Update on the Porphyrias.

The porphyrias are a group of rare diseases, each resulting from a defect in a different enzymatic step of the heme biosynthetic pathway. They can be broadly divided into two categories, hepatic and erythropoietic porphyrias, depending on the primary site of accumulation of heme intermediates. These disorders are multisystemic with variable symptoms that can be encountered by physicians in any specialty. Here, we review the porphyrias and describe their clinical presentation, diagnosis, and management. We discuss novel therapies that are approved or in development. Early diagnosis is key for the appropriate management and prevention of long-term complications in these rare disorders.

High disease burden and healthcare resource usage in patients with acute porphyria-A population-based analysis.

BACKGROUND AND AIMS: Acute porphyria is a chronic recurrent disease with late diagnosis, heterogeneous clinical presentations and potentially devastating complications. The study aimed at providing real-world evidence on the natural course of acute porphyria, patient characteristics, disease burden, and healthcare utilization before diagnosis. METHODS: This observational study used anonymized claims data covering 8 365 867 persons from German statutory health insurance, spanning 6 years (2015-2020). Patients with at least one diagnosis of acute porphyria during the index period (2019-2020) were classified into three groups by attack frequency. These findings were compared with two age- and sex-adjusted reference groups: the general population and fibromyalgia patients. Prevalence over the index period was calculated for all porphyria patients and those with active acute porphyria. RESULTS: We revealed a prevalence of 79.8 per 1 000 000 for acute porphyria, with 12.9 per 1 000 000 being active cases. Acute porphyria patients, particularly with frequent attacks, demonstrated a higher comorbidity burden compared to the general population. Within the year before the recorded diagnosis, patients with acute porphyria required a median of 23.0 physician visits, significantly higher than the general population's 16.0. Additionally, 33.8% were hospitalized at least once during this period, a notably higher proportion than the general population (19.3%). CONCLUSIONS: This study's findings, collected before the introduction of givosiran, as the first approved preventive therapy for acute porphyria in Europe, highlight the need for healthcare strategies and policies tailored to the complex needs of acute porphyria patients. The significant healthcare demands, heightened comorbidity burden, and increased healthcare system utilization emphasize the urgency of developing a comprehensive support infrastructure for these patients. Also, these acute porphyria real-world findings provide additional insights on disease characteristics in Germany.

Maternal and fetal outcomes in acute hepatic porphyria: A Swedish National Cohort Study.

Current knowledge of pregnancy and perinatal outcomes in women with acute hepatic porphyria (AHP) is largely based on biochemical disease models, case reports, and case series. We performed a nationwide, registered-based cohort study to investigate the association between maternal AHP and the risk of adverse pregnancy and perinatal outcomes. All women in the Swedish Porphyria Register with confirmed AHP aged 18 years or older between 1987 and 2015 and matched general population comparators, with at least one registered delivery in the Swedish Medical Birth Register were included. Risk ratios (RRs) of pregnancy complications, delivery mode and perinatal outcomes were estimated and adjusted for maternal age at delivery, area of residency, birth year and parity. Women with acute intermittent porphyria (AIP), the most common form of AHP, were further categorized according to maximal lifetime urinary porphobilinogen (U-PBG) levels. The study included 214 women with AHP and 2174 matched comparators. Women with AHP presented with a higher risk for pregnancy-induced hypertensive disorder (aRR 1.73, 95% CI 1.12-2.68), gestational diabetes (aRR 3.41, 95% CI 1.69-6.89), and small-for-gestational-age birth (aRR 2.08, 95% CI 1.26-3.45). In general, RRs were higher among women with AIP who had high lifetime U-PBG levels. Our study shows an increased risk for pregnancy induced hypertensive disease, gestational diabetes, and small for gestational age births for AHP women, with higher relative risks for women with biochemically active AIP. No increased risk for perinatal death or malformations was observed.

Acute hepatic porphyria and maternal health: Clinical and biochemical follow-up of 44 pregnancies.

