Abstract
Introduction
Acute hepatic porphyrias are rare, life-threatening genetic disorders that impair heme biosynthesis, often presenting with nonspecific symptoms that lead to misdiagnosis. This diagnostic challenge and low clinical recognition can delay targeted treatment, increasing morbidity and mortality. Although there have been advances in understanding porphyrias' biochemical pathways, improved diagnostic approaches are still needed, especially in acute care. This study examined diagnostic and clinical patterns of acute hepatic porphyria at a quaternary care hospital in Bogotá, Colombia, to support earlier detection and management.
Materials and Methods
This descriptive, observational, retrospective study reviewed patients diagnosed with acute hepatic porphyria at the Internal Medicine service of a Bogotá hospital from 2013 to 2023. Patients with confirmed diagnoses recorded in the hospital database were included. Data collected covered demographic characteristics, clinical presentation, diagnostic markers, and treatment. Key outcome measures were time to diagnosis, recurrence frequency, and hospitalization duration.
Results
Ten patients were included, 80% of whom were female, with a median age of 32 years. Diagnosis was confirmed by urine porphobilinogen tests. All patients reported abdominal pain during attacks; 90% had tachycardia and paresis/weakness of extremities. Attack durations ranged from 4 to 11 days, with 90% treated with hemin. Median hospital stay was 18 days. Drug use and infections were common precipitants, and 40% of female patients had premenstrual-associated attacks.
Conclusions
This study provides a clinical profile of acute hepatic porphyria in a Colombian hospital, highlighting neurovisceral symptoms and female predominance. Findings suggest the need for early diagnostic protocols to prevent treatment delays, although larger studies are required to confirm these findings across different settings.
Keywords
Introduction
Acute hepatic porphyrias (AHPs) are rare yet life-threatening genetic disorders of autosomal dominant inheritance that disrupt heme biosynthesis, leading to severe clinical manifestations.1,2 Heme is a crucial component of hemoglobin, myoglobin, and various heme enzymes such as cytochromes, cyclooxygenases, and peroxidases.3,4
The primary biosynthesis of heme consists of eight steps and occurs mainly in the liver and bone marrow, involving eight enzymatic steps in mitochondrially active cells, particularly in erythropoietic and hepatic tissues.3,4 Each type of porphyria affects a specific enzyme in these pathways, either through hereditary mutations or acquired factors, resulting in the accumulation of pathway precursors, which are subsequently excreted in urine or bile. 3
AHPs arise from hepatic overproduction of porphyrin precursors, namely delta-aminolevulinic acid (ALA) and porphobilinogen (PBG). 5 They encompass four primary conditions: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and ALA dehydratase deficiency (ALAD, also known as aminolevulinic acid dehydratase deficiency porphyria [ADP]). 5 Accurate differentiation among these types relies on genetic testing, whereas biochemical testing is essential to differentiate AHPs from other types of porphyria. 5 Non-hepatic forms of porphyria include congenital erythropoietic porphyria, erythropoietic protoporphyria, and X-linked protoporphyria, which are due to pathogenic variants of uroporphyrinogen-III synthase, ferrochelatase, and 5′-ALA synthase. 5 Porphyria cutanea tarda is a hepatic porphyria that is cutaneous and not acute. It is associated with pathogenic variants of uroporphyrinogen-III decarboxylase and may be acquired. 5
The prevalence of AHPs varies significantly, with conditions like ALA deficiency being extremely rare and AIP occurring in approximately 0.5 per 100,000 individuals. 6 Precise prevalence data for AHPs in Colombia are lacking, attributable to geographic variations, diagnostic errors, and incomplete penetrance. Notably, since 2010, Law 1392 has recognized AHPs as a matter of national interest, emphasizing the need for timely care for affected patients. 7
Although these disorders can occur in any demographic, it is noteworthy that symptomatic cases are more prevalent in women, with a ratio of two symptomatic women for every symptomatic man.1,2 Patients with AHP experience intermittent crises, characterized by acute attacks alternating with asymptomatic phases. 2 Initial symptoms are often nonspecific, with abdominal pain being the most common, followed by paresis/weakness of extremities, psychiatric disturbances, discoloration of urine, and potentially respiratory failure. 1 Additionally, it is important to note that some patients may experience chronic symptoms, not limited to acute presentations.
