Acute Hepatic Porphyria in Denmark; a retrospective study

Acute Hepatic Porphyria in Denmark; a retrospective study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Acute Hepatic Porphyria in Denmark; a retrospective study Magnus Emil Ulrich Wagner, Morten Frost, Jan Frystyk This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4848550/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Feb, 2025 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted 5 You are reading this latest preprint version Abstract Background Acute hepatic porphyria (AHP) constitutes a class of rare diseases caused by reduced function in enzymes of the heme-biosynthetic pathway. AHP includes acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP) and the extremely rare δ-aminolevulinic-dehydrase deficiency porphyria (ADP). This retrospective study describes characteristics of the Danish AHP patient population. Methods Department of Endocrinology at Odense University Hospital serves as national AHP center. We performed a 5-year retrospective description of our AHP cohort using electronic patient journals. We included general symptoms, number of acute attacks, hospitalization rates, long-term sequelae and symptoms, and grouped patients according to creatinine-adjusted urinary baseline excretion (i.e., outside attacks) of the porphyrin precursor porphobilinogen (PBG) in normal-, moderate- and high-excretion and unknown. Results The cohort contained 129 AHP patients, hereof 100 AIP, 12 HCP and 17 VP. Median age was 47.8 (32.0–62.0) years, and 85 (65.9%) were female. During the 5-years, 37 (28.7%) patients experienced symptoms. Hereof, 20 patients were hospitalized with acute attacks or chronic symptoms and treated with human hemin (n = 14). Most frequently reported symptoms were abdominal pain, nausea, vomiting, and neurological disturbances. Symptoms were more common in patients with high PBG baseline excretion (n = 39) as compared to those with moderate (n = 31) or normal (n = 40) PBG excretion (p = 0.002). Furthermore, females dominated the symptomatic group (70.3%). Conclusion As reported internationally, AHP is more commonly diagnosed and symptomatic in women, and AIP was the most frequent AHP subtype. Those with an elevated urinary baseline PBG secretion were more likely to report AHP-related symptoms. AIP VP and HCP PBG Figures Figure 1 Figure 2 Introduction Acute hepatic porphyria (AHP) constitutes a group of rare metabolic diseases caused by a genetic mutation in one of four genes encoding enzymes of the heme biosynthesis, resulting in partial enzyme deficiency. Heme functions as a prosthetic group in several hemoproteins such as hemoglobin, mitochondrial cytochromes, and cytochrome P-450 ( 1 , 2 ). Due to enzyme deficiency, neurotoxic intermediates accumulate upstream of the defective enzyme when heme synthesis is increased ( 1 , 3 ). This can result in acute episodic neurovisceral attacks that are potentially life threatening if not correctly treated ( 4 , 5 ). There are four subtypes of AHP. The three most common subtypes, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), are autosomal dominant (AD) inherited. In contrast, δ-aminolevulinic-dehydrase deficiency porphyria (ADP) is inherited in an autosomal recessive manner. The latter is extremely rare ( 6 ), and will not be further discussed. The penetrance of AHP is low, and most carriers with a pathogenic variant in the AHP genes never experience acute attacks but remain free of symptoms. According to literature, the overall penetrance of symptomatic disease is about 1% in carriers of AIP mutations, increasing to > 20% in families with symptomatic AIP patients ( 7 ). The penetrance of pathogenic HCP and VP variants is reported to be lower than for AIP ( 1 , 3 ). A defective heme synthesis constitutes the mainstay of AHP. Figure 1 shows the heme biosynthesis with all the heme intermediates and the corresponding enzymes. Heme intermediates consists of porphyrin precursors and porphyrins. In the first step, ALA synthase (ALAS) converts glycine and succinyl coenzyme A to δ-aminolevulinic acid (ALA). This process is the rate-limiting step. In the following step, two ALA molecules are combined by the enzyme ALA dehydrase (ALAD) to porphobilinogen (PBG). ALA and PBG are porphyrin precursors. PBG deaminase then performs a deamination and condensation of four PBG molecules into one molecule of hydroxymethylbilane (HMB) ( 1 , 2 ). The following enzymatic steps produce porphyrins with decreasing water solubility as the synthesis progresses. The excretion of the precursors PBG and ALA and the intermediate uroporphyrin are exclusively by renal filtration, whereas coproporphyrin is excreted both in feces and urine, and protoporphyrin in feces only ( 1 ). There are negative feedback regulations in the heme biosynthesis (as shown in Fig. 1 ). The final product, heme, exerts negative feedback on ALAS in the first step of the synthesis, which is the rate-limiting step. Accordingly, administration of exogenous hemin (NormoSang®) is used as management of acute attacks. In addition, the two porphyrins coproporphyrinogen III (COPROgen III) and protoporphyrinogen IX (PROTOgen IX) exert negative feedback on the enzyme PBG deaminase. Because of this negative feedback mechanism, patients with HCP and VP accumulate both porphyrins and porphyrin precursors, whereas patients with AIP accumulate precursors only ( 8 ). ALA and PBG are considered neurotoxic and when accumulating, they cause episodic neurovisceral attacks with severe generalized pain in particularly in the abdomen and back, which are usually accompanied with nausea, vomiting, and constipation. In this context, it is clinically impossible to differentiate between patients with AIP, HCP and VP. However, only patients with VP and HCP experience AHP-related skin lesions. The reason is that patients with HCP and VP, in contrast to AIP patients, accumulate light-absorbing porphyrins in the skin, where they act as photosensitizers, causing skin lesions when exposed to sunlight ( 6 , 8 ). An attack develops over hours to days ( 1 , 9 ). Neurological symptoms are present in up to 70% of patients experiencing an acute attack and involves the peripheral, central, and autonomous nerve system ( 8 , 10 , 11 ). Due to the non-specific symptoms and findings of an acute attack, there are often considerable delay in the diagnosis of patients suffering from AHP. The average time from onset of symptoms to final diagnosis ranges from 4 to 15 years ( 6 , 8 , 12 ). The diagnosis of symptomatic AHP involves biochemical testing, where an elevated urinary concentration of PBG is the hallmark of an acute attack, during which the urinary concentration of PBG (corrected for creatinine) is usually 5–10 times higher than the upper normal limit ( 8 , 11 , 13 ). Some of the symptomatic AIP carriers, varying from 15–44% in previous studies ( 8 , 11 ), will have a normal urine analysis when asymptomatic. Due to low penetrance of the disease ( 8 ), the gold standard of diagnosing symptomatic AHP relies on identification of an elevated urinary concentration of PBG, which is usually accompanied by elevated ALA concentrations. Both precursors can be measured with high sensitivity and specificity by quantitative column assays or mass spectrometry ( 8 ), and their concentration is usually stated as mmol per mol creatinine. Subsequently, the AHP subtype can be determined by genetic mutation analysis, which is able to identify disease-promoting mutations in 95–99% of the cases ( 4 , 8 ). Thus, a few patients may present with symptoms resembling attacks of AHP, despite a normal genetic test. In such cases, the diagnosis must rely on the presence of increased concentrations of porphyria precursors (in particularly PBG) in the urine during an attack ( 4 ). In families with a known mutation, carriers (e.g. children of an affected family member) are identifiable by genetic testing, focusing on the specific mutation running in the family. Patients with either latent or symptomatic disease have a greater risk of hypertension, chronic renal failure, and primary hepatocellular carcinoma (HCC) ( 8 , 14 , 15 ). The risk of HCC is probably highest in patients with a history of active disease (recurrent attacks and/or chronically elevated ALA- and PBG-levels). However, all AHP patients are at risk, and according to current recommendations patients ≥ 50 years of age are offered liver ultrasonography to screen for HCC either biannually (e.g. according to the Norwegian National Competence Center for Porphyria ( www.napos.no )) or annually ( 7 , 8 , 15 ). The Department of Endocrinology at Odense University Hospital serves as the national center for patients with AHP in Denmark. The Danish population of AHP patients was originally described in 1980 ( 16 ), but as our biochemical tests and DNA analyses have improved since then, we found it of interest to make a new description of this cohort. Therefore, the aim of this study was to characterize the Danish AHP patient population, their level of excretion of porphyria precursors, and risk of having symptoms. Methods Study population We identified symptomatic individuals and asymptomatic carriers attending follow-up at Department of Endocrinology at Odense University Hospital. Patients with symptomatic AHP were identified by the presence of elevated urinary PBG combined with either acute attacks or chronic symptoms, whereas asymptomatic carriers were identified by the presence of a predisposing mutation in the HMBS, CPOX or PPOX gene. We grouped patients according to their highest documented urinary concentration of PBG (U-PBG/creatinine) outside attacks (i.e., baseline) during the last 5 years. In accordance with a previous study ( 15 ), patients were categorized in three groups: U-PBG-normal (patients with a U-PBG/creatinine level never exceeding the upper limit of normal (ULN); 0.8 mmol/mol), U-PBG-moderate (0.9–3.2 mmol/mol [i.e., maximum 4xULN]) and U-PBG-high (≥ 3.3 mmol/mol). Patients with no documented U-PBG concentration formed a fourth group: U-PBG-unknown. Data collection and management Patient data were obtained from electronic patient journals after legal approval. The legislation limited us to include data for the last 5 years and to include data from our hospital’s patient journal system only. Hence, we did not have access to the Danish National Electronic Journal System (“Sundhed.dk”). Consequently, some patients may have received hospital treatment for AHP without our knowledge. Data were stored at a logged and safe web-based collaborative platform, Share-Point (Microsoft Corporation 2022, Santa Rosa, CA, USA). Statistical analysis Categorical variables are presented as numbers and percentages, and continuous variables as means and interquartile ranges (IQR). Because of the uneven distribution of patients in three AHP subgroups, (100 AIP, 12 HCP and 17 VP), HCP and VP patients were combined as one group to improve statistical power. We compared findings in AHP subtypes AIP vs. HCP + VP using Pearson’s chi-squared test. Based on differences in the three groups of known U-PBG excretion types, a subgroup analysis was performed. Data were not normal-distributed, and accordingly, we used non-parametric ANOVA, i.e., Kruskall-Wallis one-way analysis of variance. Pearson’s chi-squared test was used to test for differences between the three groups. The prevalence of AIP overall and symptomatic AIP were calculated from the number of citizens registered in Denmark primo 2022 (5.87 million) ( 17 ). Microsoft Excel v. 16.60 (Microsoft Corporation 2022, Santa Rosa, CA, USA) was used to do the descriptive statistics. STATA Statistical Software Release 17 (StataCorp 2021, StataCorp LCC, College Station, TX, USA) was used to perform all the statistical analyses. P-values < 0.05 were considered statistically significant. Ethical aspects Prior to start, the study was formally approved by the Legal Department at Odense University Hospital, and because of the retrospectivity of maximum five years, no further permissions were required to access the hospital’s electronic journal of the included patients. Furthermore, there was an approved data-management agreement. There were no conflicts of interest. Results The cohort During the period from February 2017 to February 2022, 129 patients with AHP were attending our outpatient clinic at Department of Endocrinology at Odense University Hospital. Characteristics of the AHP population are shown in Table 1 . The mean age was 46.3 years and 85 of the patients (65.9%) were females. Of our AHP population, 100 patients (77.5%) had AIP, 12 patients (9.3%) HCP and 17 patients (13.2%) VP. Table 1 Descriptive characteristics of the study population All AHP’s AIP HCP VP Total, n (%) 129 (100.0%) 100 (77,5%) 12 (9.3%) 17 (13.2%) Female sex, n (%) 85 (65.9%) 65 (65.0%) 6 (50.0%) 14 (82.4%) Age, mean (IQR) 46.3 (32.1–62.0) 48.2 (33.5–63.0) 37.8 (21.5–51.5) 41.4 (21.8–56.4) Excretion type (PBG) U-PBG normal, n (%) (≤ 0.8 mmol/mol) 40 (31.0%) 24 (24.0%) 9 (75.0%) 7 (41.2%) U-PBG moderate, n (%) (0.9–3.2 mmol/mol) 31 (24.0%) 25 (25.0%) 2 (16.7%) 4 (23.5%) U-PBG high, n (%) (≥ 3.3 mmol/mol) 39 (30.2%) 36 (36.0%) - 3 (17.6%) Unknown 19 (14.7%) 15 (15.0%) 1 (8.3%) 3 (17.6%) Excretion type (ALA) U-ALA normal, n (%) (≤ 5.0 mmol/mol) 83 (64.3%) 62 (62.0%) 10 (83.3%) 11 (64.7%) U-ALA moderate, n (%) (5.1–20.0 mmol/mol) 20 (15.5%) 16 (16.0%) 1 (8.3%) 3 (17.6%) U-ALA high, n (%) (≥ 20.1 mmol/mol) 7 (5.4%) 7 (7.0%) - - U-ALA unknown, n (%) 19 (14.7%) 15 (15.0%) 1 (8.3%) 3 (17.6%) Asymptomatic, n (%) 91 (70.5%) 67 (67.0%) 10 (83.3%) 14 (82.4%) Symptomatic, n (%) 38 (29.5%) 33 (33.0%) 2 (16.7%) 3 (17.6%) Female sex, n (%) 26 (68.4%) 22 (66.7%) 1 (50.0%) 3 (100.0%) Hospitalization, n (%) 20 (15.0%) 18 (18.0%) - 2 (11.8%) During the 5-year period, 38 patients (29.5%) reported having symptoms attributed to AHP at least once, and hereof 26 (68.4%) were female. Thus, 30.6% (26 of 85) of all female AHP patients had symptoms, while 12 of 44 (27.7%) male AHP patients had symptoms. Based on our cohort, the overall prevalence for AHP in Denmark was calculated to 2.2:100,000, whereas the prevalence for symptomatic AIP was 0.6:100,000. Hospitalizations Twenty patients (15.5%) were hospitalized one or more times due to AHP-related symptoms in the same period: 14 patients (70.0%) were hospitalized 1–4 times, whereas 6 patients were hospitalized ≥ 5 times (i.e. at least one annual admission). Eleven patients had one or more acute attacks requiring hospitalization and treatment with human hemin (Normosang®; Recordati Rare Diseases, France) for a minimum of 4 days, whereas 3 hospitalizations were due to prophylactic hemin treatment of chronic symptoms. Baseline levels of the urinary porphyria precursors PBG and ALA Thirty-one patients (24.0%) had moderately elevated U-PBG/creatinine levels (0.9–3.6 mmol/mol) and 39 patients (30.2%) had high U-PBG/creatinine levels (≥ 3.7 mmol/mol). In 40 patients (31.0%), the U-PBG/creatinine level was below the ULN (U-PBG-normal). Data were missing (U-PBG-unknown) in 19 patients (14.7%). The characteristics of the U-PBG subgroup are shown in Table 2 . Table 2 – Characteristics of the AHP population by urinary porphobilinogen (U-PBG) All AHP’s U-PBG-normal (≤ 0.8 mmol / mol creatinine) U-PBG-moderate (0.9–3.2 mmol / mol creatinine) U-PBG-high (≥ 3.3 mmol / mol creatinine) U-PBG-unknown Total, n (%) 129 (100.0%) 40 (31.0%) 31 (24.0%) 39 (30.2%) 19 (14.7%) Female sex, n (%) 85 (65.9%) 20 (50.0%) 23 (74.2%) 31 (79.5%) 11 (57.9%) Age, mean (IQR) 46.3 (32.1–62.0) 38.8 (21.1–56.8) 50.2 (43.1–62.6) 55.1 (41.5–68.4) 37.7 (22.5–52.2) PBG concentration, mean (IQR) (mmol / mol creatinine) 6.3 (0.6–5.6) 0.5 (0.4–0.67 1.6 (1.1-2.0) 15.9 (4.9–22.5) - Asymptomatic, n (%) 91 (70.5%) 33 (82.5%) 23 (74.2%) 18 (46.2%) 17 (89.5%) Symptomatic, n (%) 38 (29.5%) 7 (17.5%) 8 (25.8%) 21 (53.8%) * 2 (10.5%) Hospitalization, n (%) 20 (15.5%) 4 (10.0%) 2 (6.5%) 13 (33.3%) 1 (5.3%) Hemin treatment, n (%) 14 (10.9%) 1 (2.5%) 2 (6.5%) 10 (25.6%) 1 (5.3%) * = significantly different from U-PBG-normal (p = 0.001) and U-PBG-moderate (p = 0.018) IQR (interquartile range), U-PBG (urine porphobilinogen) An elevated U-ALA/creatinine level was recorded in 27 patients (20.9%), being moderate (5.1-20.0mmol/mol) in 20 (14.5%) and high (≥ 20.1mmol/mol) in 7 (5.1%) patients. Eighty-three patients (64.3%) had a U-ALA/creatinine level below the ULN (U-ALA normal), whereas data from 19 patients (14.7%) were missing (U-ALA unknown). Symptomatology The different symptoms of the symptomatic AHP patients are shown in Table 3 . The dominating symptom was abdominal pain, which was reported in 36 of 38 patients (94.7%) during an acute attack. Other common symptoms were nausea and vomiting (28.9%), and neurological disturbances (31.6%). Less common symptoms were constipation (15.8%), weakness (13.2%), diarrhea (10.5%), anxiety and depression (7.9%), and seizures (7.9%). Table 3 – Symptoms, precipitating factors, and co-morbidities for the study population Symptoms n (%) Precipitating factor n (%) Co-morbidities n (%) Abdominal pain 36 (97.3%) Unknown 15 (40.5%) None 84 (65.1%) Nausea, vomiting 11 (29.7%) Alcohol 6 (16.2%) Hypertension 19 (14.7%) Weakness 5 (13.5%) Stress 10 (27.0%) Reduced eGFR 9 (7.0%) Constipation 6 (16.2%) Medication 7 (18.9%) Headache 2 (1.6%) Anxiety, depression 3 (8.1%) Menstruation/hormonal 2 (5.4%) Paresis 0 (0.0%) Diarrhea 4 (10.8%) Fasting 4 (10.8%) Other 36 (27.9%) Seizures 3 (8.1%) Infection 10 (27.0%) Paresis, neurological disturbance 12 (32.4%) Precipitating factors Factors precipitating attacks in the symptomatic patients according to patients and physicians are shown in Table 3 . Fifteen of the 38 symptomatic patients had unknown precipitating factors, while other patients had several potential precipitating factors of the attack. The most frequently reported precipitating factors were stress (10 patients), infection (10 patients) and medication (7 patients). Other precipitating factors reported were alcohol (6 patients), fasting (4 patients) and menstruation/hormonal (2 patients). Comorbidities The comorbidities of the study population are shown in Table 3 . Eighty-four (65.1%) patients had no known comorbidities, whereas the remaining 45 (34.9%) patients had at least one comorbidity. The reported comorbidities were hypertension (19 patients, 14.7%), reduced estimated glomerular filtration rate (eGFR) (9 patients, 7.0%), and headache (2 patients, 1.6%). Finally, 36 patients (27.9%) had other non-AHP-related comorbidities like diabetes, asthma, osteoporosis, rheumatoid arthritis, epilepsy, etc. HCC is a known co-morbidity to AHP. Patients aged ≥ 50 years are offered a hepatic ultrasonography (ULS) either annually or biannually. In our population, 57 patients (44.2%) where in this group. Hereof, 49 patients (86.0%) had biannually ULS, and 7 patients (12.3%) had annually ULS check-up. One patient (1.7%) refrained having ULS. During the five-year study period, none of the 129 patients received a diagnosis of HCC. U-PBG subgroup analysis We could demonstrate a relationship between baseline U-PBG/creatinine levels (i.e., outside attacks) and the risk of having symptoms. Thus, the risk of having symptoms in high-excreters was significantly higher than in moderate excreters (p = 0.018) or normal excreters (p = 0.001), with no difference between the two latter groups (p = 0.40). We observed no statistical differences between the 3 different U-PBG/creatinine excretion groups as regards number of hospitalizations (0.078) or treatments (0.16). U-PBG and U-ALA during acute attacks Administration of hemin rapidly reduces the urinary levels of porphyrin precursors in all treated patients, Fig. 2 . However, at the time