The Porphyrias¶
Chapter 428 | Part 12: Endocrinology and Metabolism · Part 12 – Endocrinology & Metabolism · Chapter 428
Key Clinical Points¶
- Porphyrias are metabolic disorders resulting from the deficiency or increased activity of a specific enzyme in the heme biosynthetic pathway.
- Classification is based on site of origin (Hepatic vs. Erythropoietic) and clinical presentation (Acute/Neurovisceral vs. Cutaneous/Photosensitivity).
- Acute hepatic porphyrias (AIP, HCP, VP) present with neurovisceral symptoms (abdominal pain, neuropathy, mental disturbances), often triggered by drugs, alcohol, fasting, or hormones.
- Cutaneous porphyrias (PCT, CEP, EPP, XLP) present with photosensitivity; differentiation requires specific porphyrin profiles in urine, plasma, and feces.
- Heme synthesis involves 8 enzymatic steps and 9 genes; regulation differs between the liver (ALAS1) and erythron (ALAS2).
- AIP is common (~1 in 20,000 Caucasians; ~1 in 10,000 in Sweden); EPP is more common but varies by ethnicity; CEP is very rare (~200 cases worldwide).
- Urinary PBG is highly sensitive and specific for acute attacks of AIP, HCP, and VP.
- Genetic testing (mutation analysis) is the gold standard for definitive diagnosis and prenatal counseling.
- Acute attacks are treated with hemin or givosiran; maintenance involves avoiding porphyrinogenic drugs, alcohol, fasting, and certain hormones.
- Pregnancy: Acute porphyrias are generally well-tolerated; zinc chelation is safe, but other chelators are teratogenic.
DEFINITION & OVERVIEW¶
• Definition: Metabolic disorders resulting from the deficiency or increased activity of a specific enzyme in the heme biosynthetic pathway. • Inheritance: ◦ Most are autosomal dominant (AIP, HCP, VP) or autosomal recessive (ADP). ◦ Erythropoietic porphyrias are autosomal recessive (CEP, EPP) or X-linked (XLP). ◦ Porphyria cutanea tarda (PCT) is typically sporadic. • Classification: ◦ By Site: Hepatic (liver origin) vs. Erythropoietic (erythrocyte origin). ◦ By Presentation: Acute (neurovisceral) vs. Cutaneous (photosensitivity). • Clinical Manifestations: ◦ Acute Hepatic Porphyrias (AIP, HCP, VP): Characterized by neurovisceral symptoms including abdominal pain, peripheral motor neuropathy, and mental disturbances. ◦ Cutaneous Porphyrias (PCT, CEP, EPP, XLP): Characterized by photosensitivity; skin damage results from the excitation of excess porphyrins by long-wave ultraviolet light. • Diagnosis: ◦ Requires measurement of porphyrin precursors (5-aminolevulinic acid [ALA] and porphobilinogen [PBG]) in urine, or porphyrins in urine, plasma, feces, or erythrocytes. ◦ Definitive diagnosis requires identification of the specific gene mutation.
Detailed Classification¶
• Acute Hepatic Porphyrias: ◦ AIP, HCP, and VP. ◦ Symptoms: Neurovisceral (NV) manifestations. ◦ Diagnosis: Elevated urinary PBG. • ADP: Autosomal recessive; elevated ALA with normal or slightly elevated PBG. • Cutaneous Porphyrias: ◦ CEP: Severe blistering, similar to PCT but more severe. ◦ EPP & XLP: Immediate, severe, painful, and non-blistering photosensitivity. ◦ EPP Prevalence: 20% of patients develop minor liver issues; up to ~5% develop hepatic complications requiring transplant.
EPIDEMIOLOGY¶
• Acute Hepatic Porphyrias (Autosomal Dominant): ◦ AIP: ~1 in 20,000 Caucasians; ~1 in 10,000 in Sweden. ◦ VP: High prevalence (>10,000) in South Africa due to a 'founder effect'. • ADP (Autosomal Recessive): Extremely rare (<20 cases worldwide). • Erythropoietic Porphyrias: ◦ EPP: Most common porphyria; 1 in ~75,000 to 1 in ~150,000 Caucasians. (Common low expression allele present in ~30% of Japanese). ◦ CEP: Very rare (~200 cases worldwide). • PCT Prevalence: Correlates with higher rates of Hepatitis C and HIV.