Early diagnosis of AHPs poses significant challenges due to their rarity, the nonspecific nature of symptoms, and limited access to diagnostic tests. Confirmation typically requires demonstrating elevated levels of PBG and ALA in urine, whereas total porphyrins in blood and urine may serve as complementary diagnostic tools. 2 The main treatment objective during acute episodes is to reduce the activity of delta-aminolevulinic acid synthase 1 (ALAS1) in the liver, the first and rate-limiting enzyme in the heme synthesis pathway, thereby decreasing the production of toxic metabolic intermediates, ALA and PBG. This is often achieved through intravenous heme administration, high glucose loads, and the removal of precipitating factors. 4 Its inhibition is crucial to manage AHP. 4
The lack of awareness surrounding AHPs leads to underdiagnosis, contributing to increased morbidity and mortality rates among affected individuals. Therefore, the objective of this study was to characterize the sociodemographic and clinical profiles of patients diagnosed with hepatic porphyria at a tertiary care hospital in Bogotá, Colombia, to enhance early detection and treatment outcomes for this underrecognized condition.
Materials and methods
This study employed a descriptive, observational, retrospective design to analyze a series of patients diagnosed with AHP at the Internal Medicine department of a tertiary care hospital in Bogotá, Colombia, over the past 10 years (2013–2023). The study was conducted in accordance with the Helsinki Declaration of 1975, as revised in 2013. Since our study involves retrospective data collection, we have confirmed with our institutional review board (IRB) that formal approval was not required (IRB exemption number FSFB80231324). The reporting of this study conforms to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines. 8
Study design
The research used a descriptive and observational framework to explore the clinical and sociodemographic characteristics of patients diagnosed with hepatic porphyria. This approach enables a comprehensive analysis of the patient population and their treatment outcomes.
Sample description
The sample consisted of 10 patients diagnosed with AHP. Patients were selected based on confirmed diagnoses recorded in the hospital's medical database. The selection process was retrospective and used systematic review of patient records from January 2013 to December 2023.
Method of selection: Consecutively. All patients presenting with confirmed AHP over the study period were included. Inclusion criteria: Confirmed diagnosis through clinical presentation and urine PBG tests. Molecular confirmation for a subset of patients, where available. Exclusion criteria included patients with incomplete diagnostic data or unclear medical histories.
This selection method aimed to ensure the sample's representativeness of the patient population seen at the hospital. However, due to the rarity of the condition, potential biases may arise from the limited sample size, as not all cases may have been captured within the 10-year period. All patient details were de-identified to ensure confidentiality and compliance with ethical standards.
Measures
Data collected included demographic information (age, sex), clinical presentation (symptoms experienced), diagnostic markers (test results), and treatment regimens. The primary outcome variables for this study were as follows:
Time to diagnosis. Measured from initial presentation to confirmed diagnosis. Frequency of symptom recurrence. Documented through patient records. Hospitalization duration. Length of hospital stay during acute episodes.
Instrumentation
The primary instrument for diagnosis was the urine PBG test, which is widely recognized for its reliability and validity in confirming cases of AHP. The Watson–Schwartz and Hoesch tests were performed and considered positive at PBG concentrations in urine >9 mg/L. The psychometric characteristics of this test are well-established, ensuring standardization in its application.
Data collection procedures
Data were collected retrospectively from electronic health records at the Internal Medicine department of the hospital. The data extraction process occurred from January 2013 to December 2023, involving systematic review and documentation of patient records. The study adhered to ethical guidelines, ensuring the confidentiality of patient information throughout the research process.
Statistical analysis
The statistical treatment of the data involved descriptive statistics to summarize the findings. Data were reported as frequencies, means, ratios, and SDs, providing a comprehensive overview of the patient population. Specific statistical tests were employed for categorical variables, including chi-square tests for categorical data and t-tests for continuous variables, where applicable. p values were reported to determine statistical significance, with a 95% confidence interval applied where relevant. The power of the study (β) was noted, especially in instances where results did not reach statistical significance, to assess the ability to detect meaningful differences in subgroups.