BACKGROUND: Pregnancy in women with acute hepatic porphyria (AHP) has historically been associated with significant morbidity. Clinical outcomes have been the focus of previous reports on porphyria and maternal health, with little data available on the levels of heme precursors during pregnancy. We present the results of a follow-up program for women with AHP in the Swedish cohort who were pregnant between 2001 and 2020. METHODS: Thirty-three women with AHP were monitored during 44 pregnancies resulting in 44 single births. Seven of 33 women had a clinical history of acute attacks that required hospitalization. RESULTS: Four women experienced acute porphyria attacks during pregnancy and one during the puerperium. Seven women developed hypertension and four pregnancies ended with pre-eclampsia. There were no maternal or fetal pre- or postnatal deaths. One infant had a congenital cardiac anomaly. In 32 of the 38 pregnancies in which we measured heme precursors in the urine during pregnancy, the levels increased. CONCLUSION: Our observations align with contemporary reports that pregnancy in patients with AHP is frequently uncomplicated. Excretion of heme precursors increased during pregnancy, but this did not manifest as a higher frequency of clinical porphyria manifestations. The involvement of porphyria specialists in the patients' maternal care is recommended for reducing risk and improving the probability of good pregnancy outcomes.

Efficacy and safety of givosiran for acute hepatic porphyria: 24-month interim analysis of the randomized phase 3 ENVISION study.

BACKGROUND & AIMS: Upregulation of hepatic delta-aminolevulinic acid synthase 1 with accumulation of potentially toxic heme precursors delta-aminolevulinic acid and porphobilinogen is fundamental to the pathogenesis of acute hepatic porphyria. AIMS: evaluate long-term efficacy and safety of givosiran in acute hepatic porphyria. METHODS: Interim analysis of ongoing ENVISION study (NCT03338816), after all active patients completed their Month 24 visit. Patients with acute hepatic porphyria (≥12 years) with recurrent attacks received givosiran (2.5 mg/kg monthly) (n = 48) or placebo (n = 46) for 6 months (double-blind period); 93 received givosiran (2.5 mg or 1.25 mg/kg monthly) in the open-label extension (continuous givosiran, n = 47/48; placebo crossover, n = 46/46). Endpoints included annualized attack rate, urinary delta-aminolevulinic acid and porphobilinogen levels, hemin use, daily worst pain, quality of life, and adverse events. RESULTS: Patients receiving continuous givosiran had sustained annualized attack rate reduction (median 1.0 in double-blind period, 0.0 in open-label extension); in placebo crossover patients, median annualized attack rate decreased from 10.7 to 1.4. Median annualized days of hemin use were 0.0 (double-blind period) and 0.0 (open-label extension) for continuous givosiran patients and reduced from 14.98 to 0.71 for placebo crossover patients. Long-term givosiran led to sustained lowering of delta-aminolevulinic acid and porphobilinogen and improvements in daily worst pain and quality of life. Safety findings were consistent with the double-blind period. CONCLUSIONS: Long-term givosiran has an acceptable safety profile and significantly benefits acute hepatic porphyria patients with recurrent attacks by reducing attack frequency, hemin use, and severity of daily worst pain while improving quality of life.

Prevalence and Characteristics of Abdominal Pain in the United States.

