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Ferritin is a ubiquitous protein that is present in most tissues as a cytosolic protein. The major and common role of ferritin is to bind Fe2+, oxidize it and sequester it in a safe form in the cell, and to release iron according to cellular needs. Ferritin is also present at a considerably low proportion in normal mammalian sera and is relatively iron poor compared to tissues. Serum ferritin might provide a useful and convenient method of assessing the status of iron storage, and its measurement has become a routine laboratory test. However, many additional factors, including inflammation, infection, metabolic abnormalities, and malignancy—all of which may elevate serum ferritin—complicate interpretation of this value. Despite this long history of clinical use, fundamental aspects of the biology of serum ferritin are still unclear. According to the high number of factors involved in regulation of ferritin synthesis, secretion, and uptake, and in its central role in iron metabolism, hyperferritinemia is a relatively common finding in clinical practice and is found in a large spectrum of conditions, both genetic and acquired, associated or not with iron overload. The diagnostic strategy to reveal the cause of hyperferritinemia includes family and personal medical history, biochemical and genetic tests, and evaluation of liver iron by direct or indirect methods. This review is focused on the forms of inherited hyperferritinemia with or without iron overload presenting with normal transferrin saturation, as well as a step-by-step approach to distinguish these forms to the acquired forms, common and rare, of isolated hyperferritinemia.

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a life-threatening hematologic disorder resulting from an ineffective and pathologic activation of the immune response system that may mimic common emergency department presentations, including sepsis, acute liver failure, disseminated intravascular coagulation, and flu-like illnesses such as coronavirus disease 2019 (COVID-19).ObjectiveThis narrative review provides a summary of the disease and recommendations for the recognition and diagnostic evaluation of HLH with a focus on the emergency clinician.DiscussionThough the condition is rare, mortality rates are high, ranging from 20% to 80% and increasing with delays in treatment. Importantly, HLH has been recognized as a severe variation of the cytokine storm associated with COVID-19. Common features include a history of infection or malignancy, fever, splenomegaly or hepatomegaly, hyperferritinemia, cytopenias, coagulopathies, abnormal liver enzymes, and hypertriglyceridemia. Using specific features of the history, physical examination, laboratory studies, and tools such as the HScore, HLH-2004/2009, and hyperferritinemia thresholds, the emergency clinician can risk-stratify patients and admit for definitive testing. Once diagnosed, disease specific treatment can be initiated.ConclusionThis review describes the relevant pathophysiology, common presentation findings, and a framework for risk stratification in the emergency department.

Aceruloplasminemia is an ultra-rare and fatal autosomal recessive disease with a long lasting neurological disabling period of life caused by mutations in ceruloplasmin gene. Disease phenotype is heterogeneous and variably characterized by iron-restricted erythropoiesis and microcytic anemia, hyperferritinemia with tissue iron accumulation in liver, pancreas and brain, diabetes, retinopathy and neurodegeneration. Although most heterozygotes are asymptomatic, they might present with significant neurological symptoms at some point in their lives. We report here a patient with hyperferritinemia and severe depressive disorder, harbouring two mutations in ceruloplasmin in the compound heterozygous state (p.Pro477Leu and p.Gly895Ala). Both mutations are classified as deleterious in silico, but in vitro functional study partially confirmed it. Our findings suggest that the two mutations cooperate in inducing low ceruloplasmin production in the range observed in aceruloplasminemia heterozygotes and raise the question whether this might increase patient's susceptibility to neurologic manifestations.

We report the case of a 76-year-old man presenting with reactive haemophagocytic lymphohistiocytosis (rHLH) in the setting of disseminatedprostate cancer. This often fatal syndrome must be diagnosed early in order to maximize survival. Treatment should be initiated wheneverthe clinical diagnosis is suspected, even if the HLH-2004 criteria are not met. The HScore is a useful diagnostic tool for rHLH. In case ofneurological symptoms, an extensive assessment must be performed. The goal of this case report is to raise awareness of this rare syndromeamong oncologists., LEARNING POINTS• The association of prostate cancer and reactive haemophagocytic lymphohistiocytosis (rHLH) has rarely been described.• This often fatal syndrome must be recognized early in order to start specific treatment and maximize survival.• Specific treatment for rHLH must be accompanied by treatment of the triggering factors, info:eu-repo/semantics/published

