Follow-up evaluation and management of anemia in inflammatory bowel disease: A study by the Italian Group for Inflammatory Bowel Diseases (IG-IBD).

BACKGROUND: The RIDART I study found a 13.6% prevalence of anemia in Italian patients with inflammatory bowel disease (IBD); most cases were due to iron-deficiency anemia (IDA). AIMS: To evaluate changes in hemoglobin concentration during a 24-week follow-up of anemic patients with IBD. METHODS: Follow-up laboratory and clinical data were obtained from RIDART I study patients with anemia. Factors affecting hemoglobin concentration, the impact of anemia on fatigue and quality of life (QoL), and its relationship with treatment, disease activity and disease complications were investigated. RESULTS: Hemoglobin was 108 g/L at baseline, increased to 121 g/L at follow-up week 12 (p < 0.001) and then stabilized until week 24, but most patients remained anemic, with IDA, throughout the study. Hemoglobin improvement was greater in patients receiving either oral or parenteral iron supplementation. Following hemoglobin normalization, anemia relapse rate during follow-up was 30%. Oral iron did not cause disease reactivation. Lower follow-up hemoglobin was associated with a higher probability of having active disease, clinical complications, increased fatigue and reduced QoL. CONCLUSIONS: In anemic patients with IBD, anemia represents a long-lasting problem, in most cases persisting for up to 24 weeks, with high relapse rate and a negative impact on fatigue and QoL.

Haematological sequelae in the post-acute phase of symptomatic SARS-CoV-2 infection.

Many patients surviving SARS-CoV-2 infection suffer from long-term symptoms (long COVID or post COVID) such as shortness of breath, fatigue, loss of taste or smell and cognitive deterioration. However, few data are available concerning blood cell counts and haematological parameters during the post-COVID period. We analysed haematological data from 83 patients previously admitted to the internal medicine unit of our institution because of symptomatic SARS-CoV-2 infection; all data were obtained within 1-12 months from disease onset. A control group of 70 apparently healthy, age- and sex-matched COVID-19 negative individuals was assessed for comparison. Blood cell counts improved in the post-COVID period, but 81% of patients had persistent abnormalities, compared with 50% in the control group, p < 0.001. Most common haematological findings included anaemia (40%), reduced lymphocyte (43%) or eosinophil counts (38%) and low IgM memory B cells and correlated with advanced age, number of chronic comorbidities, female gender, altered renal function, reduced baseline Hb and procalcitonin concentrations and increased RDW. Data on lymphocytes and IgM memory B cells show that impaired immune responses may persist for up to one year in the post-COVID period, possibly contributing to long-term symptoms, especially in female patients.

Ultrasound Patterns of Hepatocellular Carcinoma and Their Prognostic Impact: A Retrospective Study.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. Abdominal ultrasound (US) is by far the most widely used first-level exam for the diagnosis of HCC. We aimed to assess whether different ultrasound patterns were related to tumor prognosis. METHODS: We retrospectively reviewed all patients with a new diagnosis of HCC (single nodule) and undergoing radiofrequency thermal ablation (RFTA) at our clinic between January 2009 and December 2021. Patients were classified according to four HCC ultrasound patterns: 1A, single capsulated nodule; 1B, well capsulated intra-node nodule; 1C, cluster consisting of capsulated nodules; and 2, non-capsulated nodule. RESULTS: 149 patients were analysed; median follow-up time was 43 months. US patterns 1A (32.9%) and 1B (61.1%) were the most commonly seen. Median overall survival (OS) and recurrence-free survival (RFS) from RFTA were 54 months (95% CI, 42-66) and 22 months (95% CI, 12-32), respectively. Pattern 1A showed the best OS. Compared to pattern 1A, 1B was independently associated with worse OS (51 months (95% CI, 34-68) vs. 46 months (95% CI, 18-62)) and RFS (34 months (95% CI, 27-41) vs. 18 months (95% CI, 12-24)). Patterns 1C and 2 were associated with worse RFS compared to 1A, while no difference was seen for OS. Among baseline clinical variables, pattern 1B exhibited higher histological grade (p = 0.048) and tumor dimension (p = 0.034) compared to pattern 1A. CONCLUSIONS: Our findings demonstrate that different US patterns correlate with different survival outcomes and tumor behavior in patients with HCC. Prospective studies are needed to confirm these results.

