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The acute porphyrias, 4 inherited disorders of heme biosynthesis, cause life-threatening attacks of neurovisceral symptoms that mimic many other acute medical and psychiatric conditions. Lack of clinical recognition often delays effective treatment, and inappropriate diagnostic tests may lead to misdiagnosis and inappropriate treatment. We review the clinical manifestations, pathophysiology, and genetics of the acute porphyrias and provide recommendations for diagnosis and treatment on the basis of reviews of the literature and clinical experience. An acute porphyria should be considered in many patients with unexplained abdominal pain or other characteristic symptoms. The diagnosis can be rapidly confirmed by demonstration of a markedly increased urinary porphobilinogen level by using a single-void urine specimen. This specimen should also be saved for quantitative measurement of porphobilinogen, 5-aminolevulinic acid, and total porphyrin levels. Intravenous hemin therapy, started as soon as possible, is the most effective treatment. Intravenous glucose alone is appropriate only for mild attacks (mild pain, no paresis or hyponatremia) or until hemin is available. Precipitating factors should be eliminated, and appropriate supportive and symptomatic therapy should be initiated. Prompt diagnosis and treatment greatly improve prognosis and may prevent development of severe or chronic neuropathic symptoms. We recommend identification of at-risk relatives through enzymatic or gene studies.

Laboratory diagnosis of erythropoietic protoporphyria (EPP) requires a marked increase in total erythrocyte protoporphyrin (300-5000 μg/dL erythrocytes, reference interval <80 μg/dL) and a predominance (85%-100%) of metal-free protoporphyrin [normal, mostly zinc protoporphyrin (reference intervals for the zinc protoporphyrin proportion have not been established)]; plasma porphyrins are not always increased. X-linked protoporphyria (XLP) causes a similar increase in total erythrocyte protoporphyrin with a lower fraction of metal-free protoporphyrin (50%-85% of the total). In studying more than 180 patients with EPP and XLP, the Porphyrias Consortium found that erythrocyte protoporphyrin concentrations for some patients were much higher (4.3- to 46.7-fold) than indicated by previous reports provided by these patients. The discrepant earlier reports, which sometimes caused the diagnosis to be missed initially, were from laboratories that measure protoporphyrin only by hematofluorometry, which is intended primarily to screen for lead poisoning. However, the instrument can calculate results on the basis of assumed hematocrits and reports results as \"free\" and \"zinc\" protoporphyrin (with different reference intervals), implying separate measurements of metal-free and zinc protoporphyrin. Such misleading reports impair diagnosis and monitoring of patients with protoporphyria. We suggest that laboratories should prioritize testing for EPP and XLP, because accurate measurement of erythrocyte total and metal-free protoporphyrin is essential for diagnosis and monitoring of these conditions, but less important for other disorders. Terms and abbreviations used in reporting erythrocyte protoporphyrin results should be accurately defined.

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are inborn errors of heme biosynthesis with the same phenotype but resulting from autosomal recessive loss-of-function mutations in the ferrochelatase ( FECH ) gene and gain-of-function mutations in the X-linked erythroid-specific 5-aminolevulinate synthase ( ALAS2 ) gene, respectively. The EPP phenotype is characterized by acute, painful, cutaneous photosensitivity and elevated erythrocyte protoporphyrin levels. We report the FECH and ALAS2 mutations in 155 unrelated North American patients with the EPP phenotype. FECH sequencing and dosage analyses identified 140 patients with EPP: 134 with one loss-of-function allele and the common IVS3-48T>C low expression allele, three with two loss-of-function mutations and three with one loss-of-function mutation and two low expression alleles. There were 48 previously reported and 23 novel FECH mutations. The remaining 15 probands had ALAS2 gain-of-function mutations causing XLP: 13 with the previously reported deletion, c.1706_1709delAGTG, and two with novel mutations, c.1734delG and c.1642C>T(p.Q548X). Notably, XLP represented ~10% of EPP phenotype patients in North America, two to five times more than in Western Europe. XLP males had twofold higher erythrocyte protoporphyrin levels than EPP patients, predisposing to more severe photosensitivity and liver disease. Identification of XLP patients permits accurate diagnosis and counseling of at-risk relatives and asymptomatic heterozygotes.

