Hepatoerythropoietic porphyria (HEP) is a rare autosomal recessive disorder of heme biosynthesis caused by severe deficiency of uroporphyrinogen decarboxylase (UROD). It typically presents in infancy or early childhood with marked photosensitivity, skin fragility, blistering, dyspigmentation, hypertrichosis, and dark urine. We report a girl from Brazil who developed blistering and ulcerative lesions of the face and upper extremities beginning at 10 months of age, along with dark urine and gray discoloration of the teeth. She was 2.5 years old when first evaluated at the Massachusetts General Hospital Porphyria Center. Prior genetic testing in Brazil had already identified two UROD variants, c.239C>G (p.Ala80Gly) and c.464C>T (p.Ala155Val). At our center, erythrocyte UROD activity was markedly reduced to approximately 5% of normal, and plasma, urine, stool, and erythrocyte porphyrins were all substantially elevated, confirming the diagnosis of HEP. Erythrocyte protoporphyrin was 83.5% zinc-chelated. The patient also had persistent mild hepatosplenomegaly and mild transaminase elevation. Management included strict photoprotection and sequential trials of cholestyramine and cimetidine, followed by serial therapeutic phlebotomy while continuing cimetidine. Neither cholestyramine nor therapeutic phlebotomy was associated with clear biochemical improvement, whereas cimetidine was temporally associated with a decline in urinary porphyrins, although other biomarkers were more variable. This case highlights the importance of considering HEP in children with blistering lesions on sun-exposed skin.

Diagnosis and management of porphyrias require appropriate biochemical testing. Tests available to practicing physicians in the US are not consistent and depend greatly on what is offered by individual laboratories. In addition, harmonization, whereby results and interpretations from different laboratories are comparable, is not assured. Members of American Porphyrias Expert Collaborative (APEX) recommend that specific tests should be available to all physicians in the US for diagnosis and monitoring of porphyrias, and that harmonization of laboratory practices and results reporting across laboratories should be achieved. These efforts will lead to the development and more effective implementation of guidelines for the diagnosis and monitoring of porphyrias by both community providers and porphyria expert centers.

Homozygous variegate porphyria (HVP) is an ultra-rare porphyria caused by biallelic pathogenic variants in PPOX. It typically presents with early childhood onset of cutaneous photosensitivity, including blistering, skin fragility, scarring, and poorly defined neurologic symptoms. We report two unrelated patients with childhood-onset photosensitivity, blistering, scarring, modest zinc-predominant erythrocyte protoporphyrin elevation, elevated plasma porphyrins that were predominantly protoporphyrin, and homozygous novel PPOX variants, findings consistent with homozygous variegate porphyria. Both patients had initially been diagnosed with erythropoietic protoporphyria because of photosensitivity and elevated total erythrocyte protoporphyrin, despite fractionation demonstrating a slight zinc predominance rather than metal-free predominance. Genetic testing revealed that both patients were homozygous for PPOX variants: c.223G>T p.Val75Phe in Case 1 and c.1070A>C p.Asp357Ala in Case 2. Neither variant was present in population genetic datasets nor previously reported in patients with variegate porphyria, and both were classified as variants of uncertain significance. A plasma fluorescence scan was performed for Case 2 and showed a peak at 624 nm, specific for variegate porphyria. A comprehensive porphyria gene panel, ideally with plasma fluorescence scanning, should be performed when total erythrocyte protoporphyrin is substantially elevated but predominantly zinc-chelated, to ensure accurate diagnosis of homozygous porphyrias such as HVP.

Postural orthostatic tachycardia syndrome (POTS) is characterized by an excessive heart rate increase upon standing, often associated with dizziness, gastrointestinal symptoms, and decreased functional capacity. Acute hepatic porphyrias (AHP) are rare metabolic disorders with nonspecific neurovisceral and autonomic symptoms, some of which overlap with POTS. The purpose of this study was to evaluate AHP by molecular and biochemical testing in patients with POTS. We studied 50 patients diagnosed with POTS and gastrointestinal symptoms at the Vanderbilt Autonomic Dysfunction Center. They underwent neuro-hormonal evaluation for POTS and genetic and biochemical screening for AHP. Genetic testing was aimed mainly at the four genes relevant to AHPs. Porphobilinogen (PBG), delta-aminolevulinic acid (ALA), and total porphyrins were measured in urine with normalization to creatinine. The average age of the patients was 33 ± 8.6 years, 96