Prevalence, Pathogenesis and Management of Anemia in Inflammatory Bowel Disease: An IG-IBD Multicenter, Prospective, and Observational Study.

BACKGROUND: Anemia is a common extraintestinal manifestation of inflammatory bowel disease (IBD), with a 6% to 74% prevalence and a negative impact on patient survival and quality of life, although the prevalence is apparently declining due to improved disease treatment. We aimed to investigate the prevalence, pathogenesis, and clinical correlates of anemia in Italian patients with IBD. METHODS: A multicenter, prospective, observational study, involving 28 Italian gastroenterology centers, was conducted to investigate the epidemiology and consequences of IBD-associated anemia. Clinical and laboratory data of anemic patients were obtained at study enrolment. RESULTS: Anemia was diagnosed in 737 of 5416 adult IBD outpatients (prevalence 13.6%); females were more commonly affected than males (odds ratio, 1.5; 95% confidence interval [CI], 1.2-1.7) and had more severe anemia. In the majority of cases, anemia was due to iron deficiency (62.5% of cases; 95% CI, 58.3%-66.6%), either isolated or in association with inflammation and/or vitamin deficiencies; anemia of inflammation accounted for only 8.3% of cases. More severe anemia was associated with increasing fatigue and worse quality of life. Only 68.9% of anemic patients with iron deficiency (95% CI, 63.4%-73.8%) and 34.6% of those with vitamin deficiencies (95% CI, 26.2%-44.2%) were properly treated with supplementation therapy. CONCLUSIONS: In Italy, the prevalence of IBD-associated anemia is lower than previously reported. Anemia of IBD is most commonly due to iron deficiency and contributes to fatigue and poor quality of life, but remains untreated in a large proportion of patients with iron and/or vitamin deficiencies. This study is registered at clinicaltrials.gov as NCT02872376.

The prevalence of inflammatory bowel disease­associated anemia is 13.6%. The prevalence is higher among females younger than 50. Anemia is usually due to iron deficiency and adversely affects fatigue and quality of life. Many patients with iron or vitamin deficiency (31% and 65%, respectively) remain untreated.

Pathophysiology and therapeutic management of anemia in gastrointestinal disorders.

INTRODUCTION: Anemia is a common complication of gastrointestinal (GI) disorders, with a prevalence up to 60% in celiac disease (CeD) and inflammatory bowel disease (IBD). Iron deficiency anemia (IDA) is the most prevalent form of anemia in these conditions, but chronic inflammation and vitamin B12 deficiency represent other common contributing mechanisms, especially in IBD. AREAS COVERED: We discuss the pathogenesis of anemia in various medical GI disorders, the sometime problematic distinction between IDA, anemia of inflammation (AI) and the association of the two, and therapeutic and preventive measures that can be useful for the management of anemia in GI disorders. Unfortunately, with the exception of IDA and AI in IBD, large RCT concerning the treatment of anemia in GI disorders are lacking. EXPERT OPINION: Anemia management strategies in GI disorders are outlined, with a focus on the main prevention, diagnostic, and therapeutic measures. Specific problems and situations such as the role of gluten-free diet for IDA treatment in CeD, the choice between oral and parenteral supplementation of iron or vitamin B12 in carential anemias, the use of endoscopic procedures to stop bleeding in intestinal angiodysplasia and preventive/treatment strategies for NSAID-associated GI bleeding are discussed.

Impact of in-hospital intravenous iron supplementation on red blood cell transfusions: experience from an Internal Medicine Unit.

