Chapter 428: The Porphyrias¶
Chapter 428 | Part 12: Endocrinology and Metabolism
KEY CLINICAL POINTS¶
- Porphyrias are metabolic disorders caused by enzyme deficiencies in heme biosynthesis, classified as hepatic or erythropoietic.
- Acute hepatic porphyrias (AIP, HCP, VP) present with neurovisceral symptoms, while erythropoietic porphyrias (EPP, XLP, CEP) manifest with cutaneous photosensitivity.
- Diagnosis relies on urinary porphyrin precursors (ALA, PBG), fecal porphyrins, and genetic testing for specific enzyme mutations.
- Treatment includes avoiding triggers, heme derivatives (hemin), gene therapy, and iron chelation for porphyria cutanea tarda (PCT).
- Special considerations include pregnancy management, genetic counseling, and differential diagnosis with other heme disorders.
1. DEFINITION & OVERVIEW¶
Porphyrias are metabolic disorders resulting from defects in heme biosynthesis enzymes. They are classified as hepatic (liver-derived porphyrin accumulation) or erythropoietic (bone marrow/erythrocyte-derived).
Table 428-1: Human Porphyrias: Major Clinical and Laboratory Features¶
| PORPHYRIA | DEFICIENT ENZYME | INHERITANCE | PRINCIPAL SYMPTOMS | ENZYME ACTIVITY % | INCREASED PORPHYRINS |
|---|---|---|---|---|---|
| Acute Intermittent Porphyria (AIP) | 5-ALA-dehydrata se | AD | Neurovisceral | ~50 | ALA, PBG, uroporphyrin |
| Porphyria Cutanea Tarda (PCT) | URO-decarboxyl ase | AD | Cutaneous photosensitivity | ~20 | Uroporphyrin, he ptacarboxylate porphyrin |
| Hereditary Coproporphyria (HCP) | COPRO-oxidase | AD | Neurovisceral/cu taneous | ~50 | Coproporphyrin III |
| Variegate Porphyria (VP) | PROTO-oxidase | AD | Neurovisceral/cu taneous | ~50 | Coproporphyrin III, protoporphyrin |
| Congenital Erythropoietic Porphyria (CEP) | URO-synthase | AR | Cutaneous photosensitivity | 1–5 | Uroporphyrin I, coproporphyrin I |
| Erythropoietic Protoporphyria (EPP) | Ferrochelatase | AR | Cutaneous photosensitivity | ~20–30 | Protoporphyrin |
| PORPHYRIA | DEFICIENT ENZYME | INHERITANCE | PRINCIPAL SYMPTOMS | ENZYME ACTIVITY % | INCREASED PORPHYRINS |
|---|---|---|---|---|---|
| X-linked Protoporphyria (XLP) | ALA-synthase 2 | XL | Cutaneous photosensitivity | >100 | Protoporphyrin |
1.1 Classification¶
Hepatic porphyrias (AIP, HCP, VP, PCT) and erythropoietic porphyrias (EPP, XLP, CEP) are distinguished by site of porphyrin overproduction. PCT is the most common, often sporadic, while CEP is rare and autosomal recessive.
1.2 Pathophysiology¶
Defects in enzymes like ALAS1, HMBS, UROD, or FECH disrupt heme synthesis, leading to porphyrin precursor accumulation. Environmental factors (drugs, hormones) and genetic mutations interact to trigger acute attacks.
2. EPIDEMIOLOGY¶
Acute hepatic porphyrias (AIP, HCP, VP) are autosomal dominant, with AIP prevalence ~1 in 20,000 Caucasians. PCT is sporadic or familial, more common in regions with hepatitis C/HIV prevalence. EPP is most common, while CEP is rare (<200 cases globally).
2.1 Risk Factors¶
Drugs (barbiturates, sulfonamides), hormones (estrogens), alcohol, fasting, and infections trigger acute attacks. Iron overload and hepatitis C/HIV increase PCT risk.
2.2 Demographics¶
AIP is common in Scandinavia and Great Britain. VP is prevalent in South Africa. CEP is rare, with consanguineous marriages contributing to its frequency.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Enzyme deficiencies in heme biosynthesis (ALA-synthase, HMBS, UROD, FECH) lead to porphyrin precursor accumulation. Genetic mutations (e.g., ALAS1, HMBS, UROD) and environmental triggers interact to cause disease.
Table 428-2: Heme Biosynthetic Enzymes and Genes¶
| ENZYME | GENE SYMBOL | CHROMOSO MAL LOCATION | CDNA (bp) | PROTEIN SIZE (KB) | EXONS | SUBCELLUL AR LOCATION |
|---|---|---|---|---|---|---|
| ALA-synthase | ALAS1 | 3p21.1 | 2199 | 17 | 11 | Mitochondria |
| ALA-synthase | ALAS2 | Xp11.2 | 1937 | 22 | 11 | Mitochondria |
| ALA-dehydrat ase | ALAD | 9q32 | 1149 | 15.9 | 12 | Cytoplasm |
| HMB-synthas e | HMBS | 11q23.3 | 1086 | 11 | 15 | Cytoplasm |
| URO-synthas e | UROS | 10q26.2 | 1296 | 34 | 10 | Cytoplasm |
| ENZYME | GENE SYMBOL | CHROMOSO MAL LOCATION | CDNA (bp) | PROTEIN SIZE (KB) | EXONS | SUBCELLUL AR LOCATION |
|---|---|---|---|---|---|---|
| URO-decarbo xylase | UROD | 1p34.1 | 1104 | 3 | 10 | Cytoplasm |
| COPRO-oxid ase | CPOX | 3q12.1 | 1062 | 14 | 7 | Mitochondria |
| PROTO-oxida se | PPOX | 1q23.3 | 1431 | 5.5 | 13 | Mitochondria |
| Ferrochelatas e | FECH | 18q21.31 | 1269 | 45 | 11 | Mitochondria |
3.1 Enzyme Deficiencies¶
ALAS1 (AIP), HMBS (AIP), UROD (PCT), FECH (EPP), ALAD (ADP), COPRO-oxidase (HCP), PROTO-oxidase (VP), URO-synthase (CEP).