of the acute admission the relative increase in the urinary excretion of porphyria precursors varied considerably between patients. E.g., some patients had urinary precursor levels that were markedly elevated, whereas in others the increase was less dramatic. Figure 2 shows the variability between patients in the urinary excretion of ALA and PBG, respectively, during hemin treatment. Measurements are corrected for urinary creatinine concentrations. Discussion 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. Abbreviations ALA synthase ALAS Aminolevulinic acid ALA Coproporphyrin COPRO Coproporphyrinogen III COPROgen III coproporphyrinogen oxidase CPOX Delta-aminolevulinic acid (ALA) dehydratase deficiency porphyria ADP Estimated glomerular filtration rate eGFR Gonadotropin-releasing hormone GnRH hepatocellular carcinoma HCC Hereditary coproporphyria HCP Hydroxymethylbilane HMB hydroxymethylbilane synthase HMBS porphobilinogen PBG Porphobilinogen PBG Protoporphyrin PROTO Protoporphyrinogen IX PROTOgen IX protoporphyrinogen oxidase PPOX Ultrasonography ULS Upper normal limit ULN Uroporphyrin URO Variegate porphyria VP Declarations Ethical approval: This was obtained from the hospital’s legal department prior to start. Consent to participate: not applicable Consent for publication: all authors agree to submit this manuscript to Orphanet J of Rare Diseases Availability of data and material. We have extracted data from patient journals and subsequently stored all at secure- and access-logged serves at the hospital. Because data contains journal information, they are not accessible for third party. Competing interests. None. Funding. None. Authors' contributions. Dr. Wagner and Professor Frystyk developed the idea to study out cohort of patients with acute hepatic porphyria. Dr. Wagner collected data from the patient journals and wrote the draft manuscript. Professor Frost and Professor Frystyk have critically reviewed the manuscript. Acknowledgements. Not applicable. DISCLOSURE STATEMENT The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. References Wang B. The acute hepatic porphyrias. Transl Gastroenterol Hepatol. 2021;6:24. Phillips JD. Heme biosynthesis and the porphyrias. Mol Genet Metab. 2019;128(3):164–77. Elder G, Harper P, Badminton M, Sandberg S, Deybach JC. The incidence of inherited porphyrias in Europe. J Inherit Metab Dis. 2013;36(5):849–57. Whatley SD, Badminton MN. Role of genetic testing in the management of patients with inherited porphyria and their families. Ann Clin Biochem. 2013;50(Pt 3):204–16. Edel Y, Mamet R, Cohen S, Shepshelovich D, Levi A, Sagy I. The clinical importance of early acute hepatic porphyria diagnosis: a national cohort. Intern Emerg Med. 2021;16(1):133–9. Gouya L, Ventura P, Balwani M, Bissell DM, Rees DC, Stölzel U, et al. EXPLORE: A prospective, multinational, natural history study of patients with acute hepatic porphyria with recurrent attacks. Hepatology. 2020;71(5):1546–58. Wang B, Bonkovsky HL, Lim JK, Balwani M. AGA Clinical practice update on diagnosis and management of acute hepatic porphyrias: expert review. Gastroenterology. 2023;164(3):484–91. Wang B, Bissell DM. The acute porphyrias. editor. Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease. Sixth Edition): Academic; 2020. pp. 953–69. JMP RNR. Kothadia JP, LaFreniere K, Shah JM. Acute Hepatic Porphyria. StatPearls. Treasure Island (FL): StatPearls Publishing. Copyright © 2024. StatPearls Publishing LLC.; 2024. Suh Y, Gandhi J, Seyam O, Jiang W, Joshi G, Smith NL, et al. Neurological and neuropsychiatric manifestations of porphyria. Int J Neurosci. 2019;129(12):1226–33. Anderson KE, Lobo R, Salazar D, Schloetter M, Spitzer G, White AL, et al. Biochemical diagnosis of acute hepatic porphyria: updated expert recommendations for primary care physicians. Am J Med Sci. 2021;362(2):113–21. Mykletun M, Aarsand AK, Støle E, Villanger JH, Tollånes MC, Baravelli C, et al. Porphyrias in Norway. Tidsskr Nor Laegeforen. 2014;134(8):831–6. Karim Z, Lyoumi S, Nicolas G, Deybach J-C, Gouya L, Puy H, Porphyrias. A 2015 update. Clin Res Hepatol Gastroenterol. 2015;39(4):412–25. Puy HP, Gouya LP, Deybach J-CP. Porphyrias Lancet The. 2010;375(9718):924–37. Lissing M, Vassiliou D, Floderus Y, Harper P, Bottai M, Kotopouli M, et al. Risk of primary liver cancer in acute hepatic porphyria patients: A matched cohort study of 1244 individuals. J Intern Med. 2022;291(6):824–36. With TK. The different types of porphyria in Denmark and the importance of family studies. Int J Biochem. 1980;12(5–6):887–9. Denmark S. Population projections https:// [ https://www.dst.dk/en/Statistik/emner/borgere/befolkning/befolkningsfremskrivning Bonkovsky HL, Maddukuri VC, Yazici C, Anderson KE, Bissell DM, Bloomer JR, et al. Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium. Am J Med. 2014;127(12):1233–41. Thunell S, Floderus Y, Henrichson A, Harper P. Porphyria in Sweden. Physiol Res. 2006;55(Suppl 2):S109–18. Innala E, Bäckström T, Bixo M, Andersson C. Evaluation of gonadotropin-releasing hormone agonist treatment for prevention of menstrual-related attacks in acute porphyria. Acta Obstet Gynecol Scand. 2010;89(1):95–100. Andersson C, Innala E, Bäckström T. Acute intermittent porphyria in women: clinical expression, use and experience of exogenous sex hormones. A population-based study in northern Sweden. J Intern Med. 2003;254(2):176–83. Hift RJ, Meissner PN. An analysis of 112 acute porphyric attacks in Cape Town, South Africa: Evidence that acute intermittent porphyria and variegate porphyria differ in susceptibility and severity. Med (Baltim). 2005;84(1):48–60. Lin CS, Lee MJ, Park SB, Kiernan MC. Purple pigments: the pathophysiology of acute porphyric neuropathy. Clin Neurophysiol. 2011;122(12):2336–44. Carvalho AA, Arçari DD. Acute intermittent porphyria after gastroplasty. Arq Neuropsiquiatr. 2011;69(6):992. Danion F, Guillot M, Castelain V, Puy H, Deybach JC, Schneider F. An uncommon option for surviving bariatric surgery: regaining weight! Am J Med. 2012;125(11):e1–2. Bonkovsky HL, Siao P, Roig Z, Hedley-Whyte ET, Flotte TJ. Case 20-2008. N Engl J Med. 2008;358(26):2813–25. Andersson C, Wikberg A, Stegmayr B, Lithner F. Renal symptomatology in patients with acute intermittent porphyria. A population-based study. J Intern Med. 2000;248(4):319–25. Lelli SM, San Martín de Viale LC, Mazzetti MB. Response of glucose metabolism enzymes in an acute porphyria model. Role of reactive oxygen species. Toxicology. 2005;216(1):49–58. Bissell DM, Anderson KE, Bonkovsky HL, Porphyria. N Engl J Med. 2017;377(9):862–72. Cite Share Download PDF Status: Published Journal Publication published 28 Feb, 2025 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted Editorial decision: Minor revision 27 Oct, 2024 Reviewers agreed at journal 15 Aug, 2024 Reviewers invited by journal 14 Aug, 2024 Editor assigned by journal 07 Aug, 2024 First submitted to journal 04 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4848550","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":340060470,"identity":"80dedb5c-cc56-4611-99d7-4015a54e8b3c","order_by":0,"name":"Magnus Emil Ulrich Wagner","email":"","orcid":"","institution":"Odense University Hospital: Odense Universitetshospital","correspondingAuthor":false,"prefix":"","firstName":"Magnus","middleName":"Emil Ulrich","lastName":"Wagner","suffix":""},{"id":340060471,"identity":"9aec44f7-b47e-40f8-afea-2a6f34612061","order_by":1,"name":"Morten Frost","email":"","orcid":"","institution":"Odense University Hospital Department of Endocrinology: Odense Universitetshospital Endokrinologisk Afdeling M","correspondingAuthor":false,"prefix":"","firstName":"Morten","middleName":"","lastName":"Frost","suffix":""},{"id":340060472,"identity":"87dbab75-ec1c-4983-9660-1ce115b7859a","order_by":2,"name":"Jan Frystyk","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6UlEQVRIie2PsQrCMBCGrxTSpaBjHMRXSHF06Ku0COlSBDdBkBOhXQpdfRiHk4BT+wBuTp0cdO9gWp0cYkeHfHDJceQ7/gBYLH+Ig/rY9C1zbu+BHKBUunxgrhik9HwUxgcpbl4TnE8qDLmU202rpujJyBysWEVAjYoLLi/XOlNz9Bv68ZdUuA9Skc+T7LpHFSNP0KyUdwFEKuyUNbZDlGPaK04XzEHWKfJHsONdEFESF1WznOyzZJ75TWRUgjINbkSL0Mtl8MR2MS09KcyKzq1zHADG/e4DMON7zex97QBG9GksFovF8sULLRNRWFG9jEMAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-5379-0961","institution":"Odense University Hospital Department of Endocrinology: Odense Universitetshospital Endokrinologisk Afdeling M","correspondingAuthor":true,"prefix":"","firstName":"Jan","middleName":"","lastName":"Frystyk","suffix":""}],"badges":[],"createdAt":"2024-08-02 12:49:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4848550/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4848550/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13023-025-03536-3","type":"published","date":"2025-02-28T15:57:24+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":66378841,"identity":"8cbb8192-2048-4f20-af26-d628ba7ef572","added_by":"auto","created_at":"2024-10-11 06:39:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":454529,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe pathway of the heme biosynthesis\u003c/strong\u003e. ALA (d-aminolevulinic acid), PBG (porphobilinogen), HMB (hydroxymethylbilane), URO (uroporphyrin), COPRO (coproporphyrin), PROTO (protoporphyrin), ADP (d-aminolevulinic-dehydrase deficiency porphyria), AIP (acute intermittent porphyria), HCP (hereditary coproporphyria), VP (variegate porphyria) \u003cstrong\u003e(2, 8, 28, 29)\u003c/strong\u003e. The precipitating factors are shown in the green box \u003cstrong\u003e(18)\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4848550/v1/6ca913aa41360faccfa0ccaf.png"},{"id":66378842,"identity":"85e42c9e-25db-4814-a257-92cb0b811f6c","added_by":"auto","created_at":"2024-10-11 06:39:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":38743,"visible":true,"origin":"","legend":"\u003cp\u003eProgress, during an acute attack of AHP, of precursors urine porphobilinogen (U-PBG) and urine d-aminolevulinic acid (U-ALA) after initiation of hemin treatment on Day 1.