BACKGROUND: Pharmacological treatment of iron deficiency anaemia can reduce red blood cell (RBC) transfusions. Intravenous iron provides a more effective and quicker correction of iron deficiency anaemia than oral iron, and third-generation high-dose intravenous iron formulations allow the complete correction of iron deficiency with just one or two drug infusions, thus facilitating iron supplementation therapy and reducing transfusion requirement. MATERIAL AND METHODS: In an observational, retrospective study we compared RBC transfusion requirement during hospitalisation and within 3 months of hospital discharge in 88 patients with iron deficiency anaemia treated with high-dose ferric carboxymaltose and in 85 patients treated with ferric gluconate while hospitalised in the Internal Medicine unit of our Institution. RESULTS: Ferric carboxymaltose reduced the number of RBC units given to each transfused patient during hospitalisation (1.81±0.84 vs 2.39±1.49, p=0.011). At hospital discharge, fewer ferric carboxymaltose patients were prescribed home therapy with iron. No differences between treatment groups were observed in the proportion of patients or the number of RBC units transfused within 3 months of discharge. At one month from discharge, however, only 2 ferric carboxymaltose patients had been transfused compared with 7 ferric gluconate patients (p=0.078). Patients transfused post-discharge were more likely to have an underlying malignancy and/or higher serum creatinine concentrations. DISCUSSION: Treatment with ferric carboxymaltose reduced the number of RBC units per transfused patient. Larger studies are required to define risk factors associated with post-discharge transfusion requirement and to establish if home therapy with iron will reduce subsequent transfusions in patients treated with ferric carboxymaltose.

Anemia in patients with Covid-19: pathogenesis and clinical significance.

COVID-19 patients typically present with lower airway disease, although involvement of other organ systems is usually the rule. Hematological manifestations such as thrombocytopenia and reduced lymphocyte and eosinophil numbers are highly prevalent in COVID-19 and have prognostic significance. Few data, however, are available about the prevalence and significance of anemia in COVID-19. In an observational study, we investigated the prevalence, pathogenesis and clinical significance of anemia among 206 patients with COVID-19 at the time of their hospitalization in an Internal Medicine unit. The prevalence of anemia was 61% in COVID-19, compared with 45% in a control group of 71 patients with clinical and laboratory findings suggestive of COVID-19, but nasopharyngeal swab tests negative for SARS-CoV-2 RNA (p = 0.022). Mortality was higher in SARS-CoV-2 positive patients. In COVID-19, females had lower hemoglobin concentration than males and a higher prevalence of moderate/severe anemia (25% versus 13%, p = 0.032). In most cases, anemia was mild and due to inflammation, sometimes associated with iron and/or vitamin deficiencies. Determinants of hemoglobin concentration included: erythrocyte sedimentation rate, serum cholinesterase, ferritin and protein concentrations and number of chronic diseases affecting each patient. Hemoglobin concentration was not related to overall survival that was, on the contrary, influenced by red blood cell distribution width, age, lactate dehydrogenase and the ratio of arterial partial oxygen pressure to inspired oxygen fraction. In conclusion, our results highlight anemia as a common manifestation in COVID-19. Although anemia does not directly influence mortality, it usually affects elderly, frail patients and can negatively influence their quality of life.

Cell Blood Count Alterations and Patterns of Anaemia in Autoimmune Atrophic Gastritis at Diagnosis: A Multicentre Study.

BACKGROUND: Autoimmune atrophic gastritis (AAG) leads to iron and/or vitamin B12 malabsorption, with subsequent haematological alterations which could represent the sole clinical manifestation. We aimed to assess patterns of anaemia and micronutrient deficiencies in patients with AAG at the time of diagnosis. METHODS: Observational, multicentre, cross-sectional study including consecutive adult patients diagnosed with AAG within the last ten years. Cell blood count, red cell distribution width, serum vitamin B12, and ferritin were collected. Multivariate analysis for predictive factors of anaemia was computed. RESULTS: 654 AAG patients (mean age 59.2 ± 13.8 years, female (F): male (M) ratio = 2.3:1) were included. Anaemia was present in 316 patients (48.3%; mean age 60.1 ± 15.8 years, F:M ratio = 2.3:1). Pernicious anaemia (132/316 cases, 41.7%) was more common in males (27.1% versus 12.4%; p = 0.001) and in older patients (63.0 ± 14.6 versus 58.9 ± 14.9 years; p = 0.014), while iron deficiency anaemia (112/316 cases, 35.4%) was more common in females (16.9% versus 10.0%; p = 0.039) and in younger patients (56.8 ± 16.6 versus 60.2 ± 14.6 years; p = 0.043). The prevalence of iron deficiency was equally distributed between anaemic and non-anaemic patients (p = 0.9). Anisocytosis (odds ratio: 10.65, 95% confidence interval: 6.13-18.50, p < 0.0001) was independently associated with anaemia. CONCLUSIONS: Anaemia is a common manifestation in AAG patients, mostly due to micronutrient deficiencies. Scant haematologic alterations and micronutrient deficiencies may precede overt anaemia.