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a life-threatening hematologic disorder resulting from an ineffective and pathologic activation of the immune response system that may mimic common emergency department presentations, including sepsis, acute liver failure, disseminated intravascular coagulation, and flu-like illnesses such as coronavirus disease 2019 (COVID-19).ObjectiveThis narrative review provides a summary of the disease and recommendations for the recognition and diagnostic evaluation of HLH with a focus on the emergency clinician.DiscussionThough the condition is rare, mortality rates are high, ranging from 20% to 80% and increasing with delays in treatment. Importantly, HLH has been recognized as a severe variation of the cytokine storm associated with COVID-19. Common features include a history of infection or malignancy, fever, splenomegaly or hepatomegaly, hyperferritinemia, cytopenias, coagulopathies, abnormal liver enzymes, and hypertriglyceridemia. Using specific features of the history, physical examination, laboratory studies, and tools such as the HScore, HLH-2004/2009, and hyperferritinemia thresholds, the emergency clinician can risk-stratify patients and admit for definitive testing. Once diagnosed, disease specific treatment can be initiated.ConclusionThis review describes the relevant pathophysiology, common presentation findings, and a framework for risk stratification in the emergency department.

Hemophagocytic lymphohistiocytosis (HLH) is an underdiagnosed but life-threatening syndrome of hyperinflammation often occurring in adults with hematological malignancies (hM-HLH). The aim of the study was to describe clinical characteristics, therapy response, and outcome of adults with hM-HLH. The study included 51 adults with hM-HLH aged 23–84 years. Hyperferritinemia ≥500 µg/L was present in 96% of patients. The serum concentration of sIL-2Rα ≥ 2400 U/mL was revealed in 94% of patients. Twenty-three patients (45%) responded to therapy and achieved remission of HLH. The probability of overall survival (OS) at 6, 12, 24, and 60 months after HLH diagnosis were 42, 20, 15, and 15%, respectively. Patients with HLH during chemotherapy showed longer OS (median 124 days) than the patients who had HLH solely attributed to malignancy (median 65 days), but this difference was not statistically significant. Awareness of HLH in lymphoid and myeloid malignancies is crucial for improved survival.

Background: The storage of glucosylceramide in macrophages produces an inflammatory response in Gaucher disease type 1 (GD1) resulting in iron metabolism dysregulation and cytokine release. Patients and methods: The study included 16 adults with GD1 aged 20-86 years. All but one patient carried at least one allele with the c.1226A > G (N370S) mutation in the GBA1 gene. Ferritinemia, iron metabolism profiles including hepcidin, and inflammatory cytokine concentrations were assessed in GD1 patients in Sweden. Results: Hyperferritinemia was present in 81% of patients. There was no correlation between hyperferritinemia and patient's gender, spleen status, or clinical status. Hepcidin was discrepantly low in relation to ferritin levels. TNF-alpha was moderately increased in 5 of 11 patients; 2 patients with the highest TNF-alpha concentrations showed mildly elevated IL-6 levels. The concentrations of IL-1 beta, IL-8, and IL-10 were normal in all patients. Upon treatment, ferritinemia ameliorated but S-ferritin levels did not normalize. The increased TNF-alpha level however, normalized in all treated patients, reaching the lowest values after 2 years of therapy and continued to be stable during the remaining 2 years of follow-up. Conclusions: Hyperferritinemia is a frequent finding in GD1 in Sweden. The relatively low hepcidin levels reveal a distorted relationship between hepcidin and ferritin in GD1. Therapy has the potential to not only ameliorate hyperferritinemia but to also normalize the serum TNF-alpha concentration in GD1.

This paper describes a case of pruritus caused by dysmetabolic hyperferritinemia treated by multiple phlebotomies.A 63-year-old man was followed for generalized pruritus, which was resistant to the usual treatments. He presented with metabolic syndrome. Physical examination showed only excoriations and lichenification on the skin. The serum ferritin was high at 1043 ng/ml, with transferrin saturation at 67%. The other biological investigations and genetic tests for hemochromatosis were negative.In spite of the dietary measures, the ferritin level was still high (853ng/ml). Magnetic resonance imaging confirmed hepatic iron overload.The association of hyperferritinemia, hepatic iron overload, and metabolic syndrome led to the diagnosis of dysmetabolic hyperferritinemia.Phlebotomies are an unusual treatment, but because the pruritus and hyperferritinemia were still present, phlebotomy wasinitiated. After 19 months, the patient reported improvement of his pruritus and normalization of ferritin levels.