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4848550/v1/49a51e8a4c1b9272a1b8cf29.png"},{"id":77622701,"identity":"cb65ef42-0c67-4e02-a79a-3255248849b1","added_by":"auto","created_at":"2025-03-03 16:09:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1641549,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4848550/v1/0899eece-7bf4-4594-80c5-c3db0e6bc418.pdf"}],"financialInterests":"","formattedTitle":"Acute Hepatic Porphyria in Denmark; a retrospective study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcute hepatic porphyria (AHP) constitutes a group of rare metabolic diseases caused by a genetic mutation in one of four genes encoding enzymes of the heme biosynthesis, resulting in partial enzyme deficiency. Heme functions as a prosthetic group in several hemoproteins such as hemoglobin, mitochondrial cytochromes, and cytochrome P-450 (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Due to enzyme deficiency, neurotoxic intermediates accumulate upstream of the defective enzyme when heme synthesis is increased (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). This can result in acute episodic neurovisceral attacks that are potentially life threatening if not correctly treated (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThere are four subtypes of AHP. The three most common subtypes, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), are autosomal dominant (AD) inherited. In contrast, δ-aminolevulinic-dehydrase deficiency porphyria (ADP) is inherited in an autosomal recessive manner. The latter is extremely rare (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), and will not be further discussed.\u003c/p\u003e \u003cp\u003eThe penetrance of AHP is low, and most carriers with a pathogenic variant in the AHP genes never experience acute attacks but remain free of symptoms. According to literature, the overall penetrance of symptomatic disease is about 1% in carriers of AIP mutations, increasing to \u0026gt;\u0026thinsp;20% in families with symptomatic AIP patients (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). The penetrance of pathogenic HCP and VP variants is reported to be lower than for AIP (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA defective heme synthesis constitutes the mainstay of AHP. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the heme biosynthesis with all the heme intermediates and the corresponding enzymes. Heme intermediates consists of porphyrin precursors and porphyrins. In the first step, ALA synthase (ALAS) converts glycine and succinyl coenzyme A to δ-aminolevulinic acid (ALA). This process is the rate-limiting step. In the following step, two ALA molecules are combined by the enzyme ALA dehydrase (ALAD) to porphobilinogen (PBG). ALA and PBG are porphyrin precursors. PBG deaminase then performs a deamination and condensation of four PBG molecules into one molecule of hydroxymethylbilane (HMB) (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The following enzymatic steps produce porphyrins with decreasing water solubility as the synthesis progresses. The excretion of the precursors PBG and ALA and the intermediate uroporphyrin are exclusively by renal filtration, whereas coproporphyrin is excreted both in feces and urine, and protoporphyrin in feces only (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThere are negative feedback regulations in the heme biosynthesis (as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The final product, heme, exerts negative feedback on ALAS in the first step of the synthesis, which is the rate-limiting step. Accordingly, administration of exogenous hemin (NormoSang\u0026reg;) is used as management of acute attacks. In addition, the two porphyrins coproporphyrinogen III (COPROgen III) and protoporphyrinogen IX (PROTOgen IX) exert negative feedback on the enzyme PBG deaminase. Because of this negative feedback mechanism, patients with HCP and VP accumulate both porphyrins and porphyrin precursors, whereas patients with AIP accumulate precursors only (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eALA and PBG are considered neurotoxic and when accumulating, they cause episodic neurovisceral attacks with severe generalized pain in particularly in the abdomen and back, which are usually accompanied with nausea, vomiting, and constipation. In this context, it is clinically impossible to differentiate between patients with AIP, HCP and VP. However, only patients with VP and HCP experience AHP-related skin lesions. The reason is that patients with HCP and VP, in contrast to AIP patients, accumulate light-absorbing porphyrins in the skin, where they act as photosensitizers, causing skin lesions when exposed to sunlight (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAn attack develops over hours to days (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Neurological symptoms are present in up to 70% of patients experiencing an acute attack and involves the peripheral, central, and autonomous nerve system (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Due to the non-specific symptoms and findings of an acute attack, there are often considerable delay in the diagnosis of patients suffering from AHP. The average time from onset of symptoms to final diagnosis ranges from 4 to 15 years (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). The diagnosis of symptomatic AHP involves biochemical testing, where an elevated urinary concentration of PBG is the hallmark of an acute attack, during which the urinary concentration of PBG (corrected for creatinine) is usually 5\u0026ndash;10 times higher than the upper normal limit (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Some of the symptomatic AIP carriers, varying from 15\u0026ndash;44% in previous studies (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), will have a normal urine analysis when asymptomatic.\u003c/p\u003e \u003cp\u003eDue to low penetrance of the disease (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), the gold standard of diagnosing symptomatic AHP relies on identification of an elevated urinary concentration of PBG, which is usually accompanied by elevated ALA concentrations. Both precursors can be measured with high sensitivity and specificity by quantitative column assays or mass spectrometry (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), and their concentration is usually stated as mmol per mol creatinine. Subsequently, the AHP subtype can be determined by genetic mutation analysis, which is able to identify disease-promoting mutations in 95\u0026ndash;99% of the cases (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Thus, a few patients may present with symptoms resembling attacks of AHP, despite a normal genetic test. In such cases, the diagnosis must rely on the presence of increased concentrations of porphyria precursors (in particularly PBG) in the urine during an attack (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). In families with a known mutation, carriers (e.g. children of an affected family member) are identifiable by genetic testing, focusing on the specific mutation running in the family.\u003c/p\u003e \u003cp\u003ePatients with either latent or symptomatic disease have a greater risk of hypertension, chronic renal failure, and primary hepatocellular carcinoma (HCC) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The risk of HCC is probably highest in patients with a history of active disease (recurrent attacks and/or chronically elevated ALA- and PBG-levels). However, all AHP patients are at risk, and according to current recommendations patients\u0026thinsp;\u0026ge;\u0026thinsp;50 years of age are offered liver ultrasonography to screen for HCC either biannually (e.g. according to the Norwegian National Competence Center for Porphyria (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.napos.no\" target=\"_blank\"\u003ewww.napos.no\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.napos.no\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e)) or annually (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe Department of Endocrinology at Odense University Hospital serves as the national center for patients with AHP in Denmark. The Danish population of AHP patients was originally described in 1980 (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e), but as our biochemical tests and DNA analyses have improved since then, we found it of interest to make a new description of this cohort. Therefore, the aim of this study was to characterize the Danish AHP patient population, their level of excretion of porphyria precursors, and risk of having symptoms.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eWe identified symptomatic individuals and asymptomatic carriers attending follow-up at Department of Endocrinology at Odense University Hospital. Patients with symptomatic AHP were identified by the presence of elevated urinary PBG combined with either acute attacks or chronic symptoms, whereas asymptomatic carriers were identified by the presence of a predisposing mutation in the HMBS, CPOX or PPOX gene.\u003c/p\u003e \u003cp\u003eWe grouped patients according to their highest documented urinary concentration of PBG (U-PBG/creatinine) outside attacks (i.e., baseline) during the last 5 years. In accordance with a previous study (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), patients were categorized in three groups: U-PBG-normal (patients with a U-PBG/creatinine level never exceeding the upper limit of normal (ULN); 0.8 mmol/mol), U-PBG-moderate (0.9\u0026ndash;3.2 mmol/mol [i.e., maximum 4xULN]) and U-PBG-high (\u0026ge;\u0026thinsp;3.3 mmol/mol). Patients with no documented U-PBG concentration formed a fourth group: U-PBG-unknown.