Prophylaxis	After 1–2 y of menopause	Years with attack	AAR during most recent 2 y
2	Severe PNP	+	1	—	No attack	None	NA	<2	No attack
3	—	—	1.5	—	No attack	None	No attack	<2	No attack
4	—	—	3	HA	No attack	None	NA	<2	No attack
5	Motor paresis and confusion	—	1.5	HA	No attack	None	NA	<2	No attack
9	—	—	1	— (S)	0.32	None	No attack	5	No attack
10	Seizure due to hyponatremia	+	0.5	—	No attack	None	NA	<2	No attack
13	PRES and bilateral radial neuropathies	—	0.5	—	No attack	None	NA	<2	No attack
14	—	—	0.5	— (S)	No attack	None	NA	<2	No attack
15	Bilateral radial neuropathies	—	1	HA	No attack	None	Male	<2	No attack
16	—	—	1	—	No attack	None	No attack	<2	No attack
17	—	—	0.5	—	No attack	None	NA	<2	No attack
18	—	—	0	—	No attack	None	Male	<2	No attack
19	—	—	2	HA	No attack	None	NA	<2	No attack
20	—	—	0.5	HA	No attack	None	NA	<2	No attack
21	Seizure due to hyponatremia	+	1	HA	0.7	None	NA	5	No attack
22	—	—	0.5	HA	No attack	None	NA	<2	No attack
24	—	—	1	HA	0.56	None	NA	4	no attack
26	—	—	2	HA	4.67	None	NA	4	4c
28	—	—	0.5	— (S)	No attack	None	NA	<2	No attack

Note: +, yes; —, no.

^aDefined as <4 clinically and/or biochemically confirmed attacks per year under routine treatment for 1–2 years after AIP diagnosis.

^bSymptoms/signs of the central or peripheral nervous system.

^cFrequent mild porphyric attacks with abdominal pain, which could be treated with i.v. glucose administration and/or pain killer with non-narcotic agents, and extra heme arginate infusion was not required.

Abbreviations: AAR, annualized attack rate; G, monthly subcutaneous injection with givosiran; HA, weekly i.v. infusion with daily heme arginate (3–5 mg/kg) during acute attacks; ICU, intensive care unit; NA, not applicable, not in menopause; PNP, polyneuropathy; PRES, posterior reversible encephalopathy syndrome; S, sugar supplement with i.v. glucose.

A total of 9 patients with frequent attacks received pharmacologic prophylactic treatment, 7 received HA, 1 received givosiran, and 1 received HA and switched to givosiran due to participation in a phase 3 clinical trial (Table 2). The AAR for the first 2 years of diagnosis, before prophylaxis initiation, after receiving prophylaxis, and the most recent 2 years of follow-up are presented in Table 2. Prophylactic treatment significantly reduced the frequency of attacks to no attack for 5 patients. The duration of prophylaxis treatment ranged between 3.25 and 15 years among patients whose prophylaxis treatment was discontinued because there had been no attacks for a period of more than 1 year (n = 5, 55.6%). Four patients are receiving ongoing HA weekly (duration of prophylaxis treatment ranged between 5 and 16+ years). Among them, 1 patient continues experiencing attacks even after 2 years in menopause (case 6, AAR = 1), 2 patients experience frequent porphyric attacks with abdominal pain but are regarded as mild severity because extra HA treatment was not always required (case 7 and 23) (Table 2).

All 19 patients with less frequent attacks in the first 2 years after diagnosis did not receive pharmacologic prophylaxis, 18 (94.7%) experienced no attacks in the most recent 2-year period. Among these 19 patients, 15 patients (79.0%) experienced attacks only in the first 2-year period after diagnosis (including 3 patients who experienced no more attacks after becoming menopausal) and 4 patients experienced attacks for 4–5 years after diagnosis (21.1%) (Table 3). Of note, patients with severe attacks (ie, seizure due to hyponatremia and severe polyneuropathy) requiring intensive care unit stay at initial presentation or first 1–2 years after AIP diagnosis were able to experience AAR reduction or even no attack in the first 2 years after diagnosis without the use of pharmacologic prophylaxis right after acute treatment (cases 2, 10, and 21 in Table 3), indicating that our practice of recommending pharmacologic prophylaxis to patients with ≥4 frequent clinically and biochemically confirmed attacks per year after routine management of 1–2 years was reasonable.

