Porphyria, Acute Intermittent
Conditions
Brief summary
The main aim of this clinical trial is to learn about the effect of carbohydrate-rich diet as a treatment for AIP (acute intermittent porphyria). Aim: Investigate the diet's impact on tissue and serum glucose, plasma insulin, cytokine levels, amino acids, and gut microbiota in AIP, and their correlation with PBG (Porphobilinogen). Aim: Assess the diet's effect on AIP symptoms and health status in AIP. Aim: Measure the effect of a high-carbohydrate diet on mitochondrial activity in AIP Aim: Map and detect potential mutations in mitochondrial genomic DNA in AIP Aim: Discover new markers in AIP through RNA sequencing and machine learning. Participants will follow two diet plans, a 4-week intervention with 60-65 E% carbohydrates and a 4 week intervention with 40-45 E% carbohydrates.
Detailed description
Acute intermittent porphyria (AIP) is an inherited disease that leads to the accumulation of porphobilinogen (PBG), resulting in severe abdominal pain, paralysis, fatigue, low-grade inflammation, and an increased risk of kidney failure and liver cancer. Studies at the cellular level and in mice have shown that elevated levels of glucose and insulin can affect heme synthesis, potentially reducing PBG levels. The investigators have previously demonstrated that individuals with AIP consume less carbohydrate (E% 40) than recommended. The investigators aim to conduct a crossover study involving 50 participants with AIP, where 50% will be subjected to a 4-week intervention with 60-65 E% carbohydrates, while the other half will consume 40-45 E% carbohydrates for 4 weeks. After a 4-week intervention-free period, the two groups will switch to the respective carbohydrate percentages. Symptoms, PBG levels, continuous tissue glucose, plasma/serum insulin, glucose, cytokines, amino acid levels, microbiota in the gut, body composition, and physical activity measured using accelerometers will be assessed before and after each intervention and compared. Mitochondrial activity will be assessed at the cellular level as oxidative activity. Mutations in mitochondrial DNA and RNA will also be examined since defects in oxidative energy metabolism are known to be associated with inflammation and cancer. The work will be carried out at Nordland Hospital and at the University of Oslo. The study will be coordinated and conducted by the Postdoc and partners at Nordland Hospital, Karolinska University Hospital Stockholm and Norrland University Hospital, Umeå, the University of Oslo, the Arctic University of Tromsø, and Nord University. Clinical nutritionists will create dietary plans, and bioengineers will perform analyses. Stay abroad for postdoc, and research cooperation, with porphyria researchers at UTMB, Texas and MGH, Boston, US.
Interventions
OTHERCarbohydrates
Half of the patients will initially follow Diet Plan A with 60-65 E% carbohydrates for 4 weeks, followed by a 4-week washout period, and then Diet Plan B with 40-45 E% carbohydrates for 4 weeks. The other half will start with Diet Plan B for 4 weeks, followed by a 4-week washout period, and then Diet Plan A for 4 weeks . Diet Plans A and B contain recommended and adequate nutrients according to the Nordic Nutrition Recommendations 2023 (NNR2023) for maintaining a stable weight.
Sponsors
Nordlandssykehuset HF
University of Oslo
Nord University
UiT The Arctic University of Norway
Norwegian University of Science and Technology
The University of Texas Medical Branch, Galveston
Karolinska University Hospital
Norrlands Universitetssjukhus, Umea, Sweden
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Masking description
Blinding is attempted by labeling the provided diet plans as A and B. The physician recording outcome variables and the researcher performing statistical analysis are blinded to the given diet.