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData collection and management\u003c/h2\u003e \u003cp\u003ePatient data were obtained from electronic patient journals after legal approval. The legislation limited us to include data for the last 5 years and to include data from our hospital\u0026rsquo;s patient journal system only. Hence, we did not have access to the Danish National Electronic Journal System (\u0026ldquo;Sundhed.dk\u0026rdquo;). Consequently, some patients may have received hospital treatment for AHP without our knowledge. Data were stored at a logged and safe web-based collaborative platform, Share-Point (Microsoft Corporation 2022, Santa Rosa, CA, USA).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eCategorical variables are presented as numbers and percentages, and continuous variables as means and interquartile ranges (IQR). Because of the uneven distribution of patients in three AHP subgroups, (100 AIP, 12 HCP and 17 VP), HCP and VP patients were combined as one group to improve statistical power. We compared findings in AHP subtypes AIP vs. HCP\u0026thinsp;+\u0026thinsp;VP using Pearson\u0026rsquo;s chi-squared test. Based on differences in the three groups of known U-PBG excretion types, a subgroup analysis was performed. Data were not normal-distributed, and accordingly, we used non-parametric ANOVA, i.e., Kruskall-Wallis one-way analysis of variance. Pearson\u0026rsquo;s chi-squared test was used to test for differences between the three groups. The prevalence of AIP overall and symptomatic AIP were calculated from the number of citizens registered in Denmark primo 2022 (5.87\u0026nbsp;million) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMicrosoft Excel v. 16.60 (Microsoft Corporation 2022, Santa Rosa, CA, USA) was used to do the descriptive statistics. STATA Statistical Software Release 17 (StataCorp 2021, StataCorp LCC, College Station, TX, USA) was used to perform all the statistical analyses. P-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eEthical aspects\u003c/h2\u003e \u003cp\u003ePrior to start, the study was formally approved by the Legal Department at Odense University Hospital, and because of the retrospectivity of maximum five years, no further permissions were required to access the hospital\u0026rsquo;s electronic journal of the included patients. Furthermore, there was an approved data-management agreement. There were no conflicts of interest.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eThe cohort\u003c/h2\u003e \u003cp\u003eDuring the period from February 2017 to February 2022, 129 patients with AHP were attending our outpatient clinic at Department of Endocrinology at Odense University Hospital. Characteristics of the AHP population are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The mean age was 46.3 years and 85 of the patients (65.9%) were females. Of our AHP population, 100 patients (77.5%) had AIP, 12 patients (9.3%) HCP and 17 patients (13.2%) VP.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDescriptive characteristics of the study population\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eAll AHP\u0026rsquo;s\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eAIP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eHCP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003eVP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e129 (100.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e100 (77,5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e12 (9.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e17 (13.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFemale sex, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e85 (65.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e65 (65.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e6 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e14 (82.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge, mean (IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e46.3 (32.1\u0026ndash;62.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e48.2 (33.5\u0026ndash;63.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e37.8 (21.5\u0026ndash;51.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e41.4\u0026nbsp;(21.8\u0026ndash;56.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eExcretion type (PBG)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eU-PBG normal, n (%)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(\u0026le;\u0026thinsp;0.8 mmol/mol)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e40 (31.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e24 (24.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e9 (75.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e7 (41.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eU-PBG moderate, n (%)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(0.9\u0026ndash;3.2 mmol/mol)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e31 (24.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e25 (25.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e2 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e4 (23.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eU-PBG high, n (%)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(\u0026ge;\u0026thinsp;3.3 mmol/mol)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e39 (30.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e36 (36.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e3 (17.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eUnknown\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e19 (14.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e15 (15.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e1 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e3 (17.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eExcretion type (ALA)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eU-ALA normal, n (%)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(\u0026le;\u0026thinsp;5.0 mmol/mol)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e83 (64.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e62 (62.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e10 (83.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e11 (64.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eU-ALA moderate, n (%)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(5.1\u0026ndash;20.0 mmol/mol)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e20 (15.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e16 (16.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e1 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e3 (17.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eU-ALA high, n (%)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(\u0026ge;\u0026thinsp;20.1 mmol/mol)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e7 (5.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e7 (7.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eU-ALA unknown, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e19 (14.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e15 (15.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e1 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e3 (17.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAsymptomatic, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e91 (70.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e67 (67.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e10 (83.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e14 (82.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSymptomatic, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e38 (29.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e33 (33.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e2 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e3 (17.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eFemale sex, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e26 (68.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e22 (66.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e1 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e3 (100.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHospitalization, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e20 (15.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e18 (18.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e2 (11.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eDuring the 5-year period, 38 patients (29.5%) reported having symptoms attributed to AHP at least once, and hereof 26 (68.4%) were female. Thus, 30.6% (26 of 85) of all female AHP patients had symptoms, while 12 of 44 (27.7%) male AHP patients had symptoms. Based on our cohort, the overall prevalence for AHP in Denmark was calculated to 2.2:100,000, whereas the prevalence for symptomatic AIP was 0.6:100,000.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eHospitalizations\u003c/h2\u003e \u003cp\u003eTwenty patients (15.5%) were hospitalized one or more times due to AHP-related symptoms in the same period: 14 patients (70.0%) were hospitalized 1\u0026ndash;4 times, whereas 6 patients were hospitalized\u0026thinsp;\u0026ge;\u0026thinsp;5 times (i.e. at least one annual admission). Eleven patients had one or more acute attacks requiring hospitalization and treatment with human hemin (Normosang\u0026reg;; Recordati Rare Diseases, France) for a minimum of 4 days, whereas 3 hospitalizations were due to prophylactic hemin treatment of chronic symptoms.