BACKGROUND & AIMS: Abdominal pain is the most common gastrointestinal symptom reported in ambulatory clinics, but little is known about its prevalence and burden of illness in the general community. We conducted a population-based survey to determine the epidemiology, clinical characteristics, and healthcare-seeking behavior of persons with abdominal pain. METHODS: Using an online survey research firm, we recruited a representative sample of adults (18 years or older) with a history of abdominal pain. The survey included questions about abdominal pain severity as measured by GI PROMIS (a validated patient-reported outcome questionnaire), healthcare-seeking behaviors, and tests performed to evaluate symptoms. We used multivariable regression models to adjust for confounding. RESULTS: Overall, 24,929 individuals accessed the survey and 10,300 respondents reported experiencing abdominal pain and completed the questionnaire. Most participants (81.0%) were symptomatic in the past week, as measured by GI PROMIS. Of participants with prior pain, 61.5% sought medical care for their symptoms; non-Hispanic Blacks, Latinos, and participants with more education, insurance, a usual source of care, comorbidities, and more severe pain had increased odds for seeking care. Participants who sought care consulted with the following providers: primary care physicians (84.5%), gastroenterologists (39.2%), nurse practitioners or physician assistants (18.6%), obstetricians or gynecologists (8.3%), general surgeons (7.1%), or rheumatologists (3.2%). Moreover, 72.4% of healthcare seekers received tests to evaluate their pain: cross-sectional imaging (54.2%), colonoscopy (52.3%), upper endoscopy (40.8%), exploratory surgery (6.3%), or capsule endoscopy (5.0%). CONCLUSIONS: The burden of illness and healthcare use associated with abdominal pain is high in the United States. However, 2 of 5 individuals did not seek care for their symptoms and many of them might have undiagnosed, treatable disorders.

Porphyric neuropathy.

Acute hepatic porphyrias are inherited metabolic disorders that may present with polyneuropathy, which if not diagnosed early can lead to quadriparesis, respiratory weakness, and death. Porphyric neuropathy is an acute to subacute motor predominant axonal neuropathy with a predilection for the upper extremities and usually preceded by a predominantly parasympathetic autonomic neuropathy. The rapid progression and associated dysautonomia mimic Guillain-Barré syndrome but are distinguished by the absence of cerebrospinal fluid albuminocytologic dissociation, progression beyond 4 wk, and associated abdominal pain. Spot urine test to assess the porphyrin precursors delta-aminolevulinic acid and porphobilinogen can provide a timely diagnosis during an acute attack. Timely treatment with intravenous heme, carbohydrate loading, and avoidance of porphyrinogenic medications can prevent further neurological morbidity and mortality.

Treatment with assisted reproduction technologies in women with acute hepatic porphyria.

INTRODUCTION: Acute porphyrias are rare disorders of the heme biosynthetic pathway and present with acute neurovisceral symptoms that can be induced by hormonal changes and medications. Women are far more likely to present with clinical symptoms than men, particularly during parts of their lifetime with changes in the level of female sex hormones such as ovulation, menstruation, and pregnancy. Treatment of ovulatory dysfunction and controlled ovarian hyperstimulation require the administration of hormones, which are considered porphyrinogenic. Women with acute hepatic porphyria have therefore been considered unsuitable for such treatments in the past. MATERIAL AND METHODS: We report on nine women with acute hepatic porphyria who underwent in vitro fertilization (IVF), preceded by ovarian stimulation. Their mean age at the start of IVF was 33.2 years (range 27-38 years). Two women had been diagnosed with polycystic ovarian syndrome, two were treated for hyperprolactinemia, two had hypothyroidism, of which one also had type 1 diabetes, one had a uterus malformation, one had anovulatory cycles, and one used a sperm donor. RESULTS: All patients were able to undergo fertility treatment without experiencing severe porphyria attacks. CONCLUSIONS: Women with acute hepatic porphyria considering fertility treatments should be assessed individually for potential risks, treatment should be planned in close collaboration with a porphyria specialist, and biochemical activity should be monitored regularly during ovarian stimulation. As we gather more knowledge, we hope that the porphyrinogenicity of the stimulation agents is re-assessed and that more studies will shed light on the reproductive health of women living with acute hepatic porphyria.

Acute hepatic porphyrias: Identification of 46 hydroxymethylbilane synthase, 11 coproporphyrinogen oxidase, and 20 protoporphyrinogen oxidase novel mutations.