This paper describes a case of pruritus caused by dysmetabolic hyperferritinemia treated by multiple phlebotomies.A 63-year-old man was followed for generalized pruritus, which was resistant to the usual treatments. He presented with metabolic syndrome. Physical examination showed only excoriations and lichenification on the skin. The serum ferritin was high at 1043 ng/ml, with transferrin saturation at 67%. The other biological investigations and genetic tests for hemochromatosis were negative.In spite of the dietary measures, the ferritin level was still high (853ng/ml). Magnetic resonance imaging confirmed hepatic iron overload.The association of hyperferritinemia, hepatic iron overload, and metabolic syndrome led to the diagnosis of dysmetabolic hyperferritinemia.Phlebotomies are an unusual treatment, but because the pruritus and hyperferritinemia were still present, phlebotomy wasinitiated. After 19 months, the patient reported improvement of his pruritus and normalization of ferritin levels.

Background & Aims: Serum levels of ferritin are commonly measured to assess iron stores but are affected by factors such as obesity and chronic disease. Published reference ranges have not changed in decades, and the number of patients whose levels exceed the upper limits has been increasing. As a result, more patients are evaluated for iron overload. Methods: We compared serum levels of ferritin in 1188 Australian adults who participated in the 2005 Busselton Population Survey with levels from the 1995 survey. Parametric regression was used to assess the effects of body weight and biochemical parameters on serum level of ferritin to derive contemporary population-appropriate reference ranges.Results: In 2005, age-adjusted levels of ferritin were 21% higher in men (P < .0001) and 10% higher in women (P = .01) than in 1995; 31% of men exceeded levels of 300 μg/L, compared with 23% in 1995. Body mass index (BMI) ≥25 kg/m2 was associated with higher levels of ferritin in men ≥35 years old and in postmenopausal women (P ≤ .002). Serum level of γ-glutamyltransferase (GGT) correlated with serum level of ferritin (P < .0001). In men, the estimated 95th percentiles ranged from 353 to 495 μg/L (<35 years), from 350 to 511 μg/L (≥35 years, BMI <25 kg/m2), and from 413 to 696 μg/L (≥35 years, BMI ≥25 kg/m2) when GGT levels were 10–75 IU/L. In women, the 95th percentiles ranged from 106 to 235 μg/L (premenopausal), from 222 to 323 μg/L (postmenopausal, BMI <25 kg/m2), and from 249 to 422 μg/L (postmenopausal, BMI ≥25 kg/m2) when GGT levels were 8–45 IU/L. Conclusion: Serum levels of ferritin increased significantly between 1995 and 2005. Reference ranges that accommodate demographic and biomedical variations will assist clinicians in identifying individuals who require further evaluation for iron overload.