ETIOLOGY & PATHOPHYISIOLOGY¶
• Heme Biosynthesis Overview: ◦ 8 enzymatic steps; 9 genes. ◦ Mitochondrial enzymes: 1st, 7th, and 8th (Note: some sources describe these as the first and last three). ◦ Cytosolic enzymes: 2nd, 3rd, 4th, and 5th. • Tissue-Specific Regulation: ◦ Liver (Housekeeping): ◦ Regulated by 'free' heme; high heme represses ALAS1 mRNA and mitochondrial transport. ◦ Induced by drugs/steroids that also induce CYP enzymes. ◦ Erythron (Specialized): ◦ ALAS2 is expressed at higher levels than housekeeping enzyme. ◦ Regulated by cell differentiation and iron transport mechanisms. • Key Enzyme Roles: ◦ ALA-synthase (ALAS1/ALAS2): Rate-limiting; first step. ◦ HMB-synthase (HMBS): Also known as PBG-deaminase; second rate-limiting step. ◦ URO-decarboxylase (UROD): Converts URO'gen III to COPRO'gen III. ◦ COPRO-oxidase (CPOX): Converts COPRO'gen III to PROTO'gen IX (releases 2 CO_2 and 2 H). ◦ PROTO-oxidase (PPOX): Oxidizes PROTO'gen IX to protoporphyrin IX. ◦ FECH (Ferrochelatase): Inserts iron into protoporphyrin IX to form heme.
Regulation of Heme Biosynthesis¶
• Liver: ◦ Housekeeping ALAS1 is regulated in a coordinated fashion with CYP enzymes. ◦ Drugs inducing hepatic ALAS-1 also induce CYP gene expression. • Erythron: ◦ Distinct nonerythroid and erythroid-specific transcripts are known for the first four enzymes. ◦ For the next three genes, both types of transcripts are produced from single genes via alternative promoters.
CLINICAL FEATURES¶
• Acute Hepatic Porphyrias: ◦ Symptoms: Abdominal pain, nausea, vomiting, tachycardia, hypertension, motor neuropathy. ◦ Triggers: Drugs (CYP inducers), alcohol, fasting, steroids, hormones (estrogens/progestins). ◦ Gender: More common in women; premenstrual attacks linked to progesterone. ◦ Pregnancy: Usually well-tolerated due to favorable metabolic changes. • Homozygous AIP (HD-AIP): ◦ Rare; <2% enzyme activity. ◦ Presentation: Infancy, failure to thrive, developmental delay, cataracts, hepatosplenomegaly. • Cutaneous Porphyrias: ◦ Mechanism: UV light excites excess porphyrins → cell damage/scarring. ◦ EPP: Non-blistering, painful; 20% have liver issues (up to 5% require transplant). ◦ XLP: Similar to EPP but with higher levels of both free and zinc protoporphyrin.
Specific Clinical Profiles¶
• ADP: ◦ Presentation varies by residual activity. ◦ High deficiency → infant failure to thrive. ◦ Low deficiency → adult motor polyneuropathy.
DIAGNOSTIC APPROACH¶
- Initial Screening (Acute): ◦ Measure spot urine PBG. ◦ Result: \uparrow\uparrow PBG → highly specific for AIP, HCP, or VP.
- Differentiation of Acute Porphyrias: ◦ Use same spot sample to measure total urinary porphyrins, fecal porphyrins, and plasma porphyrins. ◦ Differentiation: ◦ HCP: \uparrow Coproporphyrin III in urine/feces. ◦ VP: \uparrow Coproporphyrin III and Protoporphyrin in urine/feces; distinct fluorescence peak at neutral pH.
- Cutaneous Porphyria Diagnosis: ◦ Measure plasma porphyrins (flurometric method preferred). ◦ EPP: \uparrow free protoporphyrin (not zinc protoporphyrin). ◦ XLP: \uparrow both free and zinc protoporphyrin.
- Confirmatory Testing: ◦ Genetic testing (mutation analysis) of specific genes (HMBS, COPRO, PPOX, FECH, ALAS2).
