Acute hepatic porphyria (AHP) is a family of rare genetic diseases of heme biosynthesis [1,2,3]. These diseases, which include autosomal-dominant acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and the autosomal-recessive delta-aminolevulinic acid dehydratase-deficient porphyria, are characterized by acute neurovisceral attacks, chronic symptoms, and long-term complications [1,2,3]. In Europe, the prevalence of symptomatic AHP is estimated to be 0.5 case per 100,000 population [4]. Recent genetic screening has indicated that clinical penetrance of symptomatic AHP is ~ 1% in the general population [5]. Substantial urinary porphobilinogen elevation (> 3 × upper limit of normal) is a diagnostic feature of AHP, as elevations of this magnitude are not associated with diseases other than AIP, VP, and HCP [3, 6].

Acute AHP attacks can be life-threatening [6]. Severe, incapacitating abdominal pain is typical, and a variety of other symptoms that are suggestive of multisystemic effects may also be present, including gastrointestinal (e.g., nausea, vomiting), autonomic (e.g., tachycardia, hypertension), neurologic/psychiatric (e.g., mental status changes, anxiety), and others (e.g., weakness, hyponatremia) [1, 7,8,9]. Patients who experience acute attacks often require hospitalization and treatment with opioids to manage abdominal and other types of pain [7]. Aside from acute attacks, patients with AHP experience chronic symptoms and long-term complications that impact quality of life, including prolonged anxiety and depression, hypertension, liver damage, and other organ involvement [8, 10,11,12]. Altogether, these symptoms have a large impact on patient quality of life and outcomes [13, 14].

Before the approval of givosiran, long-term AHP symptom management was limited to trigger avoidance, suppression of ovulation, and off-label intravenous hemin prophylaxis [7]. Repeated, prophylactic use of hemin may be associated with a number of adverse events, including venous damage, thrombophlebitis, coagulation abnormalities, and secondary iron overload [2, 15]. Givosiran is a subcutaneously administered RNA interference therapeutic that is approved for the treatment of AHP in adults (United States, Brazil, Canada) and adults and adolescents age ≥ 12 years (Japan, European Economic Area, Switzerland) [16,17,18]. In the phase 3, double-blind ENVISION trial (NCT03338816), givosiran treatment was associated with significant reductions in annualized attack rate, use of hemin for attacks, and levels of the heme intermediates delta-aminolevulinic acid and porphobilinogen, as well as improvements in daily worst pain, compared with placebo [19].

Despite the debilitating symptoms of AHP, few longitudinal studies have been conducted to assess the impact of this disease and long-term complications associated with AHP in these patients, possibly because a diagnosis of AHP is often severely delayed [20]. Notably, an observational study of 108 patients with AHP in the United States found that the mean time from the onset of symptoms to a definitive diagnosis was 15 years [20].

The EXPLORE study, conducted in the United States and Europe, was designed as a prospective, observational study to characterize the current clinical management of patients with AHP who experience recurrent attacks (≥ 3 attacks within preceding 12 months) or are receiving prophylactic treatment [7]. In the cohort of 112 patients studied, 77% (371/483) of acute attacks were severe enough to require urgent care in a health care facility and/or treatment with intravenous hemin [7]. Additionally, approximately two-thirds of patients reported chronic symptoms between attacks, with nearly half reporting daily symptoms, which were experienced regardless of whether the patients were on hemin prophylaxis [7]. Another observational study—this one with a retrospective design—investigated the difference in severity of porphyria attacks before and after diagnosis in a small cohort of Israeli patients (N = 9) and showed that the attacks occurring prior to AHP diagnosis were much more severe than those that occurred after AHP diagnosis [21].

The objective of the present study was to provide an overview of the clinical features of AHP in Japan, including acute attacks, chronic symptoms, and long-term complications, using a nationwide health care claims database. This information may assist physicians in understanding current practice patterns and in driving early detection and diagnosis of AHP in this at-risk population.