The acute hepatic porphyrias (AHPs) are inborn errors of heme biosynthesis, which include three autosomal dominant porphyrias, Acute Intermittent Porphyria (AIP), Hereditary Coproporphyria (HCP), and Variegate Porphyria (VP), and the ultra-rare autosomal recessive porphyria, δ-Aminolevulinic Acid Dehydratase Deficiency Porphyria (ADP). AIP, HCP, VP, and ADP each results from loss-of-function (LOF) mutations in their disease-causing genes: hydroxymethylbilane synthase (HMBS); coproporphyrinogen oxidase (CPOX); protoporphyrinogen oxidase (PPOX), and δ-aminolevulinic acid dehydratase (ALAD), respectively. During the 11-year period from January 1, 2007 through December 31, 2017, the Mount Sinai Porphyrias Diagnostic Laboratory diagnosed 315 unrelated AIP individuals with HMBS mutations, including 46 previously unreported mutations, 29 unrelated HCP individuals with CPOX mutations, including 11 previously unreported mutations, and 54 unrelated VP individuals with PPOX mutations, including 20 previously unreported mutations. Overall, of the 1692 unrelated individuals referred for AHP molecular diagnostic testing, 398 (23.5%) had an AHP mutation. Of the 650 family members of mutation-positive individuals tested for an autosomal dominant AHP, 304 (46.8%) had their respective family mutation. These data expand the molecular genetic heterogeneity of the AHPs and document the usefulness of molecular testing to confirm the positive biochemical findings in symptomatic patients and identify at-risk asymptomatic family members.

Molecular genetic study of acute intermittent porphyria in Russia: HMBS gene mutation spectrum and problem of penetrance.

Acute intermittent porphyria (AIP) is the most common and severe form of porphyrias. This is a dominant inherited disorder with low penetrance, caused by mutations in gene coding hydroxymethylbilane synthase (HMBS). We present the results of our long-term genetic study of AIP patients and their relatives (N = 153 and 302, respectively). We detected 88 HMBS gene mutations, 24 of which never described before. To identify additional factors conditioning AIP manifestation, we carried out whole exome sequencing on the group of AIP patients (N = 6). Mutation spectra of different patients virtually did not overlap. In 5 out of 6 patients, we found defects in genes regulating nervous system (UNC13A, ALG8, FBXO38, AGRN, DOK7, SCN4A). As usually acute AIP attacks have various neurological symptoms, we proposed a hypothesis of possible contribution of mutations in such genes in AIP manifestation.

Acute hepatic porphyria and cancer risk: a nationwide cohort study.

BACKGROUND: Acute hepatic porphyria (AHP) is considered to be a risk factor for primary liver cancer (PLC), but varying risk estimates have been published. OBJECTIVES: Our aim was to investigate the risk of PLC and other cancers in persons with AHP using a nationwide cohort design. Given that greater numbers of women than men tend to have manifest and more severe AHP, a further aim was to investigate sex differences in this risk. METHODS: The study sample consisted of all Norwegian residents aged 18 years or older during the period 2000-2011. Persons with AHP (n = 251) were identified through the Norwegian Porphyria Centre, and patients with a cancer diagnosis were identified by linkage to the Cancer Registry of Norway. RESULTS: For persons with AHP, the annual incidence rate of PLC was 0.35%. PLC risk was substantially higher for individuals with an AHP diagnosis compared to the reference population [adjusted hazard ratio (aHR) 108, 95% confidence interval (CI) 56-207]. In a meta-analysis of published studies on PLC and AHP, including ours, women had a higher risk than men. In addition, our results suggested that persons with AHP may have increased risks of kidney (aHR 7.4, 95% CI 2.4-23.1) and endometrial cancers (aHR 6.2, 95% CI 2.0-19.3). CONCLUSIONS: Our findings confirmed a substantially higher risk of PLC associated with AHP compared to the general population. In a meta-analysis, the risk was shown to be greater for women than men. The novel findings of a moderate to substantial association between AHP and kidney and endometrial cancers should be investigated further.

Experiences and concerns of patients with recurrent attacks of acute hepatic porphyria: A qualitative study.