Diagnostic Algorithm (Table 3)¶
• Neurovisceral Path: ◦ Spot U: \uparrow\uparrow ALA and normal PBG → ADP. ◦ Spot U: \uparrow\uparrow PBG → AIP, HCP, or VP (distinguished by U, P, F porphyrin profiles). • Blistering Skin Lesions: ◦ P: \uparrow porphyrins → PCT/HEP, HCP, VP, CEP, EPP, XLP. ◦ Differentiation: ◦ EPP: \downarrow\downarrow RBC HMB-synthase; \uparrow free PROTO. ◦ XLP: \uparrow\uparrow both free and zinc PROTO.
MANAGEMENT & TREATMENT¶
- Acute Attack Management: ◦ Immediate treatment with hemin or givosiran.
- Maintenance Therapy: ◦ Identify and avoid porphyrinogenic drugs (refer to Drug Database for Acute Porphyrias). ◦ Avoid alcohol, fasting, and low-calorie diets.
- Pregnancy Management: ◦ Maintenance chelation with zinc is safe. ◦ Warning: Avoid other chelators due to teratogenicity.
- Genetic Counseling: ◦ Use mutation analysis for definitive diagnosis and prenatal counseling.
PROGNOSIS & COMPLICATIONS¶
• Acute Porphyrias: ◦ Generally well-tolerated in pregnancy. ◦ Risk of permanent neurological damage if attacks are severe/prolonged. • Erythropoietic Porphyrias: ◦ EPP: 20% develop liver issues; 5% may require transplant. ◦ XLP: Similar to EPP with potential for liver disease.
KEY PEARLS & HIGH-YIELD POINTS¶
• Rule of Thumb: Spot urine PBG is the most sensitive/specific test for acute attacks. • Differentiation: Use porphyrin profiles (U, P, F) to distinguish between AIP, HCP, and VP. • Safety: Pregnancy is usually well-tolerated in acute porphyrias; zinc is the only safe chelator. • Genetics: Mutation analysis can be performed even if biochemical markers have returned to normal.
FLOWCHARTS¶
Heme Biosynthetic Pathway & Clinical Correlation (Flowchart 1)¶
• Pathway Sequence: 1. δ-Aminolevulinic acid → [ALA-synthase] → Path: XSLA 2. δ-Aminolevulinic acid → [ALA-dehydratase] → Path: ADP 3. Porphobilinogen → [Hydroxymethylbilane synthase] → Path: CEP 4. Hydroxymethylbilane → [Uroporphyrinogen decarboxylase] → Path: PCT/HEP 5. Coproporphyrinogen III → [Coproporphyrinogen oxidase] → Path: HCP 6. Protoporphyrinogen IX → [Protoporphyrinogen oxidase] → Path: VP 7. Protoporphyrin IX → [Ferrochelatase] → Path: EPP • Regulation: Heme provides negative feedback at the ALA-synthase and Ferrochelatase steps.
Heme Biosynthetic Pathway & Biochemistry (Flowchart 2)¶
• Pathway Steps: 1. Coproporphyrin III → [decarboxylase] → Protoporphyrin IX (releases 4 ext{CO}_2) 2. Coproporphyrin III → [COPRO-oxidase] → Protoporphyrin IX (releases 2 ext{CO}_2 and 2 ext{H}) 3. Protoporphyrin IX → [PROTO-oxidase] → Heme • Location: ◦ 4 enzymes in cytosol. ◦ 4 enzymes in mitochondria.
TABLES & FIGURES¶
Table 1: Human Porphyrias Clinical/Lab Features¶
• ADP: ALA-dehydratase; AR; NV symptoms; \uparrow ALA, coproporphyrin III. • AIP: HMB-synthase; AD; NV symptoms; \uparrow PBG, URO, and COPRO. • PCT: URO-decarboxylase; AD; CP symptoms; \uparrow Uroporphyrin, 7-carboxylate porphyrin. • HCP: Coproporphyrinogen oxidase; AD; NV/CP; \uparrow Coproporphyrin III. • VP: Protoporphyrinogen oxidase; AD; NV/CP; \uparrow Coproporphyrin III, protoporphyrin. • CEP: URO-synthase; AR; CP symptoms; \uparrow Uroporphyrin I, Coproporphyrin I. • EPP: Ferrochelatase; AR; CP symptoms; \uparrow Protoporphyrin (free). • XLP: ALAS-synthase 2; XL; CP symptoms; \uparrow Protoporphyrin (free and zinc).
