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The British Journal of Dermatology Apr 2024Erythropoietic protoporphyria (EPP) patients experience lifelong painful photosensitivity resulting in a lack of sunlight exposure. Previous studies have shown that...
BACKGROUND
Erythropoietic protoporphyria (EPP) patients experience lifelong painful photosensitivity resulting in a lack of sunlight exposure. Previous studies have shown that 47-63% of EPP patients suffer from vitamin D deficiency and a high prevalence of osteoporosis. As of 2016 an effective treatment for EPP is available: the alpha-MSH analogue afamelanotide. So far studies on vitamin D levels in EPP have only investigated patients who were not treated with afamelanotide.
OBJECTIVES
To investigate the effects of afamelanotide treatment on vitamin D levels in EPP.
METHODS
A multi-centre observational cohort study, in adult patients with EPP from the Erasmus Medical Centre, the Netherlands and the University Hospital Düsseldorf, Germany. Routinely-collected vitamin D levels between 2005 and 2021 were used for analysis. Patient exposure to cholecalciferol or afamelanotide was categorized into four treatment groups; untreated, cholecalciferol, afamelanotide, and combined treatment. A linear mixed model for longitudinal data was applied to measure the effect of the treatment groups, compared to the untreated, on vitamin D levels.
RESULTS
A total of 230 patients and 1774 vitamin D measurements were included. Prevalence of vitamin D deficiency remained high despite afamelanotide treatment: <50 nmol/l in 71.8% of patients, and severe deficiency <30 nmol/l in 48.1%. Afamelanotide treatment alone did not lead to a significant average increase in vitamin D levels (β:0.5, 95% Confidence Interval [CI]: -3.2 - 4.2). In contrast, cholecalciferol and combined therapy with afamelanotide, led to a significant increase in vitamin D levels (β:11.6, CI: 7.2-15.9 and β:15.2, CI: 12.3-18.1).
CONCLUSION
Cholecalciferol remains essential for treatment of vitamin D deficiency in EPP, irrespective of new treatment options like afamelanotide. Afamelanotide treatment did not affect vitamin D levels. We suggest that future guidelines include continuous monitoring of vitamin D and prescription of cholecalciferol in all patients with EPP, including those treated with afamelanotide.
PubMed: 38634774
DOI: 10.1093/bjd/ljae148 -
Journal of Clinical Pathology Apr 2024The porphyrias are rare disorders of haem biosynthesis. Diagnosis requires demonstrating increased porphyrins or porphyrin precursors in blood, urine and faeces....
The porphyrias are rare disorders of haem biosynthesis. Diagnosis requires demonstrating increased porphyrins or porphyrin precursors in blood, urine and faeces. Patients may only be investigated once, and therefore, understanding the preanalytical factors affecting the reliability of results is crucial. Guidance for sample handling exists, but published evidence regarding the stability of porphyrins and their precursors is limited. The aim of this study was to evaluate the effect of light exposure and different storage temperatures on analyte stability for measurement of urinary aminolaevulinic acid and porphobilinogen, total urine porphyrin and plasma porphyrin. Our results confirm that all samples should be protected from light. Results from samples exposed to light for greater than 4 hours should be interpreted with caution and repeat samples requested. If transported to a specialist laboratory, samples should be stored at 4°C before transport. Transit time at ambient temperatures should be less than 24 hours.
PubMed: 38631910
DOI: 10.1136/jcp-2024-209443 -
Acute Medicine 2024Acute Intermittent Porphyria (AIP) can be a challenging diagnosis to make, due to its rarity in actual practice and presenting symptoms often being attributed to more...
Acute Intermittent Porphyria (AIP) can be a challenging diagnosis to make, due to its rarity in actual practice and presenting symptoms often being attributed to more common conditions. This is particularly the case, since many patients will likely present to acute and general hospitals where the diagnosis may often not be considered. However, it remains pivotal to diagnose the condition as early as possible to prevent significant morbidity and even death. Here we present an unexpected case of AIP, illustrating the diagnostic delay that is commonly seen with the condition and yet emphasise the importance of its detection to commence urgent treatment.
