IMPORTANCE Autosomal recessive erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare photodermatoses presenting with variable degrees of painful phototoxicity that markedly affects quality of life. The clinical variability, determinants of severity, and genotype/phenotype correlations of these diseases are not well characterized.OBJECTIVE To describe the baseline clinical characteristics, genotypes, and determinants of disease severity in a large patient cohort with EPP or XLP. DESIGN, SETTING, AND PARTICIPANTSA prospective observational study was conducted among patients with confirmed diagnoses of EPP or XLP from November 1, 2010, to December 6, 2015, at 6 academic medical centers of the Porphyrias Consortium of the National Institutes of Health Rare Diseases Clinical Research Network. Detailed medical histories, including history of phototoxicity and treatment, were collected on standardized case report forms. Patients underwent baseline laboratory testing, total erythrocyte protoporphyrin (ePPIX) testing, and molecular genetic testing. Data were entered into a centralized database. MAIN OUTCOMES AND MEASURES Results of biochemical and genetic tests were explored for association with clinical phenotype in patients with EPP or XLP. RESULTS Of the 226 patients in the study (113 female and 113 male patients; mean [SD] age, 36.7 [17.0] years), 186 (82.3%) had EPP with a FECH (OMIM 612386) mutation and the common low-expression FECH allele IVS3-48T>C, and only 1 patient had 2 FECH mutations.Twenty-two patients had XLP (9.7%; 10 male and 12 female patients), and 9 patients (4.0%) had elevated ePPIX levels and symptoms consistent with protoporphyria but no detectable mutation in the FECH or ALAS2 (OMIM 301300) gene. Samples of DNA could not be obtained from 8 patients. Patients' mean (SD) age at symptom onset was 4.4 (4.4) years. Anemia (107 [47.3%]), history of liver dysfunction (62 [27.4%]), and gallstones (53 [23.5%]) were commonly reported. Higher ePPIX levels were associated with earlier age of symptom onset (median ePPIX levels for those who developed symptoms before vs after 1 year of age, 1744 vs 1567 μg/dL; P = .02), less sun tolerance (median ePPIX levels for those reporting symptoms before vs after 10 minutes of sun exposure, 2233 vs 1524 μg/dL; P Յ .001), and increased risk of liver dysfunction (median ePPIX levels for those with liver dysfunction vs normal liver function, 2016 vs 1510 μg/dL; P = .003). Patients with EPP and FECH missense mutations had significantly lower ePPIX levels than those with other mutations (1462 vs 1702 μg/dL; P = .01). Male patients with XLP had significantly higher ePPIX levels, on average, than did patients with EPP (3574 vs 1669 μg/dL; P < .001). Marked clinical variability was seen in female patients with XLP owing to random X-chromosomal inactivation.CONCLUSIONS AND RELEVANCE These data suggest that higher ePPIX levels are a major determinant of disease severity and risk of liver dysfunction in patients with EPP or XLP. These findings provide a fra...

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Acute intermittent porphyria (AIP), the most common acute hepatic porphyria, is an autosomal-dominant disorder due to the half-normal activity of the heme biosynthetic enzyme, hydroxymethylbilane (HMB) synthase (1). Symptomatic heterozygotes, most (~90%) of which are women, experience episodic life-threatening acute neurovisceral attacks that typically begin with severe abdominal pain and may include hypertension, tachycardia, constipation, motor weakness and seizures. These attacks are precipitated by certain drugs, dieting and hormonal factors that increase the hepatic expression of 5-aminolevulinic acid synthase 1 (ALAS1) (1). When hepatic ALAS1 is induced, the half-normal activity of HMB synthase becomes ratelimiting, leading to decreased heme biosynthesis and depletion of the hepatic "free" heme pool. Depletion of the"free" heme pool leads to further induction of Acute intermittent porphyria (AIP) is an autosomal-dominant hepatic disorder caused by the half-normal activity of hydroxymethylbilane (HMB) synthase. Symptomatic individuals experience life-threatening acute neurovisceral attacks that are precipitated by factors that induce the hepatic expression of 5-aminolevulinic acid synthase 1 (ALAS1), resulting in the marked accumulation of the putative neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Here, we provide the first detailed description of the biochemical and pathologic alterations in the explanted liver of an AIP patient who underwent orthotopic liver transplantation (OLT) due to untreatable and debilitating chronic attacks. After OLT, the recipient's plasma and urinary ALA and PBG rapidly normalized, and her attacks immediately stopped. In the explanted liver, (a) ALAS1 mRNA and activity were elevated approximately ~3-and 5-fold, and ALA and PBG concentrations were increased ~3-and 1,760-fold, respectively; (b) uroporphyrin III concentration was elevated; (c) microsomal heme content was sufficient, and representative cytochrome P450 activities were essentially normal; (d) HMB synthase activity was approximately half-normal (~42%); (e) iron concentration was slightly elevated; and (f) heme oxygenase I mRNA was increased approximately three-fold. Notable pathologic findings included nodular regenerative hyperplasia, previously not reported in AIP livers, and minimal iron deposition, despite the large number of hemin infusions received before OLT. These findings suggest that the neurovisceral symptoms of AIP are not associated with generalized hepatic heme deficiency and support the neurotoxicity of ALA and/or PBG. Additionally, they indicate that substrate inhibition of hepatic HMB synthase activity by PBG is not a pathogenic mechanism in acute attacks.

Cirrhosis resulting from hepatitis C virus is presently the most common indication for liver transplantation (OLT) in the United States. A number of U.S. transplant centers require cirrhotics who are using methadone to discontinue it before proceeding with OLT. We sought to examine the outcomes of those patients who had undergone OLT at the Mount Sinai Medical Center.A retrospective chart review of 36 subjects on methadone maintenance treatment (MMT), and off heroin, at the time of OLT was performed.The median daily methadone dose pre-OLT was 50 mg. Post-OLT, there was an increase in methadone dose in 15 subjects, a decrease in four subjects, and no dose change in 17 subjects. Four subjects had documented single episodes of intravenous drug use post-OLT; only one subject had a dose change after the event. Patient and graft survival rates were comparable to the national average.There was no significant difference in post-OLT outcome in patients on MMT when compared with the general population. The few episodes of drug relapse were not related to changes in the methadone dose. Efforts should be made to allow methadoneusing cirrhotics better access to OLT without regard to methadone dosage.

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: Rates of ACR and high-degree ACR are decreased in living-related liver transplant recipients. This difference is likely genetically related as ACR rates are lower in recipient-donor pairs of increasing genetic similarity.

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