Results
This section presents a logical and orderly overview of the data collected from patients diagnosed with AHP at the hospital in Bogotá, Colombia, from 1 January 2013 to 31 December 2023.
Study population and demographic characteristics
A total of 10 patients diagnosed with hepatic porphyria were treated during the study period, with an 80% predominance of female patients. The median age at diagnosis was 28 years for women and 36 years for men. Notably, 70% of participants reported having family members with a history of porphyria.
The diagnostic methods revealed that the majority of patients were identified through urinary PBG testing. Genetic testing was performed on two patients, identifying one with HCP and another with VP. The remaining eight patients were diagnosed with AIP based on clinical presentation and elevated biochemical markers (e.g. urinary ALA and PBG levels). Importantly, there were no reported cases of ADP (Table 1).
Clinical and demographic characteristics of patients with AHP.
ADP: aminolevulinic acid dehydratase deficiency porphyria; AHP: acute hepatic porphyrias; ALA: aminolevulinic acid; BMI: body mass index; HCP: hereditary coproporphyria; IQR: interquartile range; PBG: porphobilinogen; VP: variegate porphyria.
Ninety percent of the patients consulted presented with severe crises. There were no significant differences in terms of the year of presentation or age, suggesting that the distribution of these factors was relatively uniform across the patient population. However, the sample included both male and female patients, which reflected the typical sex distribution for this condition. In terms of clinical presentation, all patients (100%) presented with abdominal pain, either as the sole symptom or in combination with other manifestations. Additional symptoms included the following:
Psychiatric symptoms. Reported in 80% of patients. Nausea and/or vomiting. Experienced by 70% of patients. Myalgias. Occurred in 60% of patients. Tachycardia. Observed in 90% of patients. Paresis and weakness of extremities. Observed in 90% of patients, which resolved after attack Gastrointestinal symptoms. Notably, diarrhea was the predominant symptom among this group, occurring in 50% of patients.
During acute crises, half of the patients exhibited changes in urine color, and only one patient experienced fever (Table 2).
Frequency of clinical manifestations.
Precipitating factors
Precipitants were identified in 60% of the acute crises. The most common triggers included the following:
Drugs. Reported as a precipitant in 70% of cases. Infections. Identified in 60% of crises. Premenstrual attacks. Noted in 40% of female patients. Psychological stress. Reported by 80% as a facilitator of crises.
Two female patients experienced pregnancies during the study period. Both had a history of recurrent attacks prior to pregnancy, but their disease activity worsened during pregnancy, necessitating multiple hospital visits and additional management due to recurrent crises (Figure 1). Both patients received treatment with intravenous hemin during pregnancy. Hemin was well tolerated, and both patients completed their pregnancies without significant complications. The neonates were delivered at term and were healthy, with no immediate complications noted postpartum.
Triggering factors of AHP attacks. AHP: acute hepatic porphyria.
Attack characteristics and treatment
Among the patients, the frequency of AHP attacks was categorized as follows:
Recurrent attacks (>4/year). Experienced by three patients. Two to three attacks/year. Reported by two patients. One attack/year. Noted in five patients.
The mean duration of attacks ranged from 4 to 11 days. This calculation includes both attacks managed at home and those requiring hospitalization, with non-hospitalized attacks typically being shorter. In contrast, the median duration of hospital stays was 18 days (range, 7–30 days), reflecting the subset of severe attacks that necessitated inpatient care and often involved complications or prolonged recovery.
Although no patients were diagnosed with AHP before the age of 20 years, retrospective analysis of patient histories revealed that some experienced episodic symptoms during adolescence consistent with AHP, such as recurrent abdominal pain and neuropathic complaints. These symptoms, which may have been influenced by hormonal fluctuations during puberty (a known trigger for AHP), were only recognized as part of the disease retrospectively upon later diagnosis. The average age of symptom onset was 15 years (range, 13–17 years), with varying severity and frequency among patients. It is important to note that not all patients experienced worsening symptoms during puberty compared with later years.
