This study provides information on the Danish population of patients with AHP. Such information is important to understand the disease manifestation of the AHP population and to recognize AHP patients in a clinical setting. Therefore, we searched our journals for information on patients with AHP during a 5-year period. This yielded 129 unique patients with AHP, with AIP being the dominant subtype (77.5%), and female sex the most prevalent sex (65.9%). Almost 30% of the AHP patients were symptomatic. According to hospitalizations and treatment in the five-year period, 15.5% of the patients had one or more hospitalizations and 10.9% had been treated with human hemin at least once. None of the 129 patients were diagnosed with HCC during the 5-years.
In general, AIP is the dominating AHP subtype, being reported to constitute between 57% and 96% of all AHP patients (3, 6, 15, 18). Our cohort has a similar predominance of AIP (77.5%). Furthermore, we observed much lower frequencies of HCP (9.3%) and VP (13.2%), again in alignment with previous findings, reporting HCP and VP in the range of 3–10% and 4–33%, respectively (3, 6, 15, 18). The highest frequency of VP patients appears to be in France, Switzerland, and United Kingdom (3). If we exclude these countries, the percentage of VP patients averages 16%; i.e., in the range observed in the present study. Thus, the Danish population of AHP patients resembles AHP populations in some other Western European countries. Finally, the distribution of patients with AIP, VP and HCP in Denmark appears to be stable as a similar distribution was reported in the first Danish AHP population study in 1980 (16).
The Danish prevalence of AHP (1.7:100,000) is lower than that found in Norway (7:100,000) (12) and Sweden (10:100,000) (19). Likewise, the prevalence of symptomatic AIP found in our study (0.6:100,000) was substantially lower than that found in Norway (4:100,000) (12), but similar to the calculated prevalence (calculated on the basis of incidence from the participating countries) in Europe (0.5:100,000) (3). The high prevalence in Sweden and Norway is most likely caused by the founder effect originating from Northern Sweden, where the estimated prevalence is 1000:100,000 (19). In addition, the awareness of AHP in Norway and Sweden may be greater due to the founder mutation, leading to a more extensive family screening and subsequently more cases being diagnosed (12). Three other studies have shown a genetic frequency of mutations predisposing to AIP ranging from 1:1300 to 1:1785 (1), which could indicate that the prevalence could be much higher than first thought.
Previous studies have reported that APH is more commonly diagnosed in females (3, 6, 15, 18), a finding in line with our study, where 65.9% of the patients were female. In other studies, the percentage of female patients varies from 53–89%. Wang et al. (8) reported that females constituted approximately 90% of the symptomatic patients, whereas we found that 68.4% of the symptomatic patients were female. The reason why more female patients are experiencing symptoms is still not fully identified. Treatment with a gonadotropin-releasing hormone (GnRH)-agonist decreases the frequency of attacks in women suffering from menstrual-related acute porphyria attacks (20). Moreover, the prevalence of symptoms generally decreases after the menopause in symptomatic female patients (20, 21). This indicates that progesterone and estrogen play an important role in precipitating acute attacks, and thereby the female sex predominance.
In general, there is consistency between symptoms being reported by the Danish AHP patients experiencing acute attacks and those observed in other studies (6, 12, 18, 22). In all studies, abdominal pain is the main symptom during attacks, being reported by 74–97% of all symptomatic patients. Although abdominal symptoms are a consistent finding, there is a difference in the percentage of the reported symptoms between the studies. This shows that even though patients are experiencing the same symptoms, the clinical picture can vary considerably between the patients.
In our study, 5 patients (13.2%) reported weakness, and 12 patients (31.6%) experienced other neurological symptoms. The symptoms and the progression of these symptoms vary among individual patients, but as described in earlier studies, the progression can be rapid with flaccid tetraplegia and respiratory paralysis appearing within days (8, 23). Indeed, the neurological symptoms may simulate symptoms of Guillain-Barré (10) and there are case reports describing patients being falsely diagnosed with and treated for Guillain-Barré, but without improvement after several days of treatment (24, 25). Finally, and of clinical relevance, 20–30% of the AHP population may present with signs of mental disturbances such as anxiety, depression, disorientation, hallucinations, and confusions (14).