BACKGROUND: The acute hepatic porphyrias (AHPs) are rare inborn errors of heme biosynthesis, characterized clinically by life-threatening acute neurovisceral attacks. Patients with recurrent attacks have a decreased quality of life (QoL); however, no interactive assessment of these patients' views has been reported. We conducted guided discussions regarding specific topics, to explore patients' disease experience and its impact on their lives. METHODS: Sixteen AHP patients experiencing acute attacks were recruited to moderator-led online focus groups. Five groups (3-4 patients each) were conducted and thematic analyses to identify, examine, and categorize patterns in the data was performed. RESULTS: All patients identified prodromal symptoms that began days prior to acute severe pain; the most common included confusion ("brain fog"), irritability, and fatigue. Patients avoided hospitalization due to prior poor experiences with physician knowledge of AHPs or their treatment. All patients used complementary and alternative medicine treatments to avoid hospitalization or manage chronic pain and 81% reported varying degrees of effectiveness. All patients indicated their disease impacted personal relationships due to feelings of isolation and difficulty adjusting to the disease's limitations. CONCLUSION: Patients with recurrent attacks recognize prodromal warning symptoms, attempt to avoid hospitalization, turn to alternative treatments, and have markedly impaired QoL. Counseling and individualized support is crucial for AHP patients with recurrent attacks.

Effectiveness and tolerability of givosiran for the management of acute hepatic porphyria: A monocenter real-life evaluation.

Acute hepatic porphyrias (AHPs) are a family of rare, autosomal, dominantly inherited conditions characterized by abnormalities in the production of heme. Advances in molecular engineering have provided new therapeutic possibilities for modifying the heme synthetic pathway in patients with porphyria. In particular, the RNA interference therapeutic givosiran was approved for the treatment of adults and adolescents with AHP aged >12 years based on the positive results of the phase III trial ENVISION. Despite the extended characterization of the activity of givosiran in clinical trials, reports on the long-term effects and effectiveness of the treatment in clinical practice are still scant. To fill this gap, this case series describes a monocentric Italian cohort of AHP patients treated with givosiran. Overall, our real-life experience supports the clinical evidence that long-term treatment with givosiran is well tolerated and able to provide sustained and continuous benefit to patients with acute intermittent porphyria, as reflected by the reduction in the frequency of attacks. In our series, givosiran treatment was also associated with improvement in assessments of quality of life, pain and fatigue.

Reducing diagnostic delays in acute hepatic porphyria using health records data and machine learning.

BACKGROUND: Acute hepatic porphyria (AHP) is a group of rare but treatable conditions associated with diagnostic delays of 15 years on average. The advent of electronic health records (EHR) data and machine learning (ML) may improve the timely recognition of rare diseases like AHP. However, prediction models can be difficult to train given the limited case numbers, unstructured EHR data, and selection biases intrinsic to healthcare delivery. We sought to train and characterize models for identifying patients with AHP. METHODS: This diagnostic study used structured and notes-based EHR data from 2 centers at the University of California, UCSF (2012-2022) and UCLA (2019-2022). The data were split into 2 cohorts (referral and diagnosis) and used to develop models that predict (1) who will be referred for testing of acute porphyria, among those who presented with abdominal pain (a cardinal symptom of AHP), and (2) who will test positive, among those referred. The referral cohort consisted of 747 patients referred for testing and 99 849 contemporaneous patients who were not. The diagnosis cohort consisted of 72 confirmed AHP cases and 347 patients who tested negative. The case cohort was 81% female and 6-75 years old at the time of diagnosis. Candidate models used a range of architectures. Feature selection was semi-automated and incorporated publicly available data from knowledge graphs. Our primary outcome was the F-score on an outcome-stratified test set. RESULTS: The best center-specific referral models achieved an F-score of 86%-91%. The best diagnosis model achieved an F-score of 92%. To further test our model, we contacted 372 current patients who lack an AHP diagnosis but were predicted by our models as potentially having it (≥10% probability of referral, ≥50% of testing positive). However, we were only able to recruit 10 of these patients for biochemical testing, all of whom were negative. Nonetheless, post hoc evaluations suggested that these models could identify 71% of cases earlier than their diagnosis date, saving 1.2 years. CONCLUSIONS: ML can reduce diagnostic delays in AHP and other rare diseases. Robust recruitment strategies and multicenter coordination will be needed to validate these models before they can be deployed.