Treatment strategies
Heme therapy. Administered to 90% of patients, either alone or in combination with other supportive therapies. Carbohydrate loading (oral or intravenous). Used in 40% of attacks. Symptomatic treatments. Including analgesics, antispasmodics, anticonvulsants, and antiemetics, were employed in 10% of cases. Givosiran is approved in several countries for the treatment of AHP. Its availability in Colombia may vary depending on healthcare policies and local regulations. None of the patients in this study received it.
The mean hospital stay was calculated as 18 ± 6 days, and the duration of attacks showed a 95% confidence interval ranging from 4 to 11 days. No statistically significant differences were identified between patients with premenstrual and non-premenstrual attacks. The power of the study (β) was noted at 0.80, suggesting limitations in detecting smaller subgroup differences.
Discussion
This observational, descriptive, retrospective study was designed to evaluate the clinical and sociodemographic characteristics of patients treated for AHP in the Internal Medicine department of a quaternary care hospital in Bogotá, Colombia. AHPs are rare genetic disorders that significantly impact patients' quality of life due to their intermittent acute attacks and associated complications. 1 The underdiagnosis and mismanagement of these conditions underscore the critical need for a better understanding of their clinical presentation, diagnostic patterns, and treatment strategies.1,2
AIP is the most common form of AHP, 1 accounting for 60% of the diagnoses in this study. Although its inheritance is autosomal dominant, clinical penetrance is low. It is important to note that the diagnosis of AIP in this study was based exclusively on clinical manifestations and elevated PBG levels, without further testing to differentiate it from HCP or VP. As a result, many patients may have been misdiagnosed, referring that without genetic testing, there is a possibility of subtype misclassification (e.g. some AIP cases could theoretically be VP or HCP), indicating limitations in the availability and interpretation of diagnostic tests in Colombia.
Our study reveals a predominance of female patients (80%) and a median age of diagnosis of 28 years for women and 36 years for men. All patients reported abdominal pain during acute crises, a finding consistent with global literature9–12 and the Colombian literature. 7 Clinical manifestations were highly variable, with 100% of patients experiencing abdominal pain, and half reporting additional symptoms such as altered urine color, psychiatric disorders, tachycardia, and paralysis/paresis.2,7,12 Interestingly, our findings regarding the frequency of tachycardia differ from other studies that report arterial hypertension as more commonly associated with AHP. 10 Although tachycardia is frequently observed in the literature, our study highlights a nuanced view where both tachycardia and hypertension coexist in a significant proportion of patients, suggesting a more complex cardiovascular involvement.
The sociodemographic characteristics and clinical manifestations identified in our study align with existing literature, indicating that AHPs predominantly affect women of childbearing age who often experience abdominal pain9,12; this is due to the fact that crises are related to menstrual cycles, highlighting the importance of natural steroids, particularly progesterone, in the development of these diseases. 13 Drugs, infections, menstruation, fasting, alcohol, or stress can trigger crises. 5 In this study, it was estimated that the main precipitating factor is the use of drugs in 60%, similar to what has been reported in Norwegian literature, where it can be the main precipitant in up to 85% of cases. 9 This same Norwegian cohort highlights that psychological stress could play a fundamental role as a crisis precipitant, as reported in this study where 80% of cases were noted. 9 This illustrates the presence of variable factors in the presentation of patients with AHP, suggesting the influence of regional determinants in their diversity.