The heme biosynthesis pathway can be induced by different precipitating factors, increasing the demand for heme and consequently, by feedback, accelerate the enzymatic activity (6). Administration of drugs that induce the synthesis of cytochrome P-450 (particularly barbiturates and other related compounds), are known precipitating factors. Other known factors are female sex hormones, stress, alcohol, smoking, infection and fasting (14). In our study, the use of drugs, stress and infections were reported as frequent precipitating factors. Drugs as a precipitating factor were reported more frequently in our study (18.4%) than in a South African study (10%) (22), but less common than in Norway (40%) (12) and USA (37%) (18). The knowledge of precipitating factors is important, because the education of genetic carriers in avoidance of these factors is central to long-term management of AHP (8). Equally important is to remember that some drugs can precipitate acute attacks. Therefore, we believe it is mandatory to check all prescribed medication when the patients is referred to the hospital (acutely or during routine checkup) and to check prescriptions new drugs for any porphyrinogenic effects prior to prescription; e.g. via public databases such as https://www.drugs-porphyria.org/.
In our cohort, self-reported stress appeared as one of the most frequent precipitating factors. However, we believe it is difficult to clarify whether the self-reported stress was the cause of the acute attacks or if the acute attack caused stress. In this context, it is important to remember that acute attacks is known for causing neurological symptoms such as depression, confusion and anxiety (14). Thus, stress may be a symptom rather than a precipitating factor.
Attacks of AHP may be provoked during weight-losing diets (i.e. calorie restriction) as well as following bariatric surgery (8). Indeed, several cases (24–26) describe healthy obese patients, not known with a genetic mutation predisposing to AHP, experiencing severe abdominal pain and neurological symptoms after undergoing bariatric surgery such as gastric bypass or sleeve gastrectomy. Common to all cases are that patients were admitted to hospital after bariatric surgery with abdominal pain and weakness progressing to paresis. Subsequently, the patients demonstrated elevated porphyria precursors and received the diagnosis AHP. In one of the cases, gastric bypass was reversed, leading to relief of symptoms (24).
A known severe complication to AHP is HCC, and many of our patients have reported on family members having had HCC. In line with this, a study (15) found that the hazard ratio of developing HCC in AHP patients is 38.0 compared to a healthy reference population, making the authors advocating for regular surveillance in patients older than 50 years. In our cohort, 98.2% of all patients ≥ 50 years had biannual or annual screening for HCC. At the time of writing, none in our cohort have been diagnosed with HCC during the five-year period. In contrast, Lissing et al. (15) identified 6.7% of their patients with HCC thereby stressing that continuous surveillance is important, as recently stated by Wang et al. in their clinical practice update (7).
Other chronic medical conditions include peripheral neuropathy, hypertension, and chronic kidney disease (18, 27). The proportion of hypertension was lower in our study (14.7%), when compared to patients in US (43%) (18), whereas the proportion of chronic kidney disease (7.0%) was similar to what has been observed in Finland (5.7%) (27). Here, the frequency in US has been reported to 29% (18).
Lissing et al. (15) studied urinary excretion of PBG outside of attacks (i.e., baseline) and they could demonstrate that 32% patients had a normal, 13% a moderate and 33% a high U-PBG/creatinine excretion. Compared to our cohort, the moderate U-PBG/creatinine excretion group differs. However, the upper normal limit (ULN) in that study (15) differs from the ULN in our study. The ULN and analytical methods can vary considerable among different laboratories (11), which makes it hard to find other studies with the exact same ULN as in our study. Nevertheless, it appears relevant to characterize the baseline excretion of PBG. Thus, in our cohort patients with a U-PBG/creatinine baseline level higher than 3.2 mmol/mol (i.e., outside of acute attacks) had a significantly higher risk of having acute attacks when compared to patients having a lower U-PBG/creatinine baseline levels. This could be of potential clinical importance by focusing follow-up and education to patients most prone to develop acute attacks.
Obviously, this 5-years retrospective description of the Odense AHP cohort houses limitations. AHP is a rare disease, which makes the sample size small, weakening the statistical strength of our findings. Second, being a database-based retrospective study we must consider the risk of information bias. Furthermore, many of the symptoms described in this study are unspecific and self-reported by the patients. At last, due to legal limitations, we were only able to perform a 5-year retrospective search in the hospital’s journal system. Thus, we may have missed admissions at other hospitals. However, our study also has some strengths. The Department of Endocrinology at Odense University Hospital serves as the national center for patients with AHP in Denmark. Accordingly, we believe our outpatient clinic is housing the vast majority of Danish AHP patients and that data therefore are representative for Denmark. Furthermore, we use the same variables as other studies, which makes it easier to compare our cohort with others.
In conclusion, this study found the cohort of Danish AHP patients to be similar to previously described patient populations in international studies. The most common type of AHP was AIP, and females dominated both overall and in the symptomatic patient group. Furthermore, only about half of the patients experiencing symptoms needed hospital admission and even fewer needed treatment with human hemin in order to get their acute attack under control. At last, the urinary PBG/creatinine concentration appears to be of prognostic value, as is predicts the risk of having symptoms, but not to the risk of hospitalization or need for treatment.