Table 2: Heme Biosynthetic Enzymes and Genes¶
• ALAS-synthase: ◦ Housekeeping (ALAS1): 3p21.1; 2199 bp; 17 exons; 640 aa. ◦ Erythroid-specific (ALAS2): Xp11.2; 1937 bp; 22 exons; 587 aa. • HMB-synthase (HMBS): 11q23.3; 1086 bp; 11 exons; 361 aa. • URO-decarboxylase (UROD): 1p34.1; 1104 bp; 3 exons; 367 aa. • Coproporphyrinogen oxidase (CPOX): 3q12.1; 1062 bp; 14 exons; 354 aa. • Protoporphyrinogen oxidase (PPOX): 1q23.3; 1431 bp; 5.5 exons; 477 aa. • Ferrochelatase (FECH): 18q21.31; 1269 bp; 45 exons; 423 aa.
Table 3: Diagnosis of Acute and Cutaneous Porphyrias¶
• Neurovisceral Path: ◦ \uparrow ALA/Normal PBG → ADP. ◦ \uparrow PBG → AIP, HCP, or VP (distinguished by U, P, F porphyrin profiles). • Cutaneous Path: ◦ \uparrow P porphyrins → PCT/HEP, HCP, VP, CEP, EPP, XLP. ◦ Differentiation: ◦ EPP: \downarrow\downarrow RBC HMB-synthase; \uparrow free PROTO. ◦ XLP: \uparrow\uparrow both free and zinc PROTO.
Reference Tables¶
TABLE 428-1 Human Porphyrias: Major Clinical and Laboratory Features PORPHYRIA Hepatic Porphyrias 5-ALA-dehydratase-…¶
Harrison's 22e, p.3341
| PORPHYRIA | DEFICIENT ENZYME |
INHERITANCE | PRINCIPAL SYMPTOMS: NV OR CP+ |
ENZYME ACTIVITY % OF NORMAL |
INCREASED PORPHYRIN PRECURSORS AND/OR PORPHYRINS | ||
|---|---|---|---|---|---|---|---|
| ERYTHROCYTES | URINE | STOOL | |||||
| Hepatic Porphyrias | |||||||
| 5-ALA-dehydratase- deficient porphyria (ADP) |
ALA- dehydratase |
AR | NV | ~5 | Zn-protoporphyrin | ALA, coproporphyrin III | — |
| HMB-synthase | AD | NV | ~50 | — | ALA, PBG, uroporphyrin | ||
| Porphyria cutanea tarda (PCT) |
URO- decarboxylase |
AD | CP | ~20 | — | Uroporphyrin, 7-carboxylate porphyrin |
Isocoproporphyrin |
| COPRO-oxidase | AD | NV and CP | ~50 | — | ALA, PBG, coproporphyrin III | ||
| Variegate porphyria (VP) | PROTO-oxidase | AD | NV and CP | ~50 | — | ALA, PBG, coproporphyrin III | Coproporphyrin III, protoporphyrin |
| Erythropoietic Porphyrias | |||||||
| Congenital erythropoietic porphyria (CEP) |
URO-synthase | AR | CP | 1–5 | Uroporphyrin I Coproporphyrin I |
Uroporphyrin Ia Coproporphyrin Ia |
Coproporphyrin I |
| Ferrochelatase | AR | CP | ~20–30 | Protoporphyrin | — | ||
| X-linked protoporphyria (XLP) |
ALA-synthase 2 | XL | CP | >100b | Protoporphyrin | — | Protoporphyrin |
TABLE 428-2 Human HEME Biosynthetic Enzymes and Genes ENZYME ALA-synthase¶
Harrison's 22e, p.3342
| ENZYME | GENE SYMBOL |
CHROMOSOMAL LOCATION |
CDNA (bp) | GENE | PROTEIN (aa) |
SUBCELLULAR LOCATION |
KNOWN MUTATIONSb |
THREE- DIMENSIONAL STRUCTUREc |
|
|---|---|---|---|---|---|---|---|---|---|
| SIZE (KB) | EXONSa | ||||||||
| ALA-synthase | |||||||||
| Housekeeping | ALAS1 | 3p21.1 | 2199 | 17 | 11 | 640 | M | — | |
| Erythroid-specific | ALAS2 | Xp11.2 | 1937 | 22 | 11 | 587 | M | >30 | — |
| ALAD ALAD |
9q32 9q32 |