Pathogenesis, diagnosis and treatment of anaemia in immune-mediated gastrointestinal disorders.

Immune-mediated disorders affecting the gastrointestinal (GI) tract may compromise GI integrity, interfere with the absorption of nutrients and cause bleeding and inflammation. All these features contribute to the pathogenesis of anaemia, the most prevalent extra-intestinal manifestation of immune-mediated GI disorders. Anaemia is most commonly due to iron deficiency and/or inflammation, but vitamin deficiencies and, more infrequently, autoimmune haemolysis or drug-induced myelosuppression can be involved. Here we address several issues related to the differential diagnosis and treatment of anaemia in immune-mediated GI disorders, giving particular relevance to the problem of iron deficiency anaemia associated with inflammation. It is emphasized how, in most cases, anaemias due to iron or vitamin deficiencies are best treated by parenteral administration of the deficient factor(s), and how the available high dose intravenous (IV) iron formulations can reduce ambulatory and social costs of IV iron supplementation, while improving patient's compliance to treatment. Actual and future treatment possibilities for anaemia of inflammation, involving the use of erythropoiesis stimulating agents, biologicals and hepcidin inhibitors are discussed.

Increase in chromogranin A- and serotonin-positive cells in pouch mucosa of patients with ulcerative colitis undergoing proctocolectomy.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with neuroendocrine cell hyperplasia. AIMS: We investigated neuroendocrine cells in J-pouches of patients with ulcerative colitis undergoing restorative proctocolectomy and ileal pouch-anal anastomosis. METHODS: Sections from pouch biopsies of 17 patients and ileal biopsies of 17 active IBD patients and 16 controls were processed by immunohistochemistry for chromogranin A (CgA) and serotonin. Mucosal tryptophan hydroxylase (TpH)-1 and serotonin-selective reuptake transporter (SERT) transcripts were measured by quantitative RT-PCR. TpH-1 and SERT transcripts were detected in pouch biopsies cultured with infliximab or its isotype control, while interleukin (IL)-6 and IL-8 were measured in biopsy supernatants. RESULTS: A significant increase in CgA-positive cells and serotonin-positive cells was observed in both pouch and IBD ileum compared to control ileum. Significantly raised transcripts of TpH-1, but not SERT, were found in IBD ileum in comparison to control ileum, with no significant difference between pouch and IBD ileum. Infliximab had no influence on ex vivo pouch expression of TpH-1 and SERT, nor on the production of IL-6 and IL-8. CONCLUSION: We here demonstrated neuroendocrine cell hyperplasia in pouch mucosa. Further studies are needed to clarify the pathophysiological implication of this finding.

Intestinal expression of genes implicated in iron absorption and their regulation by hepcidin.

BACKGROUND & AIMS: Through inhibition of iron absorption and iron mobilization from tissue stores, hepcidin exerts a negative control on iron homeostasis. Hepcidin, in fact, promotes the degradation of ferroportin (Fpn1), the iron exporter molecule expressed on the membrane of hepatocytes and macrophages, thus preventing iron release from cells to plasma. Hepcidin effects on enterocytes, however, are less clear. Aim of the present study was to further investigate the regulation of iron absorption by hepcidin. METHODS: The transcriptional response of human duodenal mucosa to hepcidin was investigated using organ cultures of duodenal biopsies perendoscopically collected from healthy controls. Biopsies were cultured for 4 h with or without hepcidin-25 and were then assayed for the expression of iron-related genes. RESULTS: In samples that had not been exposed to hepcidin, correlations were found between the expression of genes involved in iron absorption: DMT1, Fpn1, Dcytb and HCP1. In ex vivo experiments hepcidin down-regulated mRNA levels of the iron transporters Fpn1, and DMT1, of the ferric reductase Dcytb, of the ferroxidase hephaestin, and of the putative heme carrier protein HCP1. CONCLUSIONS: Through the reported transcriptional changes hepcidin can modulate several steps of the iron absorption process, including the reduction of dietary iron by Dcytb, its uptake by enterocytes through DMT1, the mucosal uptake of heme iron by HCP1, and enterocyte iron release to plasma by Fpn1 in conjunction with hephaestin.

