Clinical Pharmacist and Master’s student in Clinical Pharmacy with research interests in pharmacovigilance, behavioral interventions in mental health, and AI applications in clinical decision support. Experience includes digital health research with Bloomsbury Health (London) and pharmacovigilance practice in patient support programs. Published work covers drug awareness among healthcare providers, postpartum depression management, and patient safety reporting. 
Clinical Pharmacist and Master’s student in Clinical Pharmacy with research interests in pharmacovigilance, behavioral interventions in mental health, and AI applications in clinical decision support. Experience includes digital health research with Bloomsbury Health (London) and pharmacovigilance practice in patient support programs. Published work covers drug awareness among healthcare providers, postpartum depression management, and patient safety reporting. What was reviewed?
This review provides a comprehensive synthesis of biochemical, genetic, and clinical insights surrounding disorders of heme biosynthesis, collectively termed the porphyrias. It examines the enzymatic steps within the heme pathway, explaining how inherited or acquired defects result in toxic accumulation of intermediates that manifest as neurovisceral or phototoxic syndromes. The article also emphasizes the crucial balance between genetic predisposition and environmental influences, particularly heavy metal exposure, that alter enzymatic activity in heme synthesis. Of special importance to the Heavy Metal Tested and Certified porphyria framework is the discussion of how metals such as lead interfere with zinc-dependent enzymes, notably δ-aminolevulinic acid dehydratase (ALAD) and ferrochelatase. These insights help define diagnostic biomarkers, exposure-response relationships, and biochemical thresholds essential for regulatory certification and public health guidance. The review thus integrates molecular pathology with clinical diagnostic standards and environmental toxicology, serving as an essential reference for bridging biomedical research with industrial metal safety regulations.
Who was reviewed?
The review evaluates research spanning diverse human populations affected by both hereditary and environmentally influenced porphyrias. These include patients with acute hepatic forms such as acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and δ-aminolevulinate dehydratase deficiency porphyria, as well as erythropoietic forms such as erythropoietic protoporphyria and congenital erythropoietic porphyria. The reviewed studies encompass genetic carriers, clinically affected individuals, and populations exposed to lead and other heavy metals that mimic porphyric patterns biochemically. Data were drawn from laboratory, epidemiologic, and clinical cohorts, allowing the review to present a multidimensional understanding of porphyria expression. This approach provides a framework for interpreting metal-induced enzyme inhibition in occupational or environmental settings and informs screening protocols under a certification scheme like the Heavy Metal Tested and Certified program.
Most important findings
| Critical Point | Details |
|---|---|
| Classification and tissue specificity | Porphyrias are organized by the primary tissue of expression (hepatic or erythroid) and by clinical presentation (acute or cutaneous). This classification determines which biological matrices, urine, plasma, erythrocytes, or feces yield diagnostic clarity, offering a template for testing protocols in certification standards. |
| Lead inhibition of heme enzymes | Lead disrupts two essential points in the heme pathway: it inhibits ALAD by displacing zinc and also suppresses ferrochelatase activity. The result is elevated urinary δ-aminolevulinic acid (ALA) and coproporphyrin without significant porphobilinogen (PBG) increase. These patterns establish specific biochemical fingerprints of lead exposure relevant to heavy metal regulatory testing. |
| Biochemical differentiation of ADP and lead toxicity | Erythropoietic protoporphyria and X-linked protoporphyria cause accumulation of protoporphyrin IX, occasionally leading to hepatic failure. These findings justify the inclusion of liver function and porphyrin fractionation in ongoing certification monitoring. |
| Triggers and biochemical kinetics in AIP | Acute intermittent porphyria is characterized by transient spikes in urinary PBG (up to 200 mg/day) and ALA during attacks, often triggered by drugs, alcohol, or hormonal factors that upregulate hepatic ALAS1. Recognition of these triggers guides chemical safety certification and exposure management in industrial environments. |
| Role of iron and UROD inhibition in PCT | Porphyria cutanea tarda results from hepatic uroporphyrinogen decarboxylase inhibition, with iron overload and oxidative stress playing major roles. Iron reduction restores enzyme activity, supporting the inclusion of ferritin and hepcidin monitoring in heavy metal certification frameworks. |
| Iron control of erythroid heme synthesis | The erythroid-specific enzyme ALAS2 is translationally regulated by iron through iron-responsive elements, ensuring synthesis proceeds only when iron is sufficient. This molecular control links iron metabolism to porphyrin accumulation and validates iron balance assessment in industrial health certification. |
| Protoporphyria and hepatic outcomes | Erythropoietic protoporphyria and X-linked protoporphyria cause accumulation of protoporphyrin IX, occasionally leading to hepatic failure. These findings justify inclusion of liver function and porphyrin fractionation in ongoing certification monitoring. |
| Environmental phenocopies | Lead poisoning and metabolic disorders such as tyrosinemia can phenotypically mimic acute porphyrias through ALAD inhibition or ALA accumulation, underscoring the necessity for confirmatory testing and chemical differentiation in certification analyses. |
Key implications
For regulatory frameworks, establishing heme pathway biomarkers as heavy metal indicators provides a mechanistic foundation for exposure limits. Certification programs must incorporate matrix-specific testing for urine for ALA and PBG, plasma for porphyrins, and erythrocytes for enzyme assays to ensure comprehensive detection. These insights strengthen certification validity by linking biochemical impairment directly to exposure rather than symptomatology. Industrial applications include screening for subclinical inhibition of ALAD and ferrochelatase in high-risk sectors such as battery, pigment, and metallurgy manufacturing. Research gaps include quantifying exposure thresholds that produce measurable enzyme inhibition and elucidating hepcidin’s role in metal–iron interplay. Practically, Heavy Metal Tested and Certified guidelines should define biological reference intervals, enforce pre- and post-exposure sampling schedules, and integrate genotypic confirmation to distinguish inherited porphyrias from toxicologic mimics.
Citation
Phillips JD. Heme biosynthesis and the porphyrias. Molecular Genetics and Metabolism. 2019;128(3):164–177. doi.org/10.1016/j.ymgme.2019.04.008
