What are the causes of elevated urine porphyrin levels?

Etiology of Urine Porphyrin Elevations

Elevated urine porphyrin levels are primarily caused by various types of porphyrias, which are characterized by specific patterns of porphyrin accumulation due to enzyme defects in the heme biosynthetic pathway.

Primary Causes: Porphyrias

Cutaneous Porphyrias

• Porphyria Cutanea Tarda (PCT): Characterized by elevated uro- and heptacarboxyl porphyrins in urine, with hepta-, penta-, and isocoproporphyrins predominating in feces 1, 2
• Hepatoerythropoietic Porphyria (HEP): Shows similar urinary, fecal, and plasma porphyrin patterns as PCT, though porphyrin concentrations may be higher; erythrocyte zinc-chelated protoporphyrin is typically increased 1
• Congenital Erythropoietic Porphyria (CEP): Characterized by increased concentration of porphyrins of the isomer I type in urine, feces, plasma, and erythrocytes 1, 3
• Erythropoietic Protoporphyria (EPP) and X-linked Erythropoietic Protoporphyria (XLEPP): Characterized by acute painful photosensitivity with plasma fluorescence typically around 628-636 nm 1

Acute Hepatic Porphyrias

• Acute Intermittent Porphyria (AIP): Characterized by elevated urinary porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) with a PBG/ALA ratio of approximately 2 in patients with normal renal function 1, 4
• Variegate Porphyria (VP): Presents with both acute attacks and bullous skin symptoms, with characteristic plasma fluorescence patterns 1
• Hereditary Coproporphyria (HCP): Can present with both acute attacks and bullous skin symptoms 1
• ALA Dehydratase Deficiency Porphyria (ALAD): Rare form of acute porphyria 5

Secondary Causes and Confounding Factors

Renal Disease

• End-Stage Renal Disease (ESRD): In patients with AIP and ESRD, the PBG/ALA ratio increases significantly (above 6), and plasma porphyrin levels can rise above 1000 nmol/L, causing cutaneous lesions resembling PCT 6
• Chronic Kidney Disease: Can affect porphyrin excretion and lead to accumulation, particularly in patients with underlying porphyrias 7

Secondary Porphyrinurias

• Non-specific increases: Many patients referred with presumptive diagnosis of porphyria actually have mild, nonspecific increases in urinary porphyrin excretion (secondary porphyrinurias) due to other etiologies 8
• Medication-induced: Some medications can induce cytochrome P450 enzymes, potentially triggering porphyrin accumulation 7, 9

Other Contributing Factors

• Alcohol consumption: Can exacerbate PCT and affect porphyrin levels 2, 9
• Hepatitis C virus infection: Associated with increased risk of developing PCT 2
• Iron overload or hereditary hemochromatosis: Can contribute to porphyrin accumulation, particularly in PCT 2
• Hormonal factors: Especially progestins, which can trigger attacks in patients with acute hepatic porphyrias 9

Diagnostic Considerations

Sample Collection and Analysis

• Light protection: Samples should be protected from light to avoid falsely low results 2
• Fractionation: Fractionation of porphyrins in urine is the standard approach for investigating potential porphyria diagnoses 1, 2
• Plasma fluorescence scanning: Recommended as a first-line analysis for patients with cutaneous symptoms suggestive of porphyria 1, 2

Persistence of Elevated Levels

• Long-term elevation: In AIP, urinary PBG can remain elevated for many years after an acute attack, with a half-life of approximately 10.6 years 4
• Variable normalization: ALA and PBG levels can fall quickly after an acute attack in patients with HCP or VP, while they may remain elevated for months to years in AIP 1

Pitfalls in Interpretation

• Avoid relying solely on total urine porphyrin tests: Fractionation is necessary for accurate diagnosis 2
• Avoid overdiagnosis: Mild and nondiagnostic elevations in urinary porphyrins are often incorrectly interpreted as indicating acute hepatic porphyria 1, 8
• Consider renal function: The PBG/ALA ratio increases in parallel to the impairment of glomerular filtration 1, 6

By understanding the specific patterns of porphyrin elevation in different porphyrias and considering potential secondary causes, clinicians can more accurately diagnose and manage patients with elevated urine porphyrin levels.