1149 1154 |
15.9 15.9 |
12 (1A + 2 – 12) 12 (1B + 2 – 12) |
330 330 |
C C |
12 — |
||
| HMB-synthase | |||||||||
| Housekeeping | HMBS | 11q23.3 | 1086 | 11 | 15 (1 + 3 – 15) | 361 | C | 400 | E |
| Erythroid-specific | HMBS | 11q23.3 | 1035 | 11 | 15 (2 – 15) | 344 | C | 10 | |
| UROS UROS |
10q26.2 10q26.2 |
1296 1216 |
34 34 |
10 (1 + 2B – 10) 10 (2A + 2B – 10) |
265 265 |
C C |
45 4 |
||
| URO-decarboxylase | UROD | 1p34.1 | 1104 | 3 | 10 | 367 | C | 122 | H |
| CPOX | 3q12.1 | 1062 | 14 | 7 | 354 | M | 70 | ||
| PROTO-oxidase | PPOX | 1q23.3 | 1431 | 5.5 | 13 | 477 | M | 181 | — |
| FECH | 18q21.31 | 1269 | 45 | 11 | 423 | M | 192 |
TABLE 428-3 Diagnosis of Acute and Cutaneous Porphyrias SYMPTOMS Neurovisceral¶
Harrison's 22e, p.3343
| SYMPTOMS | FIRST-LINE TEST: ABNORMALITY |
POSSIBLE PORPHYRIA |
SECOND-LINE TESTING IF FIRST-LINE TESTING IS POSITIVE: TO INCLUDE: URINE (U), PLASMA (P), AND FECAL (F) PORPHYRINS; FOR ACUTE PORPHYRIAS, ADD RED BLOOD CELL (RBC) HMB-SYNTHASE; FOR BLISTERING SKIN LESIONS, ADD P AND RBC PORPHYRINS |
CONFIRMATORY TEST: ENZYME ASSAY AND/OR MUTATION ANALYSIS |
|---|---|---|---|---|
| Neurovisceral | Spot U: ↑↑ALA and normal PBG |
ADP | U porphyrins: ↑↑, mostly COPRO III P and F porphyrins: normal or slightly ↑ RBC HMB-synthase: normal |
Rule out other causes of elevated ALA; ↓↓RBC ALA-dehydratase activity (<10%); ALA-dehydratase mutation analysis |
| Spot U: ↑↑PBG | AIP | U porphyrins: ↑↑, mostly URO and COPRO P and F porphyrins: normal or slightly ↑ RBC HMB-synthase: usually ↓ |
HMB-synthase mutation analysis | |
| “ | HCP | U porphyrins: ↑↑, mostly COPRO III P porphyrins: normal or slightly ↑ (↑ if skin lesions present) F porphyrins: ↑↑, mostly COPRO III |
Measure RBC HMB-synthase: normal activity COPRO-oxidase mutation analysis |
|
| “ | VP | U porphyrins: ↑↑, mostly COPRO III P porphyrins: ↑↑ (characteristic fluorescence peak at neutral pH) F porphyrins: ↑↑, mostly COPRO and PROTO |
Measure RBC HMB-synthase: normal activity PROTO-oxidase mutation analysis |
|
| P: ↑ porphyrins | PCT and HEP | U porphyrins: ↑↑, mostly URO and heptacarboxylate porphyrin P porphyrins: ↑↑ F porphyrins: ↑↑, including increased isocoproporphyrin RBC porphyrins: ↑↑ zinc PROTO in HEPa |
||
| “ | HCP and VP | See HCP and VP above. Also, U ALA and PBG: may be ↑ | ||
| “ | CEP | RBC and U porphyrins: ↑↑, mostly URO I and COPRO I F porphyrins: ↑↑; mostly COPRO I |
||
| Nonblistering photosensitivity |
P: porphyrins usually ↑ |
EPP | RBC porphyrins: ↓↓, mostly free PROTO U porphyrins: normal F porphyrins: normal or ↓, mostly PROTO |
FECH mutation analysis |
| P: porphyrins usually ↑ |
XLP | RBC porphyrins: ↑↑, approximately equal free and zinc PROTO U porphyrins: normal F porphyrins: normal or ↑, mostly PROTO |
ALAS2 mutation analysis |