BACKGROUND:Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by the accumulation of protoporphyrin in the marrow, erythrocytes, plasma, skin, and liver, and present clinically with painful cutaneous phototoxicity. Liver abnormalities have been reported in over 25% of patients with EPP. Further characterization of liver involvement in protoporphyria is needed. METHODS:Patients with EPP or XLP enrolled in the longitudinal studies of the NIH-supported Porphyrias Consortium were included. Medical history, laboratory, and liver histology data were abstracted and described. RESULTS:A total of 322 patients were enrolled; 28 (8.7%) had XLP, 52% were female, and the median age at enrollment was 33.3 years. Liver chemistries were available for 235 patients, and 132 (56.2%) had abnormalities, mostly mild. Abnormal liver enzymes were associated with higher erythrocyte protoporphyrin levels. Eleven patients had advanced protoporphyric hepatopathy. In total, 54 (16.8%) underwent cholecystectomy, 8 (2.5%) had a liver transplant, 4 (1.2%) had a bone marrow transplant, and 8 (2.5%) died. At least 4 deaths were caused by liver failure due to protoporphyric hepatopathy, 2 were complications of bone marrow transplant, and 1 from HCC, which developed in a patient with EPP without cirrhosis. Patients with XLP were more likely to develop liver-related complications compared to EPP. CONCLUSIONS:Liver abnormalities are common in patients with EPP and XLP. In this national registry, only 3.4% had protoporphyric hepatopathy, with most requiring a transplant. Of the deaths, 62.5% were attributable to liver disease. Further observations are needed for guiding hepatic evaluation and management of patients with protoporphyria with or without initial hepatic abnormalities.

Background: Erythropoietic protoporphyria (EPP) is associated with accumulation of photoreactive protoporphyrin IX (PPIX) in the skin and other organs, causing debilitating phototoxic skin reactions following exposure to sunlight, and in a subset of patients, lifethreatening protoporphyric hepatopathy. Glycine transporter 1 (GlyT1) supplies extracellular glycine for the initial step of heme biosynthesis in erythroid cells. Bitopertin is an investigational, orally administered inhibitor of GlyT1. Through GlyT1 inhibition, bitopertin restricts glycine availability and decreases accumulation of the phototoxic heme pathway intermediate PPIX. Methods: AURORA is a Phase 2, double-blind, placebo-controlled study (NCT05308472) that randomized 75 participants (1:1:1) to receive oral, once-daily administration of 20-mg or 60-mg bitopertin or placebo for 17 weeks. Participants ≥18 years of age with a confirmed diagnosis of EPP were enrolled. The primary endpoint was percent change from baseline in whole-blood metal-free PPIX in participants randomized to bitopertin compared to percent change from baseline for those randomized to placebo. Results: Treatment with bitopertin resulted in significant and sustained reductions in PPIX levels compared to PPIX levels for treatment with placebo at both the 20-mg and 60-mg dose levels (least-squares [LS] mean difference relative to placebo: 29.7% [p=0.004] and 48.7% [p<0.001], respectively). The reductions in PPIX with bitopertin were observed across several prespecified subgroups, including age, sex, and disease severity. Treatment with bitopertin significantly reduced the rate of phototoxic reactions compared to the rate observed in treatment with placebo; the incidence rate ratios relative to those of placebo were 0.397 (p=0.11) in the 20mg bitopertin group and 0.247 (p=0.01) in the 60-mg bitopertin group, corresponding to 60% and 75% reductions in the phototoxic reaction rate compared to the rate in the placebo group. PPIX reductions were associated with improvements in multiple sunlight tolerance measures, including cumulative total pain-free time in sunlight, time to first prodromal symptom, occurrence of phototoxic reactions, and improvements in how participants reported feeling in the Patient Global Impression of Change. A post hoc longitudinal mixed model for repeated-measures analysis showed nominally statistically significant, time-dependent improvements in pain-free sunlight exposure with bitopertin compared to the improvements with placebo in both the 20mg and 60-mg dose groups (LS mean [±SE] difference relative to placebo: 7.1±3.2 hours [p=0.026] and 8.0±3.2 hours, [p=0.013], respectively), and participants randomized to bitopertin had a 2fold improvement in average daily sunlight exposure at the end of study relative to baseline. Overall, nearly all treatment-emergent adverse events (TEAEs) were mild to moderate in intensity. One serious adverse event of obstructive pancreatitis was reported in a participant randomized to placebo. Two participants randomized to 60 mg of bitopertin discontinued treatment due to a TEAE (dizziness, rash). The most commonly reported TEAE was dizziness, which occurred in 17%, 15%, and 44% of participants randomized to placebo, 20mg bitopertin, and 60-mg bitopertin, respectively. No meaningful changes in hemoglobin were observed. Summary/Conclusion: By reducing PPIX levels, bitopertin targets the underlying pathophysiology of EPP. PPIX reductions with bitopertin were consistently associated with improvements across multiple clinical outcome measures. Treatment with bitopertin resulted in time-dependent improvements in sunlight tolerance, with a 2-fold increase relative to baseline tolerance at the end of study. Bitopertin was well tolerated. Its safety profile in EPP is consistent with prior studies of bitopertin that enrolled more than 4000 participants in other non-EPP indications. Additional analyses will be presented at the meeting.