DISCUSSION

AIP can be a debilitating condition that greatly impacts the patient’s quality of life if not managed properly. It can progress to recurrent attacks requiring hospitalization or emergency medical attention.^1,10 In this study, we find that disease management without pharmacologic prophylaxis was able to reduce or eliminate attacks over a 1- to 2-year period for most patients who had <4 clinically and/or biochemically confirmed attacks during the first 2 years of diagnosis. Pharmacologic prophylactic treatment with HA or givosiran, which in our study was recommended to patients who have ≥4 attacks per year after routine management for 1–2 years is effective in reducing attack frequency and severity. Routine management strategy included avoidance of precipitating factors, harmful medications, and lifestyle changes, receiving daily HA (3–5 mg/kg) for 3–5 days, and symptomatic treatment during acute attacks. Our follow-up results also demonstrated that prophylaxis could be discontinued when there had been no attacks for a period of 1–2 years.

Most patients with AIP have one or a few attacks;⁹ literature has reported that recurrent severe attacks affect about 3%–8% of the patients with acute porphyria.^17,18,23 This attack frequency may persist for many years, particularly in women with a premenstrual pattern of attacks.^23,24 Our study found that without pharmacological prophylaxis, all patients with <4 attacks in the first 2 years of diagnosis experienced no further attack after <2 years of routine care. Implementation of effective strategies for preventing acute attacks likely has contributed to the improvement experienced in our patients, including the provision of regular education to patients and their families about precipitating factors, genetic counseling, lifestyle change recommendations (ie, cessation of smoking, avoiding alcohol, avoiding fasting, gaining of weight to maintain a normal body mass index, slow weight reduction for the obese patient), and the discontinuation of harmful medications.^7,14 This is consistent with the view that improved management has contributed to the reduced frequency of acute attacks in recent years.¹⁸ Additional precautions that likely have benefited the care of our patients could be the integration of 2 electronic systems in our hospital (Supplement Figure 1, http://links.lww.com/HC9/A673). Precautions taken to avoid exposing the patients to unsafe medications in our hospital include the following: (1) electronic warnings to acute hepatic porphyrias (AHP)-contraindicated medications or unsafe medications in the computerized provider order entry system and (2) integration of a clinical decision support system combined with a drug interactions database (Lexicomp) to strengthen drug safety control and prevent patients with AIP from being exposed to unsafe drugs. Both prohibited the prescription of unsafe drugs for patients with AIP. We encourage establishing similar electronic systems as part of the prevention measures before considering pharmacological prophylaxis.

Recommendations on the prophylactic management of patients with AIP with recurrent porphyric attacks remain a challenge. In some studies, prophylaxis was considered in patients with AIP exhibiting recurrent attacks (defined as those having ≥3^14,15 or 4^10,16–18 attacks per year that require hospitalization or emergency medical attention). However, there is no consensus on the requirement for biochemical confirmation for episodes of recurrent attacks.^1,2,7–11 Some have argued that urinary PBG and ALA values can remain high in patients after an attack and so an elevated value does not necessarily indicate or correlate with an attack.^14,16,25,26 Our previous findings showed that PBG/ALA levels significantly increase during attacks and gradually decrease after initiating treatment.^5,21 For patients with frequent attacks, their urinary PBG/ALA levels may not return to normal during nonattack periods. However, if the patient’s attack frequency significantly decreases, PBG/ALA levels may return to the normal range. Others have also pointed out that differential diagnosis with nonporphyric gastrointestinal or neurological disorders is imperative, and individualized urinary PGB and ALA reference values established during the periods of remission can aid in the correct diagnosis of symptoms suggestive of an acute porphyria attack.^8,9 In our hospital, we had been collecting 24-hour urine samples from patients during nonattack periods; we acknowledge and understand the difficulties of collecting 24-hour urine samples, and the drawbacks include the requirement of light-protected and refrigerated storage. Further, patients with AIP with acute attacks often require immediate treatment; therefore, our alternative approach was to collect 24-hour urine samples while the treatment is ongoing. Please refer to Supplemental Figure S2, http://links.lww.com/HC9/A674, for the records of urinary ALA and PBG for all patients. Single random urine sampling is a quick and simple method, which has been used more often recently for monitoring urine ALA and/or PBG levels; it can be used to establish individual baseline levels during attacks, particularly for patients with frequent attacks and preparing to receive the prophylactic treatment.