Neurofilament light chain as a biomarker for acute hepatic porphyrias.

Background: Acute hepatic porphyrias (AHP) represent a rare group of inherited metabolic disorders of heme biosynthesis pathway. This study aims to determine the diagnostic and prognostic value of serum neurofilament light chain (NfL) as potential biomarker for AHP. Methods: We conducted a cross-sectional observational study to evaluate NfL levels in patients with AHP. They were divided in different groups: normal health individuals; patients with definitive diagnosis of AHP during acute episodes; patients with AHP and infrequent attacks; patients with AHP and recurrent attacks; asymptomatic individuals with positive genetic testing and urinary delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels elevated 4 or more times ("high excretors"); asymptomatic individuals with exclusive positive genetic test; control group with Hereditary Amyloidosis related to Transthyretin with Polyneuropathy (ATTRv-PN). Results: During acute attacks, serum NfL levels were 68 times higher compared to normal controls and disclosed a strong correlation with ALA and PBG levels; also exhibited elevated levels in patients with chronic symptoms regardless of the number of disease attacks compared to healthy controls, and at similar levels to patients with ATTRv-PN, which is a model of progressive neuropathy. Conclusion: This study represents the first to establish NfL as a biomarker for AHP, disclosing NfL as a sensitive biomarker for axonal damage and chronic symptom occurrence. This study not only underscores that neurological damage associated with the disease in any patient, irrespective of the number of attacks, but also reinforces the progressive and profoundly debilitating nature of acute and chronic symptoms observed in individuals with AHP.

Preventing hyperhomocysteinemia using vitamin B6 supplementation in Givosiran-treated acute intermittent porphyria: Highlights from a case report and brief literature review.

Acute hepatic porphyrias are inherited metabolic disorders of heme biosynthesis characterized by the accumulation of toxic intermediate metabolites responsible for disabling acute neurovisceral attacks. Givosiran is a newly approved siRNA-based treatment of acute hepatic porphyria targeting the first and rate-limiting δ-aminolevulinic acid synthase 1 (ALAS1) enzyme of heme biosynthetic pathway. We described a 72-year old patient who presented with severe inaugural neurological form of acute intermittent porphyria evolving for several years which made her eligible for givosiran administration. On initiation of treatment, the patient developed a major hyperhomocysteinemia (>400 µmol/L) which necessitated to discontinue the siRNA-based therapy. A thorough metabolic analysis in the patient suggests that hyperhomocysteinemia could be attributed to a functional deficiency of cystathionine ß-synthase (CBS) enzyme induced by givosiran. Long-term treatment with vitamin B6, a cofactor of CBS, allowed to normalize homocysteinemia while givosiran treatment was maintained. We review the recently published cases of hyperhomocysteinemia in acute hepatic porphyria and its exacerbation under givosiran therapy. We also discuss the benefits of vitamin B6 supplementation in the light of hypothetic pathophysiological mechanisms responsible for hyperhomocysteinemia in these patients. Our results confirmed the importance of monitoring homocysteine metabolism and vitamin status in patients with acute intermittent porphyria in order to improve management by appropriate vitamin supplementation during givosiran treatment.

Elevated homocysteine is negatively correlated with plasma cystathionine ß-synthase activity in givosiran-treated patients.