Prevalence of anemia in inflammatory bowel diseases in european countries: a systematic review and individual patient data meta-analysis.

BACKGROUND: The main objective is to determine the overall prevalence of anemia in inflammatory bowel diseases (IBD) in Europe. METHODS: A systematic literature search in PubMed and Embase was performed for studies published between January 2007 and May 2012. Eligible studies were included if they were original full-paper publications originated from Europe and if the authors agreed to provide their data. An overall prevalence of anemia in IBD, disease specific, and age-gender stratified basis prevalences were estimated. The influence of disease entity (Crohn's disease/ulcerative colitis), gender, age, disease activity (remission/active disease), and IBD-specific treatment strategies on the prevalence of anemia was analyzed by a mixed logistic regression model. Thereby, the factor country of origin was included as a random effect. RESULTS: Data were available for 2192 patients, mainly treated in tertiary referral centers. The overall prevalence of anemia in IBD patients was 24% (95% confidence interval, 18-31). Age-gender stratified prevalences were estimated for the age strata 18 to 29, 30 to 39, 40 to 49, 50 to 64, 65 to 74, >74 years and ranged from 18% to 35%. Patients receiving IBD-specific medication (P = 0.0002, odds ratio 1.54), and patients with active disease status (P < 0.0001, odds ratio 2.72) were significantly more likely to have anemia compared with patients not receiving IBD-specific medication or being in remission. Patients with ulcerative colitis tended to have anemia less likely than patients with Crohn's disease (P = 0.01, odds ratio 0.77). CONCLUSIONS: The overall prevalence of anemia in patients with Crohn's disease was 27% (95% confidence interval, 19-35) and 21% (95% confidence interval, 15-27) in patients with ulcerative colitis. Thereby, 57% of the anemic patients were iron deficient.

Increase in neuroendocrine cells in the duodenal mucosa of patients with refractory celiac disease.

OBJECTIVES: Several immune-mediated gastrointestinal disorders, including celiac disease (CD), are associated with neuroendocrine cell hyperplasia. However, neuroendocrine cells have never been explored in refractory CD (RCD). METHODS: Serial duodenal sections from 17 patients with RCD (6 type 1 and 11 type 2), 16 uncomplicated CD patients before and after gluten-free diet, 14 patients with potential CD, 27 patients with non-CD villous atrophy, i.e., common variable immunodeficiency (n=12), Whipple's disease (n=10) and giardiasis (n=5), and 16 healthy subjects were processed for the immunohistochemical detection of chromogranin A (CgA), serotonin, and somatostatin. Mucosal tryptophan hydroxylase (TpH)-1 and serotonin-selective reuptake transporter (SERT) transcripts were measured by quantitative reverse transcription-PCR. Serum CgA and 24-h urine 5-hydroxyindoleacetic acid (5-HIAA) were assessed. Biopsies from treated CD patients were cultured with serotonin or peptic tryptic digest of gliadin (PT-gliadin), and interferon (IFN)-γ was detected by ELISA in culture supernatants. RESULTS: Epithelial cells positive for CgA and serotonin, but not somatostatin, were significantly increased in RCD. Raised mucosal transcripts of TpH-1, but not SERT, were found in RCD. On biopsies from treated CD patients, serotonin upregulated IFN-γ production at levels comparable to those induced by PT-gliadin. Serum CgA, but not urine 5-HIAA, was increased in RCD. No significant difference was found between RCD type 1 and type 2 in terms of neuroendocrine cells, mucosal TpH-1 transcripts, and serum CgA. CONCLUSIONS: Serotonin-producing neuroendocrine cells are increased in RCD mucosa. IFN-γ upregulation induced by serotonin suggests that this monoamine may have a role in sustaining the local inflammatory response in CD.

Serum hepcidin in inflammatory bowel diseases: biological and clinical significance.