The acute hepatic porphyrias (AHPs) are disorders of heme biosynthesis characterized by neurovisceral symptoms and significant morbidity. Acute attacks are triggered by induction of the hepatically-synthesized enzyme, aminolevulinic acid synthase-1 (ALAS-1). Common precipitating factors include medications and fluctuations in hormones, particularly progesterone, during the menstrual cycle. Notably, over 90% of patients with symptomatic AHP are female; however, existing data on the impact of the menstrual cycle, contraceptive use, pregnancy, and menopause on AHP symptoms are scarce. To address this critical knowledge gap, we sought to comprehensively characterize the influence of these reproductive health factors in AHP with the goal of informing and improving clinical decision making. We conducted a nationwide survey of adult female patients in the US with documented AHP. Patients were recruited by their porphyria specialists or by targeted advertisement through a patient advocacy organization. We collected detailed data on overall AHP severity and the relationship between AHP symptoms and menstrual cycles, contraceptive use, pregnancy, and menopause. Responses about symptom changes (much worse to much better) were scored on a 5-point ordinal scale. Only patients with at least one lifetime porphyria attack were included in the analysis. We used Wilcoxon signed-rank test and Generalized Estimating Equations to compare observed response distributions to those expected under the null hypothesis of no change. Of 120 patients contacted, 103 (85.8%) completed the survey. Three patients reported no lifetime attacks and were excluded from subsequent analysis, resulting in 100 who were eligible for inclusion. The distribution of AHPs included acute intermittent porphyria (79.0%), variegate porphyria (10.0%), hereditary coproporphyria (9.0%), and unknown subtype (2.0%). Fifty-seven percent reported ≥10 lifetime porphyria attacks. During the 5 years prior to survey completion, 51 patients received hemin and 44 received givosiran (an RNAi that suppresses hepatic ALAS-1). AHP symptoms were reported to be worse immediately before menstruation in 61 participants, during menstruation in 33, and after menstruation in 14, with respondents able to select multiple choices. Lifetime contraceptive use included combined estrogen-progestin oral contraceptive pills (cOCPs; 60 participants), levonorgestrel intrauterine device (LNG-IUD; 23 participants) progesterone-only pills (POPs; 9 participants), depot medroxyprogesterone (11 participants), and estrogen-progestin vaginal rings (7 participants). Use of cOCPs (p<0.001), POPs (p=0.048), and depot medroxyprogesterone (p=0.003) were significantly associated with symptom worsening, whereas LNG-IUD (p=0.69) and copper IUD (p=0.66) were not associated with perceived worsening or improvement in symptoms. Sixty-eight patients experienced 156 pregnancies, with a median of 2 (IQR, 1-3) per patient. During pregnancy, thirty-six patients (52.9%) reported no change in their AHP symptoms, 13 (19.1%) reported improvement, and 19 (27.9%) reported worsening. Eighteen (11.5%) of pregnancies were complicated by gestational hypertension, 12 (7.7%) by pre-eclampsia, and 6 (3.8%) by fetal growth restriction. Five patients received hemin during pregnancy, and no patient was treated with givosiran during pregnancy. Of 45 women who breastfed, 44 (97.8%) reported no worsening of their symptoms with lactation. Postmenopausal participants (n=37) reported no significant change in AHP symptoms with menopause (p=0.19), although perimenopause (n=43) was associated with symptom worsening (p<0.001). In this US nationwide study of 100 female patients with AHP, we characterized the relationships between reproductive health factors and disease burden. Use of cOCPs, POPs, and depot medroxyprogesterone was associated with worsening of AHP symptoms, while LNG and copper IUDs appeared to be better tolerated. Pregnancy and lactation generally did not exacerbate symptoms of AHP, whereas perimenopause was associated with symptom worsening. We found no significant change in symptoms during menopause. These results highlight the complex relationship between reproductive health and AHP and underscore the need for additional dedicated research in this area.