The route of administration, cost, and adverse events differ with different prophylaxis options (Figure 2); these factors should be taken into consideration when initiating prophylaxis for the prevention of recurrent attacks. Whether the patient has access to prompt medical care is also an important factor, particularly for countries where financial support for health care or availability of pharmacological prophylaxis for rare diseases may be limited. The use of exogenous hormones such as gonadotropin-releasing hormone analogs and low-dose oral contraceptives should be closely evaluated by clinicians due to the risk of provoking acute attacks, osteopenia, and menopausal complications. Weekly hemin prophylaxis has the potential risk of iron overload, increased risk of port-A thrombosis or infection and phlebitis of infusion site. Givosiran is considerably more expensive than i.v. hemin. A recent study from the United States that directly compares the total cost of AIP-related health care for patients treated with hemin or givosiran reported that the average annual total cost of care with hemin was 78% lower than with givosiran.²⁷ On the other hand, even though givosiran has greater ease of use, there are also potential risks of hepatic and renal adverse effects, as well as hyperhomocysteinemia.^12,28–33 It was proposed that more research on the dysregulation of cysteine in patients with AIP should be carried out to better understand how best to tailor RNA-based therapy, including whether or not it should be restricted to severe recurrent cases.^29,33

FIGURE 2.

Management strategies for patients with AIP with frequent attacks in our hospital. The management of patients with AIP includes the following strategies: A, Diagnosis and evaluation; B, Therapy for an acute attack; C, Therapy for recurrent attack; and D, Follow-up for long-term complications. Suggestions made based on this study are underlined. *Electronic systems consisted of a computerized provider order entry system and clinical decision support system combined with a drug interactions database (Lexicomp); together they strengthen drug safety control and prevent patients with AIP from being exposed to unsafe medications. Abbreviations: AIP, acute intermittent porphyria; δ-aminolevulinic acid; GnRH, gonadotropin-releasing hormone; PBG, porphobilinogen.

Currently, there is no clear guideline on the use of pharmacological prophylaxis. The findings from this retrospective review of long-term management and treatment of AIP could be used to guide our AIP management practice and provide clues as to whether a patient with recurrent attacks requires pharmacologic prophylaxis and when to initiate it. Based on our findings, we suggest that implementing the following measures may improve the management of patients with recurrent attacks: (1) Having an observation period to monitor the frequency and severity of porphyria attacks for 1–2 years before starting prophylaxis. During this period, routine treatment and known strategies for preventing acute attacks including evaluation of precipitating factors, discontinuation/avoidance of harmful medications, and lifestyle change recommendations should be followed. (2) Monitor urinary ALA and/or PBG level during the observation period, so that the number of biochemically confirmed attack can be determined more accurately. (3) Pharmacological prophylaxis (HA and/or givosiran) can be considered for patients with ≥4 clinically and biochemically confirmed AAR in the previous year after the routine treatment of 1–2 years. (4) Establishing and implementing electronic alerts to avoid the prescription of unsafe drugs for patients with AIP. Please refer to Figure 2 for management strategies for patients with AIP with frequent attacks in our hospital. However, since the presentation of AIP varies and multiple prophylactic options are available, prophylactic strategies should be tailored based on individual patient characteristics.

Limitations of this study include its retrospective design and the patients being from a single center. The futher studies and external validity to reach a consensus on the pharmacological prophylaxis and the treatment of AIP are required.

In conclusion, all patients with AIP presenting with <4 porphyric attacks in the first 2 years after diagnosis in our study were attacked free with routine treatment, without pharmacologic prophylaxis. Provision of prophylactic treatment should be limited to patients with frequent recurrent attacks after a thorough clinical investigation or observation period of at least 1 year, and the clinical presentations including the frequency and severity of attacks in the first 2 years after diagnosis should be examined. We recommend that pharmacologic prophylaxis be considered for patients with AIP with ≥4 clinically and biochemically confirmed annualized attacks in the previous year after the standard treatment of 1–2 years. However, since AIP presentations vary and multiple prophylactic options are available, adjustments to the prophylactic approach should be made based on the unique clinical characteristics of each patient. More studies are needed to reach a consensus on the use of pharmacologic prophylaxis and the treatment of AIP.