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eBaseline levels of the urinary porphyria precursors PBG and ALA\u003c/h2\u003e \u003cp\u003eThirty-one patients (24.0%) had moderately elevated U-PBG/creatinine levels (0.9\u0026ndash;3.6 mmol/mol) and 39 patients (30.2%) had high U-PBG/creatinine levels (\u0026ge;\u0026thinsp;3.7 mmol/mol). In 40 patients (31.0%), the U-PBG/creatinine level was below the ULN (U-PBG-normal). Data were missing (U-PBG-unknown) in 19 patients (14.7%). The characteristics of the U-PBG subgroup are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u0026ndash; Characteristics of the AHP population by urinary porphobilinogen (U-PBG)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAll AHP\u0026rsquo;s\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eU-PBG-normal\u003c/p\u003e \u003cp\u003e(\u0026le;\u0026thinsp;0.8 mmol /\u003c/p\u003e \u003cp\u003emol creatinine)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eU-PBG-moderate\u003c/p\u003e \u003cp\u003e(0.9\u0026ndash;3.2 mmol /\u003c/p\u003e \u003cp\u003emol creatinine)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eU-PBG-high\u003c/p\u003e \u003cp\u003e(\u0026ge;\u0026thinsp;3.3 mmol /\u003c/p\u003e \u003cp\u003emol creatinine)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eU-PBG-unknown\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e129 (100.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (31.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31 (24.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e39 (30.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e19 (14.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFemale sex, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e85 (65.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 (74.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31 (79.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11 (57.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge, mean (IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46.3 (32.1\u0026ndash;62.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38.8\u0026nbsp;(21.1\u0026ndash;56.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50.2\u0026nbsp;(43.1\u0026ndash;62.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e55.1 (41.5\u0026ndash;68.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e37.7\u0026nbsp;(22.5\u0026ndash;52.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePBG concentration, mean (IQR)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(mmol / mol creatinine)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.3 (0.6\u0026ndash;5.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.5\u0026nbsp;(0.4\u0026ndash;0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.6 (1.1-2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.9 (4.9\u0026ndash;22.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAsymptomatic, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e91 (70.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (82.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 (74.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18 (46.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17 (89.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSymptomatic, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (29.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (17.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (25.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21 (53.8%) *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (10.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHospitalization, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (15.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (10.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (6.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHemin treatment, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (10.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (6.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10 (25.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e* = significantly different from U-PBG-normal (p\u0026thinsp;=\u0026thinsp;0.001) and U-PBG-moderate (p\u0026thinsp;=\u0026thinsp;0.018)\u003c/p\u003e \u003cp\u003eIQR (interquartile range), U-PBG (urine porphobilinogen)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAn elevated U-ALA/creatinine level was recorded in 27 patients (20.9%), being moderate (5.1-20.0mmol/mol) in 20 (14.5%) and high (\u0026ge;\u0026thinsp;20.1mmol/mol) in 7 (5.1%) patients. Eighty-three patients (64.3%) had a U-ALA/creatinine level below the ULN (U-ALA normal), whereas data from 19 patients (14.7%) were missing (U-ALA unknown).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSymptomatology\u003c/h2\u003e \u003cp\u003eThe different symptoms of the symptomatic AHP patients are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The dominating symptom was abdominal pain, which was reported in 36 of 38 patients (94.7%) during an acute attack. Other common symptoms were nausea and vomiting (28.9%), and neurological disturbances (31.6%). Less common symptoms were constipation (15.8%), weakness (13.2%), diarrhea (10.5%), anxiety and depression (7.9%), and seizures (7.9%).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u0026ndash; Symptoms, precipitating factors, and co-morbidities for the study population\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSymptoms\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003en (%)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePrecipitating factor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003en\u0026nbsp;(%)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCo-morbidities\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003en\u0026nbsp;(%)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbdominal pain\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (97.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eUnknown\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (40.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eNone\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e84 (65.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNausea, vomiting\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (29.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eAlcohol\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (16.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eHypertension\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e19 (14.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWeakness\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (13.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eStress\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (27.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eReduced eGFR\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9 (7.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eConstipation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (16.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eMedication\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (18.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eHeadache\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (1.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAnxiety, depression\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (8.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eMenstruation/hormonal\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (5.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eParesis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiarrhea\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (10.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eFasting\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (10.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eOther\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e36 (27.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSeizures\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (8.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eInfection\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (27.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eParesis, neurological disturbance\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (32.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePrecipitating factors\u003c/h2\u003e \u003cp\u003eFactors precipitating attacks in the symptomatic patients according to patients and physicians are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Fifteen of the 38 symptomatic patients had unknown precipitating factors, while other patients had several potential precipitating factors of the attack. The most frequently reported precipitating factors were stress (10 patients), infection (10 patients) and medication (7 patients). Other precipitating factors reported were alcohol (6 patients), fasting (4 patients) and menstruation/hormonal (2 patients).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eComorbidities\u003c/h2\u003e \u003cp\u003eThe comorbidities of the study population are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Eighty-four (65.1%) patients had no known comorbidities, whereas the remaining 45 (34.9%) patients had at least one comorbidity. The reported comorbidities were hypertension (19 patients, 14.7%), reduced estimated glomerular filtration rate (eGFR) (9 patients, 7.0%), and headache (2 patients, 1.6%). Finally, 36 patients (27.9%) had other non-AHP-related comorbidities like diabetes, asthma, osteoporosis, rheumatoid arthritis, epilepsy, etc.\u003c/p\u003e \u003cp\u003eHCC is a known co-morbidity to AHP. Patients aged\u0026thinsp;\u0026ge;\u0026thinsp;50 years are offered a hepatic ultrasonography (ULS) either annually or biannually. In our population, 57 patients (44.2%) where in this group. Hereof, 49 patients (86.0%) had biannually ULS, and 7 patients (12.3%) had annually ULS check-up. One patient (1.7%) refrained having ULS. During the five-year study period, none of the 129 patients received a diagnosis of HCC.