Hepatobiliary implications and complications in protoporphyria, a 20-year study

doi:10.1016/S0009-9120(89)80081-5

Clinical Biochemistry

Volume 22, Issue 3, June 1989, Pages 223-229

https://doi.org/10.1016/S0009-9120(89)80081-5 Get rights and content

Clinical and biochemical findings in 55 patients with protoporphyria are presented in a 20-year study. The patients revealed a history of photosensitivity, but in 6 cases the diagnosis was not established until a liver abnormality appeared. Protoporphyrin was elevated in erythrocytes and plasma, and also in the feces of most patients.

Signs of impaired liver function were observed in 19 patients (35%), also males predominated in this group 72%. Seven subjects (13%) suffered from liver cirrhosis. A female, aged 20, and a male, aged 22, died from fatal liver disease. Erythrocyte protoporphyrin levels in protoporphyria patients with liver complications were 38 ± 8 μmol/L (mean ± SEM) compared to 13 ± 2 (p < 0.001) for those patients without obvious liver involvement. Patients with hepatobiliary involvement exhibited a pathologic coproporphyrinuria (419 ± 21 nmol/24h; mean ± SEM) with an increase in the proportion of isomer I ranging between 43 and 91% of the total (normal value below 31%). Protoporphyrin accumulated in hepatic tissues to various degrees depending on the stage of the disease.

Our observations suggest that (a) pathologic coproporphyrinuria with an increase in isomer I serves as a sensitive parameter for recognizing subclinical and clinical hepatobiliary disease, (b) liver involvement may occur more frequently than has previously been reported, and (c) that treatment with cholic acids results in biochemical and clinical improvement.

The pathogenetic course from the erythropoietic disease to include hepatic involvement develops in phases. Protoporphyria should be designated as erythrohepatic.

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Autosomal recessive EPP associated with palmar keratoderma has also been associated with unexplained neurological symptoms [169]. Gallstones containing large amounts of protoporphyrin are common, and may require cholecystectomy at an unusually early age [187]. Liver function and liver protoporphyrin content are usually normal in EPP.
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Porphyrias may also be classified as either erythropoietic or hepatic, depending on the principal site of accumulation of pathway intermediates. The erythropoietic porphyrias are congenital erythropoietic porphyria (CEP), and erythropoietic protoporphyria (EPP). The acute hepatic porphyrias include ALA dehydratase deficiency porphyria, acute intermittent porphyria (AIP), hereditary coproporphyria (HCP) and variegate porphyria (VP). Porphyria cutanea tarda (PCT) is the only porphyria that has both genetic and/or environmental factors that lead to reduced activity of uroporphyrinogen decarboxylase in the liver.
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Accumulation of protoporphyrin IX (PPIX) and Zn-PPIX, are the clinical hallmarks of protoporphyria. Phenotypic expression of protoporphyria is due to decreased activity of ferrochelatase (FECH) or to increased activity of aminolevulinic acid synthase (ALAS) in red blood cells. Other genetic defects have been shown to contribute to disease severity including loss of function mutations in the mitochondrial AAA-ATPase, CLPX and mutations in the Iron-responsive element binding protein 2 (IRP2), in mice. It is clear that multiple paths lead to a common phenotype of excess plasma PPIX that causes a phototoxic reaction on sun exposed areas. In this study we examined the association between mitochondrial iron acquisition and utilization with activity of FECH. Our data show that there is a metabolic link between the activity FECH and levels of MFRN1 mRNA. We examined the correlation between FECH activity and MFRN1 mRNA in cell lines established from patients with the classical protoporphyria, porphyria due to defects in ALAS2 mutations. Our data confirm MFRN1 message levels positively correlated with FECH enzymatic activity in all cell types.
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The activity of the erythroid-specific isoenzyme of 5-aminolevulinic acid synthase (ALAS2), the first and rate-limiting enzyme in heme biosynthesis, is down-regulated during iron-deficiency. Ferrochelatase (FECH), the last enzyme of this pathway, inserts iron into protoporphyrin IX (PPIX) to form heme. Patients with erythropoietic protoporphyria (EPP), an inherited deficiency in FECH, often show signs of iron deficiency in addition to phototoxicity which is caused by PPIX accumulation. However, iron supplementation often leads to exacerbation of phototoxicity. We report three EPP patients who had reduced erythrocytic PPIX concentrations when they were iron-deficient and their microcytic and hypochromic anemia deteriorated. Additionally, we found a significant increase in the amount of ALAS2 mRNA and protein among EPP patients. To verify the connection between FECH deficiency and ALAS2 over-expression, we inhibited FECH in cultured cells and found a subsequent increase in ALAS2 mRNA. We conclude that the primary deficiency in ferrochelatase leads to a secondary increase in ALAS2 expression. The combined action of these two enzymes within the heme biosynthetic pathway contributes to the accumulation of PPIX. Furthermore, we hypothesize that EPP patients may benefit from a mild iron deficiency since it would limit PPIX production by restricting ALAS2 over-expression.
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View full text

Hepatobiliary implications and complications in protoporphyria, a 20-year study

Am J Med

Gastroenterology

Int J Biochem

Lancet

Am J Med

Clinics in Haematology

Gastroenterology

Am J Med

J Pediatr

Gastroenterology

Gastroenterology

Protoporphyria

Semin Liver Dis

Erythropoietic protoporphyria

Semin Dermatol

The histopathology and ultrastructure of liver disease in erythropoietic protoporphyria

Brit J Dermatol

Hepatic disease in erythropoietic protoporphyria

Dermatologica

Congenital erythropoietic protoporphyria. 1. Case reports, clinical studies and porphyrin analyses in two brothers

Blood

Hepatobiliary changes in erythropoietic protoporphyria

Arch Pathol

Erythropoietic porphyrin hepatitis

J Clin Pathol

Erythropoietic protoporphyria. A clinical and genetic study

JAMA

Genetic aspects of erythropoietic protoporphyria

Ann Hum Genet

Porphyrins and porphyrin precursors

A micromethod for free erythrocyte porphyrins: the FEP test

J Lab Clin Med