Erythropoietic protoporphyria (EPP) is caused by loss-of-function mutations in ferrochelatase (FECH), leading to the accumulation of its substrate, protoporphyrin IX (PPIX). PPIX is primarily produced in the bone marrow and transported to the liver for excretion. Because PPIX is hydrophobic, its elevated levels can cause bile duct blockage, cholestatic liver injury, and even liver failure. However, the specific transporter responsible for PPIX uptake into hepatocytes remains unclear. The OATP1B1/1B3 transporters, which are expressed in hepatocytes, facilitate the uptake of coproporphyrin III, a structural analog of PPIX. Additionally, OATP1B1/1B3 mediates the uptake of bilirubin, a biomarker of liver injury, from plasma into the liver for excretion. Therefore, we aimed to determine the role of OATP1B1/1B3 in regulating PPIX and bilirubin homeostasis under EPP conditions. A mouse strain carrying a Fech mutation was used as an EPP model. Building on this, we generated a new EPP mouse model with Oatp1a/1b deficiency. Using these EPP mouse models, along with OATP1B1/1B3-overexpressing cells, our study revealed that PPIX is not a substrate of OATP1B1/1B3. Notably, our work found that genetic deficiency or pharmacologic suppression of Oatp1a/1b exacerbates hyperbilirubinemia in EPP mice without worsening liver injury. Mechanistically, Oatp1a/1b deficiency impairs bilirubin uptake from plasma, while Fech deficiency leads to PPIX-mediated bile duct blockage and reduced bilirubin excretion, synergistically exacerbating hyperbilirubinemia. In summary, our work demonstrated that deficiency or suppression of Oatp1a/1b exacerbates hyperbilirubinemia in EPP mouse models, suggesting that assessment of OATP1B1/1B3 function is crucial in EPP patients with EPP with hyperbilirubinemia. SIGNIFICANCE STATEMENT: This work revealed that serum bilirubin levels are not paralleled with liver damage in the erythropoietic protoporphyria mouse models with Oatp1a/1b deficiency. Our findings suggest that assessment of OATP1B1/1B3 function is crucial in patients with erythropoietic protoporphyria with hyperbilirubinemia.

