Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver.

BACKGROUND: Acute intermittent porphyria (AIP) is an inherited disorder of haem metabolism characterized by life-threatening acute neurovisceral attacks due to the induction of hepatic δ-aminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency. So far, the treatment of choice is hemin which represses ALAS1. The main issue in the medical care of AIP patients is the occurrence of debilitating recurrent attacks. OBJECTIVE: The aim of this study was to determine whether chronic hemin administration contributes to the recurrence of acute attacks. METHODS: A follow-up study was conducted between 1974 and 2015 and included 602 French AIP patients, of whom 46 had recurrent AIP. Moreover, we studied the hepatic transcriptome, serum proteome, liver macrophage polarization and oxidative and inflammatory profiles of Hmbs-/- mice chronically treated by hemin and extended the investigations to five explanted livers from recurrent AIP patients. RESULTS: The introduction of hemin into the pharmacopeia has coincided with a 4.4-fold increase in the prevalence of chronic patients. Moreover, we showed that both in animal model and in human liver, frequent hemin infusions generate a chronic inflammatory hepatic disease which induces HO1 remotely to hemin treatment and maintains a high ALAS1 level responsible for recurrence. CONCLUSION: Altogether, this study has important impacts on AIP care underlying that hemin needs to be restricted to severe neurovisceral crisis and suggests that alternative treatment targeting the liver such as ALAS1 and HO1 inhibitors, and anti-inflammatory therapies should be considered in patients with recurrent AIP.

Body composition assessed by dual-energy X-ray absorptiometry predicts early infectious complications after liver transplantation.

BACKGROUND: It is challenging to identify malnutrition, which is a risk factor for poor outcome in patients with liver cirrhosis. In the present study, we aimed to investigate the prevalence of malnutrition among patients listed for liver transplantation, as assessed by different methods, and also to relate dual-energy X-ray absorptiometry (DXA) to short-term post-transplant outcomes. METHODS: In this retrospective cohort study, we reviewed the medical records of 106 patients who underwent liver transplantation in 2009-2012. Body composition was assessed by the fat-free mass index (FFMI) and fat mass index (FMI) obtained using DXA. Severe infections within 1 month, length of stay in intensive care unit and length of hospital stay were endpoints of primary interest. RESULTS: The prevalence of malnutrition was 2-20% depending on sex and the assessment method. Thirty-nine (37%) patients developed severe infections within 1 month after liver transplantation. In multivariate analysis with logistic regression, body composition was significantly associated with post-operative infection when measured with FFMI (P = 0.043) but not with FMI (P = 0.087). Post-operative dialysis (P = 0.004) and post-operative infections (P < 0.001) were significantly associated with length of stay in hospital. Post-operative bleeding (P = 0.015), duration of mechanical ventilation (P < 0.001) and the need for dialysis (P < 0.001), but not body composition, were significant predictors of the length of stay in the intensive care unit. CONCLUSIONS: The prevalence of malnutrition depends on assessment method. FFMI is an independent predictor for early post-transplant infections. Body composition measured by DXA during the pretransplant evaluation provides valuable information about nutritional status in patients with liver cirrhosis.

Maternal and fetal outcome in Swedish women with erythropoietic protoporphyria.

BACKGROUND: Painful photosensitivity is characteristic of erythropoietic protoporphyria (EPP). In women, symptoms may be affected by menstrual cycle and pregnancy but very little is known about maternal and fetal outcome. OBJECTIVES: To investigate the impact of menstruation, pregnancy and breast-feeding on photosensitivity and possible effects of EPP on maternal, fetal and neonatal outcome. METHODS: Retrospective study screening all 20 Swedish women alive and older than 18 years diagnosed with EPP with a total of 33 deliveries. Data were retrieved for 19 women and 32 deliveries in medical records and completed by a questionnaire sent to the patients. RESULTS: Photosensitivity worsened in five of 19 (26%) women around menstruation whereas amelioration was reported in 17 of 32 (53%) pregnancies and during 11 of 32 (34%) breast-feeding periods. Fertility rate was normal and there were no maternal or fetal complications apart from minor arterial hypertension in one woman. CONCLUSIONS: The study confirms changes in photosensitivity during menstruation and pregnancy. Amelioration during breast-feeding is a new finding. Pregnancy appears safe without increased risks of pregnancy complications or adverse effects on fetal or neonatal health.

Erythropoietic protoporphyria in Sweden: demographic, clinical, biochemical and genetic characteristics.

OBJECTIVE: To investigate the demographic, clinical, biochemical and genotypic features of patients with erythropoietic protoporphyria (EPP) in a Swedish cohort. DESIGN: Cross-sectional questionnaire, biochemical and genetic study. SETTING: Sweden. SUBJECTS: Fifty-one Swedish individuals known in 2008 to have EPP confirmed by molecular diagnosis. There were no exclusion criteria; all patients were included in the demographic and genetic study. A total of 92% participants completed the questionnaire study and 82% the biochemical study. RESULTS: The prevalence of EPP was 1 : 180,000. Nine novel ferrochelatase gene mutations were found. The most commonly reported age at onset of symptoms was the first year of life and the mean age at diagnosis was 22 years. Painful photosensitivity was the main symptom. Exogenous factors other than sunlight were frequently reported to cause cutaneous symptoms. One in five patients reported a positive effect of beta-carotene therapy. A marked impact of EPP on quality of life was reported. Women had a significantly lower mean erythrocyte protoporphyrin concentration than men. Of all participants, 84% had insufficient vitamin D concentrations, 44% had below normal serum ferritin or transferrin saturation levels and red cell abnormalities were common. CONCLUSIONS: The notably delayed diagnosis suggests the need for an increased awareness of EPP. Disturbed erythropoiesis, biochemical signs of iron deficiency and low vitamin D levels are frequent findings in this disease. New and better treatments are needed as current treatment options for symptom amelioration are limited. Vitamin D supplementation should be considered.

The difficult clinical diagnosis of erythropoietic protoporphyria.

We give a short survey of the Swedish erythropoietic protoporphyria patients (EPP) with respect to the lapsed time between symptom debut and diagnosis. With two examples we illustrate the consequence of undiagnosed EPP for the patient and also the family. We recall efforts to spread information among health workers in order to investigate patients suffering from extreme sun-exposure intolerance for this uncommon kind of porphyria as well.

Comparison of Staphylococcus aureus carriage and skin infection rates in hospital and office employees.

The incidence of Staphylococcus aureus in the nose, throat and superficial wound infections of 99 office staff, 129 psychiatry staff and 115 surgical staff was studied over a 4-week period with the purpose of assessing the potential risk to hospital personnel of staphylococcal infection. Incidence rates, both average and cumulative, were essentially similar in the three groups but certain differences in the ecology of the staphylococcal phage groups were observed. Surgical staff appeared to have a more labile pattern of carriage. As in other Scandinavian studies throat carriage rates were high. Staphylococcal carriage seems largely to depend on individual characteristics rather than environmental factors.