Andrea Ricci

Introduction: Sarcoidosis is an inflammatory disease driven by immune-mediated mechanisms, characterized by the formation of epithelioid cell granulomas and a wide range of clinical manifestations. Its phenotype is the result of a complex interplay of genetic and environmental factors, the precise roles and interactions of which remain poorly defined. Aim: To identify candidate genes and risk loci associated with sarcoidosis from large population datasets. To estimate the genetic heritability of the phenotype in selected ancestries. Population and methods: Public summary statistics from the FinnGen release 12 (European ancestry), pan UK BioBank Project (UKBB - European and African ancestry), Million Veteran Program (MVP - European and African ancestry), and Japan BioBank (East Asian ancestry) were included for European, African and multi-ancestry meta-analysis through sample size-based analysis. Novel risk loci and single nucleotide polymorphisms (SNPs) significantly associated with the disease were critically reviewed on the basis of the available literature. For each risk locus, SNPs highly correlated with the lead SNP were selected based on Combined Annotation Dependent Depletion (CADD) scores. Genetic heritability (h ² ) scores were obtained through ancestry-specific linkage-disequilibrium score calculation. Result: Overall 9659 cases (7559 European, 1880 African, 220 East Asian) and 1,665,804 controls (1,361,726 European, 126,411 African, 177,667 East Asian) were analysed. Nineteen and two risk loci were identified in European and African ancestry, respectively; h2 scores were 0.25 (European) and 0.19 (African). Candidate non-MHC genes for further explorations through functional studies included IL23R, PUS10, ACOXL, PLCL1, FAM117B, BMPR2, PPARG, ESYT2, ANXA11, CCDC88B, ATXN2, CCL24, RP11−540O11.1, HOMER2, CD19, UBASH3A, RNF215, and others. Interferon gamma signaling, meiotic recombination/condensation of prophase chromosomes, and DNA methylation were the most enriched gene sets in European and multi-ancestry meta-analysis. Multi-ancestry meta-analysis was confronted with FinnGen+UKBB+MVP meta-analysis (released by FinnGen freeze 12) yielding consistent results (18 risk loci identified) Conclusion: Nineteen and two risk loci were significantly associated with sarcoidosis for European and African ancestries, respectively. Moderate genetic heritability was observed for both ancestries. A set of significantly associated non-MHC genes and SNPs was obtained to investigate functional validation. Although further studies are warranted, epigenetic alterations may contribute to the risk of developing sarcoidosis

In humans, an enzyme dysfunction in heme biosynthesis results in a heterogenous group of diseases collectively known as porphyrias. From a clinical standpoint, porphyrias can be classified as erythropoietic (congenital erythropoietic porphyria—CEP, erythropoietic/X-linked protoporphyria—EPP/XLP) or hepatic (acute hepatic porphyrias—AHPs, porphyria cutanea tarda—PCT), according to the site of organ dysfunction deemed to be responsible for the disease. In terms of total heme production, the liver accounts for the second major heme-synthesizing organ, after the bone marrow. In fact, heme is necessary as a prosthetic group in countless biologic functions, to which hepatic contribution is essential. Furthermore, the pathway of heme biosynthesis is inscribed into a network of fundamental metabolic reactions largely occurring in hepatocytes. Independent of their classification, all porphyrias share some degree of involvement of the liver, either in the pathogenesis, clinical manifestations, or as a preferential target of damage. Crucially, even those types of porphyrias that have been classically defined as erythropoietic do present a hepatic involvement, which can lead to poor clinical outcomes if neglected. Therefore, hepatologists should consider porphyrias as a differential diagnosis for otherwise unexplained presentations of liver disease. At the same time, a multidisciplinary team dealing with the diagnostic workup and clinical management of all types of porphyrias must include an expert in liver diseases. In this review, we aimed to recapitulate the main aspects of liver involvement in porphyrias, while also providing practical tools to recognize and manage these conditions from the hepatologist’s perspective.

Erythropoietic protoporphyria (EPP) is a disorder of haem biosynthesis characterized by a reduction in ferrochelatase and subsequent accumulation of protoporphyrin IX. Haematological aberrations in EPP have been described, though they remain poorly understood. We present a detailed analysis of haematological parameters in EPP, drawing upon data from four large cohorts in the United States and Europe. We show an association between protoporphyrin levels and both platelet count and spleen size, and in a case-control analysis, we describe significant differences between haematological indices in EPP patients versus controls.

Hemorrhage within the biliary system (hemobilia), is an infrequent complication that can arise during percutaneous procedures involving the liver. The clinical diagnosis of hemobilia is often challenging, as symptoms are quite unspecific and often display a late onset. In such cases, sonography of the gallbladder can play a crucial role in the early detection of hemobilia. A case report is provided of a 72-year-old man who underwent a sonography-guided percutaneous biopsy of a 22-mm focal lesion, within the eighth segment of the liver. In this patient, asymptomatic active hemobilia was promptly identified through contrast-enhanced ultrasound (CEUS) which was performed immediately after the invasive procedure. Crucially, this postprocedural complication may have gone undiagnosed without an early postprocedure grayscale visual analysis and CEUS evaluation, since the patient was completely asymptomatic. In conclusion, a grayscale sonogram of the gallbladder is suggested and should be considered before and immediately after percutaneous invasive procedures of the liver. In the instances where suspicion of hemobilia arises, CEUS can be used to assess the presence of active bleeding. Implementing this type of imaging protocol may possibly reveal a higher frequency of hemobilia than is commonly reported.