Background: PORT-77 is a novel, orally bioavailable inhibitor of the ATP-binding cassette subfamily G member 2 (ABCG2, also known as BCRP) transport protein that is under development for the treatment of erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP). EPP and XLP are rare, genetic photodermatoses that result in the accumulation of protoporphyrin IX (PPIX), primarily in the marrow reticulocytes and secondarily in circulating RBCs, plasma, and bile. When activated by sunlight through the skin, PPIX generates singlet oxygen free radicals that lead to cutaneous damage and excruciating pain. PPIX is cleared through the bile, and it can accumulate in the biliary system and damage cholangiocytes and hepatocytes, leading to cholestatic liver disease that can be rapidly progressive. The ABCG2 transport protein mediates the transport of PPIX from RBCs into the plasma. We hypothesize that inhibition of ABCG2 by PORT-77 decreases PPIX efflux from circulating erythroid cells and reduces plasma PPIX concentrations, potentially ameliorating PPIX-mediated skin phototoxicity and liver damage. Previously shared preclinical data support a protective role of PORT-77 in the relevant EPP mouse model, BALB/c Fechm1Pas (Shah et al., 2024). Here, we first examine the in vitro effects of PORT-77 on PPIX efflux from EPP and XLP patients' RBCs, and second, compare plasma PPIX levels before and after dosing with PORT-77 in healthy human volunteers without EPP or XLP. Methods: Fresh whole blood samples were obtained from EPP and XLP patients (EPP N=2, XLP N=1) and baseline PPIX levels were measured by LC-MS/MS. RBCs were then isolated and incubated with increasing concentrations of PORT-77. PPIX was extracted from the conditioned media and measured using the same LC-MS/MS assay. Plasma samples from healthy adult volunteers in an ongoing Phase 1 study (NCT06346509) were collected before and after dosing with PORT-77 at ascending concentrations. Samples from single-dose (N=64) and 14-day (N=40) dosing regimens were analyzed by LC-MS/MS. Given the exquisite light lability of the PPIX molecule, study protocols included amber blood collection tubes, rapid freezing, processing under filtered light, and storage and shipping in opaque containers. Results: Whole blood PPIX levels were 889 and 598 μg/dL for the EPP donors, and 319 μg/dL for the XLP donor (normal levels for those without EPP/XLP: <80 ug/dL whole blood and <1 μg/dL plasma). PORT-77 demonstrated dose-dependent inhibition of PPIX efflux from these RBCs with >50% reduction in media PPIX compared to vehicle control, with an IC50 (half-maximal inhibitory concentration) in the low-nanomolar range. In the healthy volunteer study, PORT-77 was well-tolerated, with no serious adverse events and no safety or tolerability signals identified to date. Mean baseline plasma PPIX concentrations were 0.15 μg/dl (range 0.01 – 0.88 μg/dL). Oral dosing of PORT-77 resulted in a rapid and dose-dependent reduction of plasma PPIX concentrations, with >50% reduction from baseline as early as 6 hours after a single dose. Once daily oral dosing of PORT-77 for 14 days resulted in a sustained reduction of plasma PPIX concentrations lasting for 48 hours after the last dose, with no subsequent rebound above pretreatment levels through the final assessment. Conclusions: These in vitro studies using RBCs from EPP and XLP patients and in vivo observations in healthy human volunteers provide the first-ever human evidence that PORT-77-mediated inhibition of ABCG2 is sufficient to reduce efflux of PPIX from RBCs and lower plasma PPIX levels, respectively. These data in healthy human volunteers and patient-derived RBCs support further investigation of PORT-77 in the ongoing Phase 2 study (NCT06971900) of individuals with EPP.

Porphyrins and porphyrin precursors are normally detected in small amounts in healthy individuals but are found in large quantities in the urine, feces, blood, plasma, bone marrow, and liver in patients with various types of porphyrias. These are intermediates, or are derived from intermediates, in the pathway for heme biosynthesis. Heme is synthesized in all body tissues but in the largest amounts in the bone marrow and liver. Accurately measuring these compounds is important for diagnosis and monitoring of porphyrias. In addition, measurement of enzyme activities and mutation analyses by DNA sequencing enables confirmation of a porphyria diagnosis and genetic counseling. Biochemical approaches described here include measurements of porphyrin precursors and porphyrins in the urine, feces, plasma, erythrocytes, and liver, and determination of specific enzyme activities in erythrocytes and other cells. © 2025 Wiley Periodicals LLC.

Erythropoietic protoporphyria (EPP) is a disorder of haem biosynthesis characterized by a reduction in ferrochelatase and subsequent accumulation of protoporphyrin IX. Haematological aberrations in EPP have been described, though they remain poorly understood. We present a detailed analysis of haematological parameters in EPP, drawing upon data from four large cohorts in the United States and Europe. We show an association between protoporphyrin levels and both platelet count and spleen size, and in a case-control analysis, we describe significant differences between haematological indices in EPP patients versus controls.

Porphyrias are rare, mostly inherited disorders resulting from altered activity of specific enzymes in the haem synthesis pathway that lead to accumulation of pathway intermediates. Photocutaneous symptoms occur when excess amounts of photoreactive porphyrins circulate in the blood to the skin, whereas increases in potentially neurotoxic porphyrin precursors are associated with neurovisceral symptoms. Current therapies are suboptimal and their mechanisms are not well established. As described here, emerging therapies address underlying disease mechanisms by introducing a gene, RNA or other specific molecule with the potential to cure or slow progression of the disease. Recent progress in nanotechnology and nanoscience, particularly regarding particle design and formulation, is expanding disease targets. More secure and efficient drug delivery systems have extended our toolbox for transferring specific molecules, especially into hepatocytes, and led to proof-of-concept studies in animal models. Repurposing existing drugs as molecular chaperones or haem synthesis inhibitors is also promising. This review summarizes key examples of these emerging therapeutic approaches and their application for hepatic and erythropoietic porphyrias.