Topics: Humans; Delayed Diagnosis; Hospitals, General; Porphyria, Acute Intermittent
PubMed: 38619170
DOI: 10.52964/AMJA.0972 -
Liver International : Official Journal... Apr 2024The acute hepatic porphyrias (AHPs) include three autosomal dominant disorders, acute intermittent porphyria, variegate porphyria and hereditary coproporphyria, and... (Review)
Review
The acute hepatic porphyrias (AHPs) include three autosomal dominant disorders, acute intermittent porphyria, variegate porphyria and hereditary coproporphyria, and the ultra-rare autosomal recessive 5-aminolevulinic acid dehydratase-deficient porphyria. All four are characterized by episodic acute neurovisceral attacks that can be life-threatening if left untreated. The attacks are precipitated by factors that induce hepatic 5-aminolevulinic acid synthase 1 (ALAS1), resulting in accumulation of the porphyrin precursors, 5-aminolevulinic acid and porphobilinogen, which are believed to cause neurotoxicity. Diagnosis of these rare disorders is often delayed because the symptoms are non-specific with many common aetiologies. However, once clinical suspicion of an AHP is raised, diagnosis can be made by specialized biochemical testing, particularly during attacks. Moderate or severe attacks are treated with intravenous hemin infusions, together with supportive care to relieve pain and other symptoms. Prophylactic treatments are recommended in patients with confirmed recurrent attacks (≥4 attacks in a maximum period of 12 months), the most effective being givosiran, an RNAi therapeutic targeting hepatocyte ALAS1 mRNA. AHP patients with clinically and/or biochemically active disease are at elevated risk for developing long-term complications, including chronic kidney disease, chronic hypertension and hepatocellular carcinoma, thus, surveillance is recommended. Here, using a case-based format, we provide an update on the pathogenesis, diagnosis and treatment of the AHPs based on literature review and clinical experiences.
PubMed: 38618923
DOI: 10.1111/liv.15924 -
Cureus Mar 2024Acute intermittent porphyria (AIP) is a rare autosomal dominant metabolic disorder with low penetrance, often presenting with a broad spectrum of clinical...
Acute intermittent porphyria (AIP) is a rare autosomal dominant metabolic disorder with low penetrance, often presenting with a broad spectrum of clinical manifestations. Acute neurovisceral attacks commonly occur in young women, mimicking signs and symptoms of other medical and psychiatric conditions, thus delaying the diagnosis. We present the case of an 18-year-old female college student with recurrent hospitalizations for intractable abdominal pain, now again with pain and new subjective hematuria. The patient had previously undergone an endoscopy/colonoscopy with negative biopsies and serologies for acute pathology, including celiac disease. Celiac studies were repeated, given the possibility of inadvertent gluten exposure before the onset of the latest symptoms, but were negative. Basic labs and repeat imaging, including contrast-enhanced CT, MRI, and magnetic resonance (MR) enterography of the abdomen, continued to be unremarkable, and the patient's symptoms were felt to be functional in etiology. The patient's urinalysis was normal, and pregnancy was also ruled out. The patient continued to have pain despite receiving opiate analgesics, thus prompting a psychiatry consultation. She was diagnosed with acute adjustment disorder with anxiety and was started on hydroxyzine. Due to persistent symptoms, serum and urine samples were sent, revealing low levels of porphobilinogen deaminase (PBGD) and hydroxymethylbilane synthase (HMBS) gene mutation, confirming the diagnosis of AIP. She was treated with oral glucose and outpatient IV hemin infusions with the resolution of symptoms. AIP presents a nonspecific and highly variable clinical picture, often making it a challenging diagnosis due to such a broad differential. While our patient was thought to have acute adjustment disorder due to an unremarkable initial workup, further testing revealed otherwise. This case demonstrates how clinicians must have a high suspicion of AIP when caring for young females, manifesting with neurovisceral and psychiatric signs and symptoms. Timely diagnosis improves a patient's quality of life and can decrease overutilization of healthcare resources.
PubMed: 38618379
DOI: 10.7759/cureus.56222 -
Hepatology (Baltimore, Md.) Apr 2024The acute hepatic porphyrias (AHPs) are a group of rare, inherited disorders of the heme biosynthesis pathway, usually manifesting with attacks of acute abdominal pain...
The acute hepatic porphyrias (AHPs) are a group of rare, inherited disorders of the heme biosynthesis pathway, usually manifesting with attacks of acute abdominal pain and other neurovisceral symptoms, with or without cutaneous manifestations. AHP are characterized by the accumulation of porphyrin precursors, porphobilinogen (PBG) and/or aminolevulinic acid (ALA), in the blood. The diagnosis is often missed or delayed due to both inadequate testing and the improper use of available laboratory tests. In this review, we describe the various clinical presentations of the four AHPs, elucidate the approach to diagnosis, and provide recommendations for immediate as well as long-term management. We also describe the different complications that can occur with long-standing AHP, including the development of hepatocellular carcinoma. The AHPs are very treatable conditions, with excellent outcomes if diagnosed and treated early. A high index of suspicion for the presence of these disorders along with accurate testing and timely treatment will help reduce the burden of disease and prevent irreversible complications in patients with AHP.
PubMed: 38607698
DOI: 10.1097/HEP.0000000000000880 -
Lasers in Surgery and Medicine Jul 2024Fluorescence spectroscopy of human urine is a method with the potential to gain importance as a diagnostic tool in the medical field, e.g., for measuring Coproporphyrin...