On the other hand, it has been described that pregnancy increases the risk of attacks due to elevated levels of estrogen and progesterone. In this study, two women became pregnant and experienced a greater number of attacks during pregnancy. However, these attacks were primarily precipitated by a known porphyrinogenic compound and an infection, rather than solely by hormonal changes. Although pregnancy does elevate hormonal concentrations, the findings from this study indicate that attacks occurring during pregnancy are largely due to exposure to typical precipitants, rather than complications solely associated with hormonal fluctuations
It is believed that an acute porphyria episode results from increased hepatic activity of ALAS1, leading to the accumulation of neurotoxic heme precursors, ALA and PBG1,4; however, intravenous heme controls and improves symptom management after these attacks. 13 This medication was introduced to Colombia in 1980, and since then, an improvement in the quality of life of patients with AHP has been observed, evidenced by fewer hospital admissions, less frequent crises, and consequently lower mortality from attacks. 7 It is likely that advances in medical equipment, greater availability of intensive care units, and mechanical ventilatory support have also contributed. Nevertheless, the mortality from AHP in Colombia remains approximately three times higher than in other countries.9–12 The main determinants appear to be delays in diagnosis and inadequate treatment.
Although this study provides valuable insights into the characteristics of hepatic porphyria in the Colombian context, the small sample size limits the generalizability of our findings to broader populations. The specific demographic and clinical patterns observed may not reflect those in other regions or healthcare settings. The primary limitation of this study is its small sample size of 10 patients, which may not adequately represent the full spectrum of hepatic porphyria cases. Additionally, the retrospective nature of the study relies on the accuracy of medical records, which can vary and potentially introduce bias. The absence of standardized diagnostic criteria across different healthcare facilities may also contribute to inconsistencies in identifying and managing AHP cases.
We accept the research hypothesis that the characterization of patients with AHP will reveal significant clinical and demographic patterns that can inform better diagnostic and treatment protocols.
Our study raises several new questions for future research: How do genetic variations among different populations affect the presentation and management of AHPs? What are the long-term outcomes for patients diagnosed with AHP, and how can healthcare systems enhance early detection and treatment to improve symptom management? Additionally, how do lifestyle factors and comorbid conditions impact the frequency and severity of acute attacks?
We recommend enhanced education and training for healthcare professionals on recognizing the symptoms of AHP to facilitate earlier diagnosis and treatment. Institutions should create standardized diagnostic and treatment protocols to improve care consistency and reduce the risk of complications. Moreover, larger, multicenter studies are needed to investigate the epidemiology, clinical features, and long-term outcomes of patients with hepatic porphyria. Exploring the psychosocial impact of the disease on patients and families may also yield valuable insights.
Conclusions
The clinical and sociodemographic characterization of the population with porphyria provides valuable insight into identifying individuals at risk, potentially reducing diagnostic delays and preventing disease progression and adverse outcomes. This study highlights a predominance of female patients and variability in symptoms, with neurovisceral manifestations as the most common. Although AIP remains, the principal type identified clinically, these findings emphasize the importance of rigorous diagnostic protocols to accurately distinguish between specific forms of porphyria. Given that genetic testing was not conducted in all cases, AIP was primarily diagnosed based on clinical presentation, including characteristic symptoms and clinical history suggestive of acute porphyria. Increased awareness and education on this disease are essential in Colombia to improve patient care and outcomes. In conclusion, our study underscores the critical need for timely diagnosis, standardized management, and a concerted effort to raise awareness of AHPs to reduce their significant associated morbidity.
Abbreviations
aminolevulinic acid dehydratase deficiency porphyria acute hepatic porphyria acute intermittent porphyria aminolevulinic acid ALA dehydratase deficiency aminolevulinic acid synthase 1 hereditary coproporphyria institutional review board porphobilinogen variegate porphyria
Footnotes
Acknowledgements
The authors would like to acknowledge the support of the Fundación Santa Fe de Bogotá.
Authors’ contributions
MCM-Á and SPC collected the database. ALAC contributed information from literature search. MCM-Á, SPC, and ALAC wrote the manuscript. EM-A checked and proofread the manuscript. All authors equally contributed to the elaboration of this article.
Consent for publication
No written consent has been obtained from the patients as there are no patient-identifiable data included in this review.
Data availability statement
The data analyzed in this study are available from the corresponding author upon reasonable request.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical approval
Ethical approval was not required for this retrospective study as it involved the use of anonymized patient data, and no direct clinical interventions or changes to patient care were made. The study adhered to ethical guidelines for data confidentiality and patient privacy.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
