Porphyria is a group of rare inherited metabolic disorders caused by deficiencies in specific enzymes in the heme synthesis pathway. The disease can manifest as multiple systemic involvements, including the skin, digestive system, and nervous system. Previous studies have found that some patients with porphyria test positive for autoantibodies, making porphyria easily confused with autoimmune diseases. Our article analyzes the clinical, immunologic, and genetic characteristics of patients diagnosed with porphyria at our institution, with a focus on immunological features and autoantibody prevalence. The objective was to provide clinicians with a more comprehensive basis for differential diagnosis.

A retrospective review of all patients with porphyria from 2000 to the present seen at our institution was performed. In addition, searches were conducted on PubMed and CNKI using the keywords "Porphyria cutanea tarda", "Acute intermittent porphyria", "Erythropoietic protoporphyria", "Hereditary coproporphyria", "delta-aminolevulinate dehydratase (ALA-D) porphyria", "Variegate porphyria", and “X-Linked protoporphyria”, limiting the article type to "Case Report" and the search time range to 2000 to the present. Supplementary searches were also conducted on Web of Science, Embase, Scopus, VIP, and Wanfang, including cases that underwent both genetic testing and antinuclear antibody (ANA) testing (Most PCT porphyria are acquired; genetic testing and/or pathological biopsy and/or porphyrin metabolite testing are considered the gold standard).

Our study enrolled 26 patients with porphyria who presented to our hospital; 18 (69.2%) exhibited multisystem involvement. 11.5% (3/26) of the patients met the classification criteria for autoimmune diseases. Some patients met criteria for autoimmune diseases, underscoring the clinical importance of immunological findings. Of the 20 patients tested for the Comprehensive Immunological Panel, 45% (9/20) showed decreased complement C3 or C4 levels, and 35% (7/20) had immunoglobulin G (IgG) abnormalities. Of the 21 patients tested for autoantibodies, eight (38.1%) were positive for at least one autoantibody. Among the hepatic porphyria group, 2 of 7 tested (28.6%) were ANA-positive; both were porphyria cutanea tarda (PCT) patients carrying HFE or UROD mutations. In patients with erythropoietic protoporphyria (EPP) linked to FECH gene mutations, two of three tested (66.7%) were ANA-positive. In this cohort of 26 patients with porphyria, six were initially suspected of having an autoimmune disease; however, final diagnostic results revealed that only one patient had a real co-occurring connective tissue disease.

Including our index case, 103 patients with porphyria were included in the study: 32 with EPP, 31 with acute intermittent porphyria (AIP), 30 with PCT, 4 with variegate porphyria (VP), 3 with hereditary coproporphyria (HCP), 2 with congenital erythropoietic porphyria (CEP), and 1 with ALA-D porphyria (ADP). Of these, 12 patients (10 with PCT, 1 with HCP, and 1 with AIP) had coexisting autoimmune diseases, including SLE, Sjögren’s syndrome, systemic sclerosis, and other connective tissue diseases, and all were ANA-positive. To assess differences in ANA positivity among porphyria subtypes and reduce potential confounding from concomitant autoimmune diseases, these 12 patients were excluded from subsequent analyses.

After exclusion of patients with clearly defined concomitant autoimmune diseases, the overall ANA positivity rate in the remaining 91 patients with porphyria was 14.2% (13/91). Among the three major subtypes, ANA positivity was 9.4% (3/32) in EPP, 13.3% (4/30) in AIP, and 25.0% (5/20) in PCT. Fisher’s exact test revealed no significant difference among the three groups (P = 0.3254), despite a numerically higher rate in PCT. Notably, 33.3% (10/30) of patients with PCT had coexisting autoimmune diseases.

We found that patients with PCT may be more likely to have positive ANA, but there was no significant difference in ANA positivity rates among porphyria subtypes. The presence of these autoantibodies is associated with acute-onset clinical symptoms, suggesting a possible link between persistent oxidative stress and phototoxicity caused by protoporphyrin accumulation. Furthermore,  one-third of patients with PCT had concomitant autoimmune diseases. This finding emphasizes that, in clinical practice, when evaluating patients with suspected porphyria—particularly PCT—who are positive for antinuclear antibodies, clinicians should carefully differentiate porphyria from systemic autoimmune disorders such as SLE. Recognizing coexisting autoimmune disease is crucial for appropriate management, underscoring the importance of accurate differential diagnosis in clinical practice.