Background and Aim: Notwithstanding the improvement in therapies, patients affected by thalassemia major (TM) and intermedia (TI) are still at high risk of cardiac complications. This study aimed at evaluating the incidence and predictive factors for developing cardiac events in adult β‐TM and TI patients.Population and Methods: Data on diagnosis and clinical history were collected retrospectively; prospective data on new‐onset cardiac failure and arrhythmias, echocardiographic parameters, biochemical variables including non‐transferrin‐bound iron (NTBI) and labile plasma iron (LPI), magnetic resonance imaging (MRI) T2* measurement of hepatic and cardiac iron deposits, and iron chelation therapy were recorded during a 6‐year follow‐up.Results: Thirty‐seven patients, 29 TM and 8 TI, were included. At baseline, 8 TM patients and 1 TI patient had previously experienced a cardiac event (mainly heart failure). All patients were on chelation therapy and only 3 TM patients had mild‐to‐severe cardiac siderosis. During follow‐up, 11 patients (29.7%) experienced a new cardiac event. The occurrence of cardiac events was correlated to high LPI levels (OR 12.0, 95% CI 1.56–92.3, p .017), low mean pre‐transfusion haemoglobin (OR 0.21, 95% C.I. 0.051–0.761, p .21) and echocardiographic parameters suggestive of myocardial hypertrophy. Multivariate analysis disclosed high LPI and left ventricle mass index (LVMI) as independent variables significantly associated with cardiac events. Cardiac iron deposits measured by MRI T2* failed to predict cardiac events.Conclusion: LPI, Hb levels and echocardiographic parameters assessing cardiac remodelling are associated with cardiac events in adult TM and TI patients. LPI might represent both a prognostic marker and a potential target for novel treatment strategies. Further studies are warranted to confirm our findings on larger populations.

Given its remarkable property to easily switch between different oxidative states, iron is essential in countless cellular functions which involve redox reactions. At the same time, uncontrolled interactions between iron and its surrounding milieu may be damaging to cells and tissues. Heme—the iron-chelated form of protoporphyrin IX—is a macrocyclic tetrapyrrole and a coordination complex for diatomic gases, accurately engineered by evolution to exploit the catalytic, oxygen-binding, and oxidoreductive properties of iron while minimizing its damaging effects on tissues. The majority of the body production of heme is ultimately incorporated into hemoglobin within mature erythrocytes; thus, regulation of heme biosynthesis by iron is central in erythropoiesis. Additionally, heme is a cofactor in several metabolic pathways, which can be modulated by iron-dependent signals as well. Impairment in some steps of the pathway of heme biosynthesis is the main pathogenetic mechanism of two groups of diseases collectively known as porphyrias and congenital sideroblastic anemias. In porphyrias, according to the specific enzyme involved, heme precursors accumulate up to the enzyme stop in disease-specific patterns and organs. Therefore, different porphyrias manifest themselves under strikingly different clinical pictures. In congenital sideroblastic anemias, instead, an altered utilization of mitochondrial iron by erythroid precursors leads to mitochondrial iron overload and an accumulation of ring sideroblasts in the bone marrow. In line with the complexity of the processes involved, the role of iron in these conditions is then multifarious. This review aims to summarise the most important lines of evidence concerning the interplay between iron and heme metabolism, as well as the clinical and experimental aspects of the role of iron in inherited conditions of altered heme biosynthesis.

Background Acute hepatic porphyrias (AHPs) are a group of rare diseases caused by dysfunctions in the pathway of heme biosynthesis. Although acute neurovisceral attacks are the most dramatic manifestations, patients are at risk of developing long-term complications, several of which are of a vascular nature. The accumulation of non-porphyrin heme precursors is deemed to cause most clinical symptoms. Aim We measured the serum levels of endothelin-1 (ET-1) and nitric oxide (NO) to assess the presence of endothelial dysfunction (ED) in patients with AHPs. Forty-six patients were classified, according to their clinical phenotype, as symptomatic (AP-SP), asymptomatic with biochemical alterations (AP-BA), and asymptomatic without biochemical alterations (AP-AC). Results Even excluding those under hemin treatment, AP-SP patients had the lowest NO and highest ET-1 levels, whereas no significant differences were found between AP-BA and AP-AC patients. AP-SP patients had significantly more often abnormal levels of ED markers. Patients with the highest heme precursor urinary levels had the greatest alterations in ED markers, although no significant correlation was detected. Conclusions ED is more closely related to the clinical phenotype of AHPs than to their classical biochemical alterations. Some still undefined disease modifiers may possibly determine the clinical picture of AHPs through an effect on endothelial functions.