Iron is an essential trace metal whose extracellular concentration and stores are efficiently regulated. Systemic iron homeostasis assures a stable milieu in which each cell regulates its iron uptake to meet its own requirements. The system is challenged by variable availability of iron in the diet, by occasional iron losses through bleeding and by the fluctuations in the iron request by iron requiring processes such as erythropoiesis, growth, pregnancy and lactation ;but also by pathologic processes involving aberrant iron retention leading to tissue iron overload and finally to end organ damage. A low serum ferritin is 100 % specific for iron deficiency ;conversely hyperferritinemia is not a reliable sign of iron overload. Iron deficiency is a pan-ethnic disorder more prevalent in western and ageing people. Anemia represents the end stage of iron deficiency. During inflammatory states, iron becomes unavailable for erythropoiesis although adequate stores are present. This phenomenon is called functional iron deficiency and is characteristic of anemia of chronic disorders. Hyperferritinemia may exist in the presence or in the absence of iron overload. A cut off value of > 45 % for transferrine saturation has been suggested to discriminate both settings. All the acquired conditions associated with hyperferritinemia must be excluded before performing genetic testing. Perfect understanding of iron homeostasis regulation as well as an adequate use of analyses exploring iron metabolism are mandatory for proper clinical management of iron deficiency and overload states., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: The ferroportin Q248H mutation is relatively common in sub-Saharan Africa. No previous study examined its relationship with atypical diabetes mellitus (DM) in this area. Objective: To determine the potential interactions between ferroportin Q248H mutation, hyperferritinemia and DM in South Kivu (RDC). Methodology: Presence of ferroportin Q248H mutation and iron status were investigated in diabetic patients (n = 179, age (mean) 57.7 years, CRP (median) 0.16 mg/L) and non-diabetic subjects (n = 86, age 44.5 years, CRP 0.07 mg/L) living in the city of Bukavu. Hyperferritinemia was considered for values greater than 200 and 300 μg/L in women and in men, respectively. Results: The prevalence of ferroportin Q248H mutation [12.1%] was non-significantly higher in diabetics than non-diabetics [14.0% vs. 8.1%, p = 0.17]. Similarly, hyperferritinemia frequency was higher in diabetic patients with Q248H mutation [44.0% vs. 14.3%, p = 0.16] and in mutation carriers [37.0% vs 16.5%, p = 0.001] than in the control groups, respectively. The association between Q248H mutation and DM was nevertheless not significant [adjusted OR 1.70 (95% CI: 0.52-5.58), p = 0.37], whereas hyperferritinemia [OR 2.72 (1.24-5.98), p = 0.01] showed an independent effect after adjustment for age and metabolic syndrome. Conclusions: The present work suggests a potential association between abnormal iron metabolism, ferroportin Q248H mutation and atypical DM in Africans, which may be modulated by environmental factors. © 2013 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Iron is an essential trace metal whose extracellular concentration and stores are efficiently regulated. Systemic iron homeostasis assures a stable milieu in which each cell regulates its iron uptake to meet its own requirements. The system is challenged by variable availability of iron in the diet, by occasional iron losses through bleeding and by the fluctuations in the iron request by iron requiring processes such as erythropoiesis, growth, pregnancy and lactation ;but also by pathologic processes involving aberrant iron retention leading to tissue iron overload and finally to end organ damage. A low serum ferritin is 100 % specific for iron deficiency ;conversely hyperferritinemia is not a reliable sign of iron overload. Iron deficiency is a pan-ethnic disorder more prevalent in western and ageing people. Anemia represents the end stage of iron deficiency. During inflammatory states, iron becomes unavailable for erythropoiesis although adequate stores are present. This phenomenon is called functional iron deficiency and is characteristic of anemia of chronic disorders. Hyperferritinemia may exist in the presence or in the absence of iron overload. A cut off value of > 45 % for transferrine saturation has been suggested to discriminate both settings. All the acquired conditions associated with hyperferritinemia must be excluded before performing genetic testing. Perfect understanding of iron homeostasis regulation as well as an adequate use of analyses exploring iron metabolism are mandatory for proper clinical management of iron deficiency and overload states., SCOPUS: ar.j, info:eu-repo/semantics/published