BACKGROUND: Hepcidin, a peptide produced by hepatocytes, regulates body iron homeostasis. Inflammation increases serum hepcidin, and its determination can be useful in the differential diagnosis of anemias during inflammatory diseases. METHODS: We measured serum hepcidin-25 and hepcidin-20 isoforms in 54 patients with inflammatory bowel diseases (IBD) and 54 reference subjects (36 healthy controls and 18 anemic patients without inflammation or renal failure). Disease activity, blood counts, iron status, and erythropoiesis-related parameters were obtained for all study subjects. RESULTS: In IBD hepcidin-25, the peptide bioactive isoform correlated positively with C-reactive protein and serum ferritin; an inverse correlation was observed with transferrin, the soluble transferrin receptor, and the soluble transferrin receptor to Log(ferritin) ratio. Similar correlations were found in reference subjects. Patients with anemia of inflammation had higher hepcidin-25 levels than those with iron deficiency anemia or a combination of iron deficiency anemia and inflammation (P = 0.0061). In patients with inflammation and serum ferritin concentration 100 to 200 ng/mL, hepcidin-25 was low, suggesting that these patients had iron deficiency. A serum hepcidin-25 concentration below 2.0 nM differentiated 85% of patients with iron deficiency anemia (with or without inflammation) from patients with anemia of inflammation. In IBD, hepcidin-20 correlated with both hepcidin-25 and C-reactive protein. CONCLUSIONS: In IBD, iron stores, inflammation, and iron requirement for erythropoiesis influence serum hepcidin-25. Hepcidin-25 determination can be useful in the differential diagnosis of IBD-associated anemias. Serum hepcidin-20 is linked to hepcidin-25, but inflammation has an independent regulatory role on its concentration, indicating that hepcidin-20 may have a biological function.

Effects of mitochondrial ferritin overexpression in normal and sideroblastic erythroid progenitors.

In myelodysplastic syndromes with ring sideroblasts (MDS-RS), the iron deposited in the mitochondria of RS is present in the form of mitochondrial ferritin (FTMT), but it is unknown whether FTMT overexpression is the cause or the result of mitochondrial iron deposition. Lentivirus FTMT-transduced CD34(+) bone marrow cells from seven healthy donors and CD34(+) cells from 24 patients with MDS-RS were cultured according to a procedure that allowed the expansion of high numbers of erythroid progenitors. These cells were used to investigate the possible influence of experimentally-induced FTMT overexpression on normal erythropoiesis and the functional effects of FTMT in sideroblastic erythropoiesis. In MDS-RS progenitors, FTMT overexpression was associated with reduced cytosolic ferritin levels, increased surface transferrin receptor expression and reduced cell proliferation; FTMT effects were independent of SF3B1 mutation status. Similarly, FTMT overexpressing normal erythroid progenitors were characterized by reduced cytosolic ferritin content and increased CD71 expression, and also by higher apoptotic rate in comparison with the FTMT- controls. Significantly lower levels of STAT5 phosphorylation following erythropoietin stimulation were found in both sideroblastic and normal FTMT(+) erythroid cells compared to the FTMT- cells. In conclusion, experimental overexpression of FTMT may modify mitochondrial iron availability and lead to ineffective erythropoiesis.

Spleen endothelial cells from patients with myelofibrosis harbor the JAK2V617F mutation.

Increased microvessel density contributes to abnormal BM and spleen microenvironment in myelofibrosis (MF). Taking advantage of the JAK2V617F mutation as a marker of malignancy, in the present study, we investigated whether splenic endothelial cells (ECs) obtained from capillaries by laser microdissection or from fresh spleen tissue by cell culture or cell sorting harbored such mutation in patients bearing the mutation in their granulocytes and undergoing splenectomy for therapeutical reasons. To extend the analysis to the ECs of large vessels, endothelial tissue from the splenic vein was also studied. We found JAK2V617F(+) ECs in 12 of 18 patients also bearing the mutation in their granulocytes. In 3 patients, the mutation was found in at least 2 different EC samples obtained by laser microdissection, cell culture, or cell sorting. The mutation was detected in the splenic vein ECs of 1 of 6 patients investigated. In conclusion, we provide evidence that some ECs from the spleen and splenic veins of patients with MF bear the JAK2V617F mutation. We suggest that splenic ECs are involved in the process of malignant transformation in MF.