3.2 Genetic Inheritance¶
Autosomal dominant (AIP, HCP, VP, PCT), autosomal recessive (ADP, CEP, EPP), or X-linked (XLP).
4. CLINICAL FEATURES¶
Acute hepatic porphyrias present with neurovisceral symptoms (abdominal pain, neuropathy), while erythropoietic porphyrias cause cutaneous photosensitivity. PCT has chronic blistering, and CEP causes severe cutaneous manifestations.
4.1 Acute Hepatic Porphyrias¶
Neurologic symptoms (pain, neuropathy), psychiatric manifestations (anxiety, hallucinations), and autonomic instability (tachycardia, hypertension).
4.2 Cutaneous Porphyrias¶
Blistering skin lesions, photosensitivity, scarring, and hypertrichosis. CEP has severe cutaneous involvement with nonimmune hydrops fetalis.
5. DIFFERENTIAL DIAGNOSIS¶
Distinguish from other heme disorders (e.g., hemochromatosis, lead poisoning), metabolic diseases, and psychiatric conditions. Consider hereditary tyrosinemia and lead toxicity in ALA-dehydratase deficiency.
6. INVESTIGATIONS & DIAGNOSIS¶
Urinary ALA and PBG levels, fecal porphyrins, plasma porphyrin analysis, and genetic testing. Fluorometric scanning distinguishes VP and PCT. Enzyme assays for specific mutations confirm diagnosis.
Table 428-3: Diagnosis of Acute and Cutaneous Porphyrias¶
| SYMPTOMS | FIRST-LINE TEST | POSSIBLE PORPHYRIA | SECOND-LINE TESTING | CONFIRMATORY TEST |
|---|---|---|---|---|
| Neurovisceral | Spot U: ››ALA, normal PBG | ADP | U porphyrins: ›› COPRO III | Mutation analysis |
| SYMPTOMS | FIRST-LINE TEST | POSSIBLE PORPHYRIA | SECOND-LINE TESTING | CONFIRMATORY TEST |
|---|---|---|---|---|
| Neurovisceral | Spot U: ››PBG | AIP | U porphyrins: ›› URO, COPRO | HMB-synthase assay |
| Blistering skin lesions | P: › porphyrins | PCT/HEP | U porphyrins: ›› URO, heptacarboxylate | URO-decarboxylase assay |
| Nonblistering photosensitivity | P: porphyrins › | EPP | RBC protoporphyrin flfl | FECH mutation analysis |
| Nonblistering photosensitivity | P: porphyrins › | XLP | RBC protoporphyrin ›› | ALAS2 mutation analysis |
6.1 Diagnostic Criteria¶
Urinary PBG elevation in AIP, HCP, VP; fecal porphyrins in CEP. Plasma porphyrin analysis for VP. Genetic testing for specific mutations.
6.2 Laboratory Tests¶
Quantitative porphyrin analysis, ALA-dehydratase activity, URO-decarboxylase assay, and FECH activity. DNA sequencing for mutation confirmation.
7. MANAGEMENT & TREATMENT¶
Avoid triggers (drugs, fasting), heme derivatives (hemin, givosiran), iron chelation for PCT, and gene therapy. Supportive care includes hydration, pain management, and transfusions for severe cases.
7.1 Acute Attacks¶
Intravenous hemin (3–4 mg/kg/day) or givosiran (2.5 mg/kg/month). Avoid barbiturates, phenytoin, and alcohol.
7.2 Long-term Management¶
Phlebotomy for PCT, chloroquine/hydroxychloroquine for porphyrin excretion, and iron chelation. Gene therapy (AAV-HMBS) for AIP.
8. PROGNOSIS & COMPLICATIONS¶
Acute attacks are treatable but may lead to liver failure or renal disease. Chronic complications include hepatic fibrosis, neuropathy, and anemia. PCT may progress to hepatocellular carcinoma.
8.1 Complications¶
Liver failure, renal disease, neuropathy, and hepatocellular carcinoma. PCT patients with hemochromatosis require iron chelation.
9. SPECIAL CONSIDERATIONS¶
Pregnancy: Avoid phlebotomy; use zinc acetate for chelation. Pediatric cases: EPP is most common, while CEP is rare. Elderly patients: Monitor for renal complications and drug interactions.
9.1 Pregnancy¶
Maintain copper chelation during pregnancy; avoid breastfeeding. Zinc acetate is preferred over penicillamine.
9.2 Pediatrics¶
EPP is most common in children; CEP presents with cutaneous photosensitivity and nonimmune hydrops fetalis.
10. KEY POINTS & CLINICAL PEARLS¶
- Porphyrias are metabolic disorders caused by heme biosynthesis enzyme defects.
- Acute attacks require heme derivatives (hemin, givosiran) and avoidance of triggers.
- PCT is managed with phlebotomy and iron chelation.
- Genetic testing confirms diagnosis and guides family counseling.
- EPP is the most common porphyria, while CEP is rare and severe.