A prospective study was carried out to determine if hyperferritinemia is a predictive factor for immunosuppression in patients with acquired immunodeficiency syndrome (AIDS). The population consisted of 40 patients hospitalized at the University Hospital of Maracaibo (Hospital Universitario de Maracaibo), from January to October, 2010. Twenty-seven (67.50%) patients were male and 13 (32.50%) were female. 22.50% had a T CD4+ lymphocyte count between 200-400 cells/mm3 with a mean ferritin of 144.2 ± 127.1 ng/mL; 77.50% had a T CD4+ lymphocyte count of <200 cells/mm3 and a ferritin average of 1100.0 ± 984.7 ng/mL (p = 0.01). An inverse negative correlation was found between high ferritin levels and low T CD4+ lymphocyte count (r = 0.3135, p= 0.030), low numbers of leukocytes (r = 0, 7458 p = 0.012), low levels of protein (r = 0.5814, p =0.01), and a directly proportional relation with the increase of ESR (r = 0.7422, p = 0.001). In patients who died, the mean ferritin level (1180.0 ± 1,072) statistically (p = 0.018) was higher compared with the average ferritin level (474 ± 440.2) of patients who survived. Conclusions are that these results are sufficiently relevant to take hyperferritinemia into account as a prognostic factor for the immunosuppression of diagnosed AIDS patients., Se realiza una investigación prospectiva con el objetivo de determinar si la hiperferritinemia es un factor pronóstico de inmunosupresión en pacientes con síndrome de inmunodeficiencia adquirida (SIDA). La población estuvo conformada por 40 pacientes hospitalizados en el Hospital Universitario de Maracaibo, durante los meses de Enero a Octubre del 2010. 27 (67,50%) pacientes fueron de sexo masculino y 13 (32,50%) femeninos. El 55,00% presentó hiperferritinemia. 22,50% presentaron contaje de linfocitos T CD4+ entre 200-400 cel/mm3 con un promedio de ferritina de 144,2 Ó 127,1 ng/mL y, el 77,50% contaje de linfocitos T CD4+ < 200 cel/mm3 con un promedio de ferritina de 1100,0 Ó 984,7 ng/mL (p = 0,01). Se demostró una correlación inversamente negativa entre niveles elevados de ferritina con niveles bajos de contaje de linfocitos T CD4+ (r = 0,3135, p = 0,030), cifras bajas de leucocitos (r= 0, 7458, p= 0,012), cifras bajas de proteínas (r= 0,5814, p= 0,01) y una relación directamente proporcional con el aumento de la VSG (r = 0,7422, p= 0,001). En los pacientes fallecidos el promedio de ferritina (1180,0 Ó 1.072) estadísticamente (p= 0,018) fue más elevado en comparación con el promedio de ferritina (474 Ó 440,2) de los pacientes que sobrevivieron. Se concluye que se puede tomar en cuenta a la hiperferritinemia como factor pronóstico de inmunosupresión en pacientes con diagnóstico de SIDA.

The aim of this study was to search for SLC40A1 mutations in iron overloaded patients, which tested negative for HFE mutations and other iron-related genes. After a careful differential diagnosis, we selected 56 patients with unexplained iron overload whose phenotype could suggest the ferroportin disease. Iron overload was assessed by liver biopsy or by superconducting quantum interference device. SLC40A1 exons and intron-exon boundaries were amplified by polymerase chain reaction and sequenced. We also evaluated the presence of the insulin-resistance hepatic iron overload and of non-alcoholic fatty liver disease. Iron status was assessed in 44 families. We identified two novel mutations (D157N and V72F) at the heterozygous state in two probands. Phenotype heterogeneity was observed in both families, suggesting variable penetrance and expression. Including the two affected ones, 25 of the 44 families (57%) available for the iron study had one or more relatives with increased serum iron indices. Our findings not only suggest that the presence of major alterations of serum iron parameters in probands' relatives is a main criteria to improve the power of the genetic testing for ferroportin disease but also indicate that a number of patients exists in which the etiology of iron overload remains still undefined.

The presence of hyperferritinemia has to rule out acquired causes such as chronic inflammatory disorders, hemolytic anemia, liver diseases as hepatitis B or C, alcohol abuse and non alcoholic fatty liver disease, specially in patients with normal transferrine saturation. Genetic testing for hemochromatosis is systematically indicated in all patients with elevated transferrine saturation. When an iron overload is demonstrated in the absence of these classic causes, second-line genetic testing should be considered to exclude non HFE hemochromatosis. The aim of this paper is to propose a practical algorithm in the diagnosis of hyperferritinemia and to precise the diagnostic and therapeutic management of genetic hemochromatosis., SCOPUS: ar.j, info:eu-repo/semantics/published

To study the clinical correlates of the H63D mutation we have analysed the phenotype of H63D homo-zygotes identified through mutation analysis in a referral laboratory. A total of 366 blood samples referred for HFE analysis were screened for C282Y and H63D mutations. Four H63D homozygotes were identified. All had raised serum ferritin but normal transferrin saturation. They were negative for hepatitis B and C and only one patient consumed excess alcohol. In all 4 cases ultrasonography revealed fatty liver. In two patients a liver biopsy was done and showed mild siderosis with an unusual distribution and macrovesicular steatosis. These data confirm the association between fatty liver, hyperferritinaemia and increased hepatic iron, but do not clarify whether siderosis was related to steatosis rather than homozygosity for the H63D mutation. Patients with fatty liver may complicate the interpretation of data in population studies of the expression of H63D homozygosity.