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eU-PBG subgroup analysis\u003c/h2\u003e \u003cp\u003eWe could demonstrate a relationship between baseline U-PBG/creatinine levels (i.e., outside attacks) and the risk of having symptoms. Thus, the risk of having symptoms in high-excreters was significantly higher than in moderate excreters (p\u0026thinsp;=\u0026thinsp;0.018) or normal excreters (p\u0026thinsp;=\u0026thinsp;0.001), with no difference between the two latter groups (p\u0026thinsp;=\u0026thinsp;0.40). We observed no statistical differences between the 3 different U-PBG/creatinine excretion groups as regards number of hospitalizations (0.078) or treatments (0.16).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eU-PBG and U-ALA during acute attacks\u003c/h2\u003e \u003cp\u003eAdministration of hemin rapidly reduces the urinary levels of porphyrin precursors in all treated patients, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. However, at the time of the acute admission the relative increase in the urinary excretion of porphyria precursors varied considerably between patients. E.g., some patients had urinary precursor levels that were markedly elevated, whereas in others the increase was less dramatic. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the variability between patients in the urinary excretion of ALA and PBG, respectively, during hemin treatment. Measurements are corrected for urinary creatinine concentrations.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis 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.\u003c/p\u003e \u003cp\u003eIn general, AIP is the dominating AHP subtype, being reported to constitute between 57% and 96% of all AHP patients (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). 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\u0026ndash;10% and 4\u0026ndash;33%, respectively (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). The highest frequency of VP patients appears to be in France, Switzerland, and United Kingdom (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). 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 (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe Danish prevalence of AHP (1.7:100,000) is lower than that found in Norway (7:100,000) (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) and Sweden (10:100,000) (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). 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) (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), but similar to the calculated prevalence (calculated on the basis of incidence from the participating countries) in Europe (0.5:100,000) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). 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 (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). 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 (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Three other studies have shown a genetic frequency of mutations predisposing to AIP ranging from 1:1300 to 1:1785 (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), which could indicate that the prevalence could be much higher than first thought.\u003c/p\u003e \u003cp\u003ePrevious studies have reported that APH is more commonly diagnosed in females (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), 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\u0026ndash;89%. Wang et al. (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) 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 (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Moreover, the prevalence of symptoms generally decreases after the menopause in symptomatic female patients (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). This indicates that progesterone and estrogen play an important role in precipitating acute attacks, and thereby the female sex predominance.\u003c/p\u003e \u003cp\u003eIn general, there is consistency between symptoms being reported by the Danish AHP patients experiencing acute attacks and those observed in other studies (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). In all studies, abdominal pain is the main symptom during attacks, being reported by 74\u0026ndash;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.\u003c/p\u003e \u003cp\u003eIn 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 (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Indeed, the neurological symptoms may simulate symptoms of Guillain-Barr\u0026eacute; (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) and there are case reports describing patients being falsely diagnosed with and treated for Guillain-Barr\u0026eacute;, but without improvement after several days of treatment (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Finally, and of clinical relevance, 20\u0026ndash;30% of the AHP population may present with signs of mental disturbances such as anxiety, depression, disorientation, hallucinations, and confusions (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe heme biosynthesis pathway can be induced by different precipitating factors, increasing the demand for heme and consequently, by feedback, accelerate the enzymatic activity (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). 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 (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). 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%) (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), but less common than in Norway (40%) (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) and USA (37%) (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). 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 (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). 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 \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.drugs-porphyria.org/\u003c/span\u003e\u003cspan address=\"https://www.drugs-porphyria.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eIn 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 (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Thus, stress may be a symptom rather than a precipitating factor.\u003c/p\u003e \u003cp\u003eAttacks of AHP may be provoked during weight-losing diets (i.e. calorie restriction) as well as following bariatric surgery (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Indeed, several cases (\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) 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 (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA 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 (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) 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\u0026thinsp;\u0026ge;\u0026thinsp;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. (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) 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 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOther chronic medical conditions include peripheral neuropathy, hypertension, and chronic kidney disease (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). The proportion of hypertension was lower in our study (14.7%), when compared to patients in US (43%) (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), whereas the proportion of chronic kidney disease (7.0%) was similar to what has been observed in Finland (5.7%) (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Here, the frequency in US has been reported to 29% (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eLissing et al. (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) 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 (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) differs from the ULN in our study. The ULN and analytical methods can vary considerable among different laboratories (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), 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.\u003c/p\u003e \u003cp\u003eObviously, 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\u0026rsquo;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.\u003c/p\u003e \u003cp\u003eIn 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.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Taba\" border=\"1\"\u003e\n \u003ccolgroup cols=\"6\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003eALA synthase\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" style=\"width: 17.3542%;\"\u003e\n \u003cp\u003eALAS\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003eAminolevulinic acid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 17.3542%;\"\u003e\n \u003cp\u003eALA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003eCoproporphyrin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 17.3542%;\"\u003e\n \u003cp\u003eCOPRO\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003eCoproporphyrinogen III\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 18.8248%;\"\u003e\n \u003cp\u003eCOPROgen III\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003ecoproporphyrinogen oxidase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 17.3542%;\"\u003e\n \u003cp\u003eCPOX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003eDelta-aminolevulinic acid (ALA) dehydratase deficiency porphyria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 17.3542%;\"\u003e\n \u003cp\u003eADP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003eEstimated glomerular filtration rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 17.3542%;\"\u003e\n \u003cp\u003eeGFR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003eGonadotropin-releasing hormone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 17.3542%;\"\u003e\n \u003cp\u003eGnRH\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003ehepatocellular carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 17.3542%;\"\u003e\n \u003cp\u003eHCC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003eHereditary