OBJECTIVES
Fluorescence spectroscopy of human urine is a method with the potential to gain importance as a diagnostic tool in the medical field, e.g., for measuring Coproporphyrin III (CPIII) as an indicator of cancer and acute types of porphyria. Food can change human urine's color, which could influence the urine fluorescence spectrum and the detection of CPIII in urine. To determine if there is a noticeable influence on the urine fluorescence spectrum or on the detection of CPIII in urine, 16 vitamin supplements, and three food items were tested. Such investigation may also prevent false interpretation of measured data.
METHODS
Urine samples were collected before and after (overnight, ca. 8 h) intake of each test substance. Samples were investigated by fluorescence spectrum analysis. At excitation wavelengths from 300 to 500 nm and emission wavelengths from 400 to 700 nm excitation-emission-matrices were measured. Data obtained from urine before intake were compared to the data from overnight urine. Furthermore, the investigation of any interference with the CPIII concentration was performed at an excitation wavelength of 407 ± 3 nm and emission wavelengths of 490-800 nm.
RESULTS
Only vitamin B2, but none of the other tested substances, showed noticeable influence on the urine fluorescence spectrum. None of the tested substances showed noticeable interference with the recovery rate of CPIII.
CONCLUSIONS
The correct interpretation of measured data by fluorescence spectroscopy is possible with the exception if vitamin B2 supplementation was performed; thus, the consumption of vitamin B2 supplements before fluorescence testing of the patient's urine should be avoided and/or must be requested. CPIII concentrations could reliably be measured in all cases.
Topics: Humans; Spectrometry, Fluorescence; Vitamins; Food; Dietary Supplements; Urinalysis; Riboflavin
PubMed: 38605494
DOI: 10.1002/lsm.23785 -
International Journal of Dermatology Apr 2024Erythropoietic protoporphyria (EPP) causes painful light sensitivity, limiting quality of life. Our objective was to develop and validate a wearable light exposure...
BACKGROUND
Erythropoietic protoporphyria (EPP) causes painful light sensitivity, limiting quality of life. Our objective was to develop and validate a wearable light exposure device and correlate measurements with light sensitivity in EPP to predict and prevent symptoms.
METHODS
A wearable light dosimeter was developed to capture light doses of UVA, blue, and red wavelengths. A prospective observational pilot study was performed in which five EPP patients wore two light dosimeters for 3 weeks, one as a watch, and one as a shirt clip.
RESULTS
Standard deviation (SD) increases from the mean in the daily blue light dose increased the odds ratio (OR) for symptom risk more than the self-reported outdoor time (OR 2.76 vs. 2.38) or other wavelengths, and a one SD increase from the mean in the daily blue light wristband device dose increased the OR for symptom risk more than the daily blue light shirt clip (OR 2.45 vs. 1.62). The area under the receiver operator curve for the blue light wristband dose was 0.78, suggesting 78% predictive accuracy.
CONCLUSION
These data demonstrate that wearable blue light dosimetry worn as a wristband is a promising method for measuring light exposure and predicting and preventing symptoms in EPP.
PubMed: 38602089
DOI: 10.1111/ijd.17166 -
Molecular Genetics and Metabolism... Jun 2024Acute hepatic porphyrias are inherited metabolic disorders of heme biosynthesis characterized by the accumulation of toxic intermediate metabolites responsible for...
Preventing hyperhomocysteinemia using vitamin B 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 β-synthase (CBS) enzyme induced by givosiran. Long-term treatment with vitamin B, 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 B 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.
PubMed: 38601120
DOI: 10.1016/j.ymgmr.2024.101076 -
Molecular Therapy. Oncology Mar 2024Thanks to its very high genome-editing efficiency, CRISPR-Cas9 technology could be a promising anticancer weapon. Clinical trials using CRISPR-Cas9 nuclease to edit and...
Thanks to its very high genome-editing efficiency, CRISPR-Cas9 technology could be a promising anticancer weapon. Clinical trials using CRISPR-Cas9 nuclease to edit and alter immune cells are ongoing. However, to date, this strategy still has not been applied in clinical practice to directly target cancer cells. Targeting a canonical metabolic pathway essential to good functioning of cells without potential escape would represent an attractive strategy. We propose to mimic a genetic metabolic disorder in cancer cells to weaken cancer cells, independent of their genomic abnormalities. Mutations affecting the heme biosynthesis pathway are responsible for porphyria, and most of them are characterized by an accumulation of toxic photoreactive porphyrins. This study aimed to mimic porphyria by using CRISPR-Cas9 to inactivate , leading to porphyrin accumulation in a prostate cancer model. Prostate cancer is the leading cancer in men and has a high mortality rate despite therapeutic progress, with a primary tumor accessible to light. By combining light with gene therapy, we obtained high efficiency and , with considerable improvement in the survival of mice. Finally, we achieved the preclinical proof-of-principle of performing cancer CRISPR gene therapy.
PubMed: 38596305
DOI: 10.1016/j.omton.2024.200772