Background Erythropoietic protoporphyria (EPP) and X‐linked Protoporphyria (XLP) are rare photodermatoses presenting with severe phototoxicity. Although anecdotally, providers who treat EPP patients acknowledge their life‐altering effects, tools that fully capture their impact on quality of life (QoL) are lacking. Methods Adult patients with EPP/XLP were given four validated QoL tools: the Patient Reported Outcomes Measurement Information System 57 (PROMIS‐57), the Hospital Anxiety and Depression Scale (HADS), the Illness Perception Questionnaire Revised (IPQR), and an EPP‐Specific tool. All patients received the PROMIS‐57 while the HADS, IPQR, and EPP‐Specific tools were introduced at a later date. Associations between responses and clinical phenotypes were explored. Results Two hundred and two patients were included; 193 completed PROMIS‐57, 104 completed IPQR, 103 completed HADS, and 107 completed the EPP‐Specific tool. The IPQR showed that patients strongly believed EPP/XLP had a negative impact on their lives. Mean scores in anxiety and depression domains of both HADS and PROMIS‐57 were normal; however, anxiety scores from HADS were borderline/abnormal in 20% of patients. The EPP‐Specific tool revealed a decreased QoL in most patients. The PROMIS‐57 showed that 21.8% of patients have clinically significant pain interference. Several tool domains correlated with measures of disease severity, most being from the PROMIS‐57. Conclusions Impaired QoL is an important consequence of EPP/XLP. PROMIS‐57 was most sensitive in evaluating impaired QoL in EPP/XLP. Further research is needed to compare the effectiveness of it for assessing response to treatment.

In patients with erythropoietic protoporphyria, sensitivity to the sun leads to pain and compromised quality of life. In two clinical trials, one in Europe and one in the United States, a peptide analogue of an α-melanocyte–stimulating hormone alleviated symptoms. Erythropoietic protoporphyria is a rare, autosomal recessive inborn error of metabolism that typically manifests in early childhood as severe painful photosensitivity. The photosensitivity results from accumulated protoporphyrin in erythroid cells and tissues because of the decreased activity of ferrochelatase, the heme biosynthetic enzyme that inserts iron into protoporphyrin to form heme. 1 – 4 An X-linked form of erythropoietic protoporphyria 5 , 6 that accounts for 2 to 10% of cases results from a gain of function of erythroid-specific aminolevulinic acid synthase 2. Pathophysiologically, protoporphyrin is released from erythroid cells into the circulation, gains access to the vascular endothelium and liver, and is excreted . . .

Background and Aim Autoimmune (AI) markers are reported in patients with steatohepatitis-related liver disease. However, their clinical significance is unclear. Methods Charts of patients due to alcoholic liver disease (ALD) or nonalcoholic fatty liver disease (NAFLD) were stratified for antinuclear antigen (ANA > 1:80), antismooth muscle antibody (ASMA > 1:40), or antimitochondrial antibody (AMA > 1:20). Study outcomes were patient survival and complications of liver disease. Results Of 607 patients (401 NAFLD), information about AI markers was available for 398 (mean age 50 ± 15 year; 52 % males; median body mass index (BMI) 38; 44 % diabetic; 62 % nonalcoholic steatohepatitis (NASH) as type of steatohepatitis; median MELD score 9). A total of 78 (19.6 %) patients were positive for AI markers without differences for ALD versus NAFLD, cirrhosis versus no cirrhosis, and NASH versus no NASH. There were no differences for age, gender, BMI, cirrhosis at presentation, MELD score, endoscopic findings, and histology based on AI markers. Serum ALT was higher among patients with AI markers (65 ± 46 vs. 59 ± 66 IU/l; P  = 0.048). Data remained unchanged on analyzing NAFLD patients. None of the 11 ANA-positive patients (1:640 in 4) showed findings of AI hepatitis. Biopsy in three AMA-positive patients showed mild bile duct damage in one patient. On median follow-up of about 3 years, there were no differences in liver disease outcomes (ascites, encephalopathy, variceal bleeding), hepatocellular carcinoma, transplantation, and survival. Conclusions Autoimmune markers are frequently present in steatohepatitis-related liver disease patients. Their presence is an epiphenomenon without histological changes of autoimmune hepatitis. Further, their presence does not impact clinical presentation and follow-up outcomes.

Joseph Bloomer1, Yongming Wang1 and Dongquan Chen2 1Division of Gastroenterology/Hepatology and 2Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama Abstract Ferrochelatase (FECH) activity is decreased in erythropoietic protoporphyria (EPP), causing increased production and excretion of protoporphyrin. This study examined whether the level of expression of the nonmutant FECH allele is a determinant of phenotype in a mouse model of EPP that carries a heterozygous deletion of exon 10 in FECH. Two mice strains that had a two-fold difference in FECH mRNA levels in bone marrow and liver (low expressing C3H/HeJ and high expressing CBA/J) were used to establish congenic strains containing the mutation. Erythrocyte protoporphyrin levels in C3H/HeJ heterozygous mice were significantly higher than in their wildtype littermates, whereas levels in CBA/J heterozygous mice did not differ significantly from their wildtype littermates. Biliary excretion of protoporphyrin was also significantly higher in C3H/HeJ heterozygous mice. The levels of normal FECH mRNA in bone marrow measured by real time PCR were 138 +/- 30 copies per ug total RNA in C3H/HeJ +/- mice, 320 +/- 59 in C3H/HeJ +/+ mice and 634 +/- 38 in CBA/J +/+ mice. Levels in liver tissue of the mice differed significantly in the same pattern. Thus, the level of expression of the nonmutant FECH allele is a determinant of phenotype in a mouse model of EPP as has been demonstrated in human EPP.