coproporphyria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 17.3542%;\"\u003e\n \u003cp\u003eHCP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003eHydroxymethylbilane\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 17.3542%;\"\u003e\n \u003cp\u003eHMB\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003ehydroxymethylbilane synthase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 17.3542%;\"\u003e\n \u003cp\u003eHMBS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003eporphobilinogen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 17.3542%;\"\u003e\n \u003cp\u003ePBG\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003ePorphobilinogen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 17.3542%;\"\u003e\n \u003cp\u003ePBG\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003eProtoporphyrin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 17.3542%;\"\u003e\n \u003cp\u003ePROTO\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003eProtoporphyrinogen IX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 18.8248%;\"\u003e\n \u003cp\u003ePROTOgen IX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003eprotoporphyrinogen oxidase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 17.3542%;\"\u003e\n \u003cp\u003ePPOX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003eUltrasonography\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 17.3542%;\"\u003e\n \u003cp\u003eULS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003eUpper normal limit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 17.3542%;\"\u003e\n \u003cp\u003eULN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003eUroporphyrin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 17.3542%;\"\u003e\n \u003cp\u003eURO\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 82.5058%;\"\u003e\n \u003cp\u003eVariegate porphyria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 17.3542%;\"\u003e\n \u003cp\u003eVP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003cbr\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthical approval: This was obtained from the hospital\u0026rsquo;s legal department prior to start.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent to participate: not applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent for publication: all authors agree to submit this manuscript to Orphanet J of Rare Diseases\u003c/p\u003e\n\u003cp\u003eAvailability of data and material. We have extracted data from patient journals and subsequently stored all at secure- and access-logged serves at the hospital. Because data contains journal information, they are not accessible for third party.\u003c/p\u003e\n\u003cp\u003eCompeting interests. None.\u003c/p\u003e\n\u003cp\u003eFunding. None.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions. Dr. Wagner and Professor Frystyk developed the idea to study out cohort of patients with acute hepatic porphyria. Dr. Wagner collected data from the patient journals and wrote the draft manuscript. Professor Frost and Professor Frystyk have critically reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgements. Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDISCLOSURE STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWang B. The acute hepatic porphyrias. Transl Gastroenterol Hepatol. 2021;6:24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePhillips JD. Heme biosynthesis and the porphyrias. Mol Genet Metab. 2019;128(3):164\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eElder G, Harper P, Badminton M, Sandberg S, Deybach JC. The incidence of inherited porphyrias in Europe. J Inherit Metab Dis. 2013;36(5):849\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWhatley SD, Badminton MN. 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Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium. Am J Med. 2014;127(12):1233\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThunell S, Floderus Y, Henrichson A, Harper P. Porphyria in Sweden. Physiol Res. 2006;55(Suppl 2):S109\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInnala E, B\u0026auml;ckstr\u0026ouml;m T, Bixo M, Andersson C. Evaluation of gonadotropin-releasing hormone agonist treatment for prevention of menstrual-related attacks in acute porphyria. Acta Obstet Gynecol Scand. 2010;89(1):95\u0026ndash;100.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAndersson C, Innala E, B\u0026auml;ckstr\u0026ouml;m T. Acute intermittent porphyria in women: clinical expression, use and experience of exogenous sex hormones. A population-based study in northern Sweden. J Intern Med. 2003;254(2):176\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHift RJ, Meissner PN. An analysis of 112 acute porphyric attacks in Cape Town, South Africa: Evidence that acute intermittent porphyria and variegate porphyria differ in susceptibility and severity. Med (Baltim). 2005;84(1):48\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLin CS, Lee MJ, Park SB, Kiernan MC. Purple pigments: the pathophysiology of acute porphyric neuropathy. Clin Neurophysiol. 2011;122(12):2336\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarvalho AA, Ar\u0026ccedil;ari DD. Acute intermittent porphyria after gastroplasty. Arq Neuropsiquiatr. 2011;69(6):992.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDanion F, Guillot M, Castelain V, Puy H, Deybach JC, Schneider F. An uncommon option for surviving bariatric surgery: regaining weight! Am J Med. 2012;125(11):e1\u0026ndash;2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBonkovsky HL, Siao P, Roig Z, Hedley-Whyte ET, Flotte TJ. Case 20-2008. N Engl J Med. 2008;358(26):2813\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAndersson C, Wikberg A, Stegmayr B, Lithner F. Renal symptomatology in patients with acute intermittent porphyria. A population-based study. J Intern Med. 2000;248(4):319\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLelli SM, San Mart\u0026iacute;n de Viale LC, Mazzetti MB. Response of glucose metabolism enzymes in an acute porphyria model. Role of reactive oxygen species. Toxicology. 2005;216(1):49\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBissell DM, Anderson KE, Bonkovsky HL, Porphyria. N Engl J Med. 2017;377(9):862\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"AIP, VP and HCP, PBG","lastPublishedDoi":"10.21203/rs.3.rs-4848550/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4848550/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAcute hepatic porphyria (AHP) constitutes a class of rare diseases caused by reduced function in enzymes of the heme-biosynthetic pathway. AHP includes acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP) and the extremely rare δ-aminolevulinic-dehydrase deficiency porphyria (ADP). This retrospective study describes characteristics of the Danish AHP patient population.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eDepartment of Endocrinology at Odense University Hospital serves as national AHP center. We performed a 5-year retrospective description of our AHP cohort using electronic patient journals. We included general symptoms, number of acute attacks, hospitalization rates, long-term sequelae and symptoms, and grouped patients according to creatinine-adjusted urinary baseline excretion (i.e., outside attacks) of the porphyrin precursor porphobilinogen (PBG) in normal-, moderate- and high-excretion and unknown.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe cohort contained 129 AHP patients, hereof 100 AIP, 12 HCP and 17 VP. Median age was 47.8 (32.0\u0026ndash;62.0) years, and 85 (65.9%) were female. During the 5-years, 37 (28.7%) patients experienced symptoms. Hereof, 20 patients were hospitalized with acute attacks or chronic symptoms and treated with human hemin (n\u0026thinsp;=\u0026thinsp;14). Most frequently reported symptoms were abdominal pain, nausea, vomiting, and neurological disturbances. Symptoms were more common in patients with high PBG baseline excretion (n\u0026thinsp;=\u0026thinsp;39) as compared to those with moderate (n\u0026thinsp;=\u0026thinsp;31) or normal (n\u0026thinsp;=\u0026thinsp;40) PBG excretion (p\u0026thinsp;=\u0026thinsp;0.002). Furthermore, females dominated the symptomatic group (70.3%).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eAs reported internationally, AHP is more commonly diagnosed and symptomatic in women, and AIP was the most frequent AHP subtype. Those with an elevated urinary baseline PBG secretion were more likely to report AHP-related symptoms.\u003c/p\u003e","manuscriptTitle":"Acute Hepatic Porphyria in Denmark; a retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-11 06:39:32","doi":"10.21203/rs.3.rs-4848550/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2024-10-27T06:17:50+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-08-15T11:33:35+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-14T06:53:07+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-07T14:53:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2024-08-05T03:49:56+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"60bfe2c6-3c94-4e9d-b9cf-d1c9dbdcf18a","owner":[],"postedDate":"October 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-03-03T16:04:35+00:00","versionOfRecord":{"articleIdentity":"rs-4848550","link":"https://doi.org/10.1186/s13023-025-03536-3","journal":{"identity":"orphanet-journal-of-rare-diseases","isVorOnly":false,"title":"Orphanet Journal of Rare Diseases"},"publishedOn":"2025-02-28 15:57:24","publishedOnDateReadable":"February 28th, 2025"},"versionCreatedAt":"2024-10-11 06:39:32","video":"","vorDoi":"10.1186/s13023-025-03536-3","vorDoiUrl":"https://doi.org/10.1186/s13023-025-03536-3","workflowStages":[]},"version":"v1","identity":"rs-4848550","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4848550","identity":"rs-4848550","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}