Intervention model description
The study is a crossover study involving 50 individuals with AIP. The study design was chosen to determine whether the treatment has an effect compared to baseline analyses and whether the sequence of treatment has an effect, as well as whether one of the interventions is more effective than the other.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of AIP
Exclusion criteria
* Not having diagnosis of AIP * Undergoing treatment as part of other clinical research on AIP * Pregnancy * Diabetes * Below 18 years of age
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Urine Porphobilinogen/creatinine | Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B | AIP biochemical disease activity. First morning Urine Porphobilinogen/creatinine. Change from baseline before diet A to immediately after diet A, and change from baseline before diet B to immediately after diet B |
| Urine Porphobilinogen/creatinine concentration, percentage change of repeated measurements | Day 1 ,4, 8, 11, 15, 18, 22, 25 and 29 of Diet Intervention A and of Diet Intervention B | AIP biochemical disease activity, repeated measurements Percentage change in the median of repeated measurements of Urine Porphobilinogen/creatinine concentrations between Diet A and Diet B The repeated measurements in urine analyzed in urine samples from Day 1 ,4, 8, 11, 15, 18, 22, 25 and 29 of Diet A and of Diet B, and calculated median of Urine Porphobilinogen/creatinine concentration for diet A and median for diet B |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Hospitalizations,sick leaves, and doctor visits due to AIP | Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B | Using questionnaire counting Number of hospitalizations, sick leaves, and doctor visits due to AIP * In the 4 weeks before Diet A, measured at baseline immediately before Diet A * In the 4 weeks of Diet A, measured immediately after Diet A. * In the 4 weeks before Diet B, measured at baseline immediately before Diet B * in the 4 weeks of Diet B, measured immediately after Diet B |
| Health status | Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B | A standardized questionnaire assessing health (RAND-36) with a 4-week time frame from 0 (worst functioning) to 100 (best functioning), where 2 to 5 points represent a clinically meaningful difference based on data from other chronic diseases. |
| Plasma Glucose level | Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B | Plasma glucose concentration |
| Interstitial fluid glucose level | Day 15 and 29 of diet A and day 15 and 29 of diet B | Glucose measured in the interstitial fluid (ISF) Measuring is performed continuously by ISF glucose sensor FreeStyle Libre 3 in the 4 weeks of Diet A and in the 4 weeks of Diet B. Outcome is percentage change in the mean of repeated measurements between Diet A and Diet B. Each tissue glucose sensor lasts 14 days, and hence the outcome measure will be assessed each 14 days, and read in the LibreView program. The sensor is placed on the back of the participants upper arm |
| Number of hypoglycemic events | Day 15 and 29 of diet A and day 15 and 29 of diet B | Tissue glucose measured continuously by tissue glucose sensor FreeStyle Libre 3 (Abbott) in the 4 weeks during diet A and in the 4 weeks of diet B. Counting number of hypoglycemic events during the 4 weeks of diet A and comparing to counted number of hypoglycemic events during the 4 weeks of diet B. Each tissue glucose sensor lasts 14 days, and hence the outcome measure will be assessed each 14 days, and read in the LibreView program. Assessing is performed day 15 and day 29 of diet A and day 15 and 29 of diet B. |
| Amino acid profile | Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B | Levels of amino acids measured |
| Plasma insulin, glucose, c-peptide | Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B | Concentration levels measured in plasma |
| HOMA score | Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B | HOMA score (Homeostatic Model Assessment) including estimated beta cell function, HOMA%B (%B), insulin sensitivity, HOMA%S (%S), and insulin resistance HOMA-IR (IR), calculated from insulin, glucose and C-peptide in plasma, using an Excel spreadsheet from the University of Oxford. |
| HbA1c | Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B | Concentration levels measured in blood |
| Cytokines in plasma | Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B | Cytokines, chemokines and growth factors measured using Multiplex assay from BioRad Lab, Bio-Plex 27-plex kit: Interleukin (IL)-1β, IL-1RA (IL-1 receptor antagonist), IL-2, IL-4, IL-5, IL-6, IL-7, chemokine (C-X-C) motif 8 (CXCL8), IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, chemokine (C-C motif) ligand 5 (CCL5), chemokine ligand 11 (CCL11), basic fibroblast growth factor (FGF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ, CXCL10, CCL2, CCL3, CCL4, platelet-derived growth factor-BB (PDGF-BB), tumour necrosis factor (TNF) and vascular endothelial growth factor (VEGF). |
| Intestinal microbiota composition | Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B | Sequencing of fecal samples, Gut Health Panel from Bio-Me, covering 100 different bacterias |
| Physical activity | Immediately after one week of Diet A, and immediately after one week of Diet B | Accelerometer (AX3 Axivity Newcastle, UK), attached to the thigh and worn for 7 consecutive days in the first week of diet A and in the first week of diet B. Moderate to vigorous physical activity (MVPA) is detected in 5-second intervals. Measuring time (min/day) spent in MVPA during the first week of diet A and during the first week of diet B. |
| Blood pressure | Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B | 20 min measurement |
| Body composition, metabolic age | Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B | Tanita Body Composition Analyzer |
| Mitochondrial oxygen consumption rate | Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B | SeaHorse, mononuclear cells in peripheral blood |
| ALAS1mRNA | Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B | TaqMan gene expression assay |
| Urine-ALA/creatinine & urine-porphyrins | Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B | level measurement of concentration in urine |
| Mitochondrial function-related genes | At baseline immediately before each participants first diet intervention | Paxgen tubes, qPCR, Mitochondrial genome sequencing |
Countries
Norway, Sweden
Contacts
CONTACTElin Storjord, MD PhD
CONTACTHilde Thunhaug, Nurse
PRINCIPAL_INVESTIGATORElin Storjord, MD PhD
Nordlandssykehuset HF
PRINCIPAL_INVESTIGATORPer Dahlqvist, MD PhD
Norrland University Hospital, Umeå
PRINCIPAL_INVESTIGATOREliane Sardh, MD PhD
Studieenheten, Akademiskt Specialistcentrum, Stockholm Läns Sjukvårdsområde, Region Stockholm
Outcome results
None listed