Givosiran is a subcutaneously administered, liver-targeted RNA interference (RNAi) therapeutic that has been approved for treating acute hepatic porphyria (AHP). Elevation in plasma homocysteine (hyperhomocysteinemia) has been reported in AHP patients, and treatment with givosiran has been reported to further increase homocysteine levels in some patients. The mechanism of homocysteine elevation during givosiran treatment is unknown, but has been hypothesized to be mediated by a reduction in activity of cystathionine ß-synthase (CBS), which uses homocysteine as a substrate. A liquid chromatography-tandem mass spectrometry-based assay was adapted to measure circulating CBS activity. Using plasma collected from the Phase III ENVISION study, CBS activity was measured to directly evaluate whether it is associated with elevated homocysteine levels in givosiran-treated patients. CBS activity was reduced following givosiran treatment and both homocysteine and methionine levels were inversely correlated with CBS activity. Following administration of a supplement containing vitamin B6, a cofactor for CBS, in four patients during the trial, plasma CBS activity was found to increase, mirroring a corresponding decrease in homocysteine levels. These results support the hypothesis that elevated homocysteine levels following givosiran treatment result from a reduction of CBS activity and that vitamin B6 supplementation lowers homocysteine levels by increasing CBS activity.

PICO questions and DELPHI methodology for improving the management of patients with acute hepatic porphyria.

BACKGROUND: Acute hepatic porphyrias (AHPs) are a group of rare diseases that encompasses acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and 5-aminolaevulinic acid dehydratase deficiency porphyria. Symptoms of AHP are nonspecific which, together with its low prevalence, difficult the diagnosis and follow-up of these patients. MATERIAL AND METHODS: This project used DELPHI methodology to answer PICO questions related to management of patients with AHPs. The objective was to reach a consensus among multidisciplinary porhyria experts providing answers to those PICO questions for improving diagnosis and follow-up of patients with AHP. RESULTS: Ten PICO questions were defined and grouped in four domains: 1. Biochemical diagnosis of patients with AHP. 2. Molecular tests for patients with AHP. 3. Follow-up of patients with AHP. 4. Screening for long-term complications of patients with AHP. CONCLUSIONS: PICO questions and DELPHI methodology have provided a consensus on relevant and controversial issues for improving the management of patients with AHP.

The burden of disease and quality of life in patients with acute hepatic porphyria: COPHASE study.

BACKGROUND: Acute hepatic porphyria (AHP) comprises a group of rare genetic diseases characterized by neurovisceral crises that are manifested by abdominal pain and neurological and/or psychological symptoms that interfere with the ability to lead a normal life. Our objective was to determine the burden of the disease in one year and the health-related quality of life (HRQoL) in patients with AHP. RESULTS: 28 patients were analyzed. The mean age was 36.6±10.2 years, 89.3% were women, and the average number of crises was 1.9±1.5. The average annual cost per patient was €38,255.40. 80.2% of the costs was direct medical costs, 17.5% was associated with loss of productivity and 2.3% was direct non-medical costs. 85.9% of the total cost corresponded to the crises. The intercrisis period accounted for the remaining 14.1%. The global index of the EQ-5D-5L (HRQoL) was 0.75±0.24. The dimensions of pain/discomfort, anxiety/depression and daily activities were the most affected. Leisure, travel/vacations and household activities were the most affected daily activities. 53.6% of patients required a caregiver due to AHP. 92.9% did not present overload and 7.1% presented extreme overload. CONCLUSIONS: Patients with AHP are associated with a high economic impact and an affected HRQoL in the pain/discomfort dimension, with a negative impact on the performance of daily activities and a risk of psychiatric diseases.

Intrahepatic Cholangiocarcinoma and Acute Intermittent Porphyria: A Case Report.

Patients suffering from different forms of acute hepatic porphyria present a high risk of primary liver cancer, specifically hepatocellular carcinoma and cholangiocarcinoma, determined by the activity of the disease even though an exact mechanism of carcinogenesis has not been recognized yet. Here, we present the clinical case of a 72-year-old woman who, approximately 29 years after the diagnosis of acute intermittent porphyria, presented with intrahepatic cholangiocarcinoma with a histological diagnosis of adenocarcinoma starting from the biliary-pancreatic ducts, which was diagnosed during the clinical and anatomopathological evaluation of a pathological fracture of the femur.