Levy, Cynthia; Dickey, Amy K.; Anderson, Karl E.; Keel, Sioban B.; Balwani, Manisha Author Information

BACKGROUND AND AIMS:Hepatocellular carcinoma (HCC) is a long-term complication of acute hepatic porphyria (AHP) inclusive of acute intermittent porphyria [AIP], variegate porphyria [VP], or hereditary coproporphyria [HCP]. Data on HCC risk in AHP patients are limited and heterogeneous. We performed this meta-analysis with aims to (a) determine incidence of HCC in AHP and specific subtypes of AHP and (b) examine high-risk groups for HCC. METHODS:Data from studies reporting HCC development in AHP patients were pooled and reported per 100 person years with 95% confidence intervals (CI). RESULTS:12 observational (5 prospective) studies (11 Europe and 1 US) on 2735 patients (mean age 54.8 yrs., 62% females) with AHP (80% AIP) were analyzed. 115 HCC cases were observed with HCC incidence per 100 person years of 0.3 (0.2-0.5) in AHP, 0.4 (0.2-0.6) in AIP, 0.3 (0-0.4) in VP, and 0.2 (0.1-0.6) in HCP. The risk was 0.4 (0.2-0.6) in females, 0.3 (0.1-0.5) in males, 0.9 (0.1-1.7) in symptomatic, and 0.5 (0-1.6) in asymptomatic patients. Analyses were heterogeneous with publication bias. AHP patients with HCC were older females with a higher prevalence of cirrhosis, alcohol use, and viral hepatitis. CONCLUSIONS:The annual incidence of HCC in AHP patients is 0.3%, with higher risk in AIP, older females, symptomatic patients, and those with other risk factors of liver disease. Future studies pooling individual patient data and overcoming limitations of the current meta-analysis are needed as a basis for deriving a effective screening and surveillance approach for HCC in patients with AHP.

Background: Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare disorders of heme biosynthesis characterized by severe cutaneous phototoxicity. Afamelanotide, an α-melanocyte-stimulating hormone analogue, is the only approved treatment for protoporphyria and leads to increased light tolerance and improved quality of life (QoL). However, published experience with afamelanotide in the US is limited. Methods: Here, we report on all adults who received at least one dose of afamelanotide at the Massachusetts General Hospital Porphyria Center from 2021 to 2022. Changes in the time to phototoxic symptom onset, QoL, and laboratory parameters were assessed before and during treatment with afamelanotide. Results: A total of 29 patients with protoporphyria were included, 26 of whom (72.2%) received ≥2 afamelanotide implants. Among the patients who received ≥2 implants, the median time to symptom onset following sunlight exposure was 12.5 min (IQR, 5–20) prior to the initiation of afamelanotide and 120 min (IQR, 60–240) after treatment (p < 0.001). Improvements in QoL during afamelanotide treatment were measured using two QoL tools, with good correlation observed between these two instruments. Finally, we found no improvements in the median levels of metal-free erythrocyte protoporphyrin, plasma protoporphyrin, or liver biochemistries during versus prior to the initiation of afamelanotide treatment. Conclusions: This study highlights a dramatic clinical benefit of afamelanotide in relation to light tolerance and QoL in protoporphyria, albeit without improvement in protoporphyrin levels or measures of liver function.

Erythropoietic protoporphyria and X-linked protoporphyria are rare genetic photodermatoses. Limited expertise with these disorders among physicians leads to diagnostic delays. Here, we present evidence-based consensus guidelines for the diagnosis, monitoring, and management of erythropoietic proto-porphyria and X-linked protoporphyria. A systematic literature review was conducted, and reviewed among subcommittees of experts, divided by topic. Consensus on guidelines was reached within each subcommittee and then among all members of the committee. The appropriate biochemical and genetic testing to establish the diagnosis is reviewed in addition to the interpretation of results. Prevention of symptoms, management of acute phototoxicity, and pharmacologic and nonpharmacologic treatment options are discussed. The importance of ongoing monitoring for liver disease, iron deficiency, and vitamin D deficiency is discussed with management guidance. Finally, management of pregnancy and surgery and the safety of other therapies are summarized. We emphasize that these are multisystemic disorders that require longitudinal monitoring. These guidelines provide a structure for evidence-based diagnosis and management for practicing physicians. Early diagnosis and management of these disorders are essential, particularly given the availability of new and emerging therapies. ( J Am Acad Dermatol 2023;89:1227-37.)