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Hintergrund und Ziele: Die Hyperferritinämie ist ein unspezifischer Befund, der häufig im Zusammenhang mit Eisenüberladung, Entzündung und Zelltod auftritt. Eins der Ziele dieser Arbeit war es, einen diagnostischen Algorithmus zur Differentialdiagnose von Patienten mit hohem Serumferritin zu etablieren, der auf klinischen, biochemischen, genetischen und radiologischen Studien basiert. Über 80% der Patienten mit Hämochromatose zeigen eine Homozygotie für die C282Y-Variante in HFE. Rezente Studien haben gezeigt, dass pathogene Varianten in HAMP, HJV, HFE, TFR2 oder SLC40A1 nur bei einer Minderheit der Patienten mit klinisch vermuteter non-HFE-Hämochromatose vorhanden sind. Ein weiteres Ziel dieser Arbeit war es, die Landschaft und Häufigkeit von Mutationen in Hämochromatose-Genen zu beschreiben und festzustellen, ob die Patientenauswahl durch nicht-invasive Eisenquantifizierung mit R2* Magnetresonanztomographie (MRT) den positiven Vorhersagewert der Next-Generation-Sequenzierung (NGS) verbessert. Da das Zusammentreffen von Eisen und Fett in der Leber die R2* Werte beeinflussen kann, haben wir die Fettsättigungs- (FS) und nicht-FS-MRT-Methoden verglichen. Die Ferroportin-Erkrankung (FE) ist eine autosomal-dominante Störung, die mit Varianten des Funktionsverlusts im Ferroportin-kodierenden Gen SLC40A1 assoziiert ist. Die Pathogenese der systemischen Eisenüberladung im Rahmen eines verringerten zellulären Eisenexports bleibt jedoch unklar. Im zweiten Teil dieser Arbeit führten wir umfassende in vitro Experimente zu R178Q und Kontrollvarianten im Ferroportin durch und untersuchten ein neues Konzept, bei dem ein verringerter zellulärer Eisenexport auch mit einer Hepcidinresistenz zusammenhängen könnte. Methoden: Eine Kohorte von 410 Leberklinikpatienten mit hohem Serumferritin (definiert als ≥ 200 μg/L für Frauen und ≥ 300 μg/L für Männer) wurde mittels HFE-Genotypisierung und abdominaler R2* MRT zur Eisenquantifizierung untersucht. In einer Untergruppe ausgewählter Patie, Background and aims: Hyperferritinemia is a non-specific finding commonly present in association with iron overload, inflammation and cell death. Here, we set out to establish a diagnostic algorithm based on clinical, biochemical, genetic and radiological studies for evaluation of patients with high serum ferritin. Over 80% of patients with hemochromatosis are homozygous for the C282Y variant in HFE. Recent studies have shown that pathogenic variants in HAMP, HJV, HFE, TFR2 or SLC40A1 are present in only a minority of patients with clinically suspected non-HFE hemochromatosis. Another aim of this thesis was to describe the landscape and frequency of mutations in hemochromatosis genes and determine if patient selection by non-invasive iron quantification with R2* magnetic resonance imaging (MRI) improves the positive predictive value of next-generation sequencing (NGS). As coincidence of iron and fat in the liver can influence R2* values, we compared fat-saturation (FS) and non-FS MRI methods. Ferroportin disease (FD) is an autosomal dominant disorder associated with “loss of function” variants in the ferroportin encoding gene SLC40A1. The pathogenesis of systemic iron overload in a context of reduced cellular iron export remains unclear. In the second part of this thesis, we carried out in vitro studies on R178Q mutant ferroportin and explored a novel molecular disease mechanism of FD, where reduced cellular iron export might be also associated with hepcidin resistance. Methods: A cohort of 410 unselected liver clinic patients with high serum ferritin (defined as ≥200 μg/L for women and ≥300 μg/L for men) was investigated by HFE genotyping and abdominal R2* MRI for iron quantification. Evaluation for non-HFE hemochromatosis was carried out by NGS in a subgroup of selected patients. Furthermore, in order to compare two different R2* MRI methods with or without FS, 134 liver clinic patients with suspected iron overload were included in a prospective study where linear, Abweichender Titel laut Übersetzung der Verfasserin/des Verfassers, Kumulative Dissertation aus zwei Artikeln, Dissertation Medical University of Innsbruck 2020