Background: A diet rich in fiber, especially soluble fiber, causes cholestatic liver damage and fibrosis in animal models with intestinal dysbiosis, high serum bile acid concentrations, and congenital portosystemic shunts (PSs), but no data on patients with cirrhosis (CIRs) are available. Objectives: To investigate whether dietary fiber consumption was associated with clinical outcomes of CIRs and whether their effect differed according to the presence of PSs. Methods: Daily soluble and insoluble fiber intake was extrapolated from 3-d food diaries in 25 patients with chronic hepatitis (CH) and 80 CIRs outpatient liver transplant candidates abstinent from alcohol and nonviremic for ≥6 mo. In CIRs, the presence of PSs was verified by computed tomography, and the model for end-stage liver disease (MELD) score was calculated at enrollment and after 6 mo. Results: PSs were present in 48 (60%) CIRs. The MELD score after 6 mo, compared with enrollment, had improved in 19 and 10 CIRs with and without PSs, respectively. By adjusting for confounders in logistic regression models we found that improvement in MELD over time was inversely associated with insoluble fiber consumption expressed in milligrams per kilogram (mg/kg) body weight in CIRs without PSs [odds ratio (OR): 0.968; 95% confidence interval (CI): 0.939, 0.997; P = 0.005] but with soluble fiber consumption in CIRs with PSs [OR: 0.946; 95% CI: 0.912, 0.982; P = 0.001]. In CIRs with PSs, soluble fiber consumption was inversely associated with normal serum alkaline phosphatase values at enrollment [OR: 0.964; 95% CI: 0.963, 0.993; P = 0.010]. CHs with normal serum alanine transaminase consumed significantly more soluble fiber (p=0.015) than those with abnormal alanine transaminase. Conclusions: The clinical impact of dietary fiber changes from beneficial to harmful as the stage of chronic liver disease progresses. In particular, in the advanced cirrhosis stage with PSs, soluble fiber intake appears to significantly influence disease progression and should be kept low.

BACKGROUND AND AIMS:We aimed to characterize the epidemiologic and comorbidities profiles of patients with chronic Hepatitis D (CHD) followed in clinical practice in Italy and explored their interferon (IFN) eligibility. METHODS:This was a cross-sectional study of the PITER cohort consisting of consecutive HBsAg-positive patients from 59 centers over the period 2019-2023. Multivariable analysis was performed by logistic regression model. RESULTS:Of 5492 HBsAg-positive enrolled patients, 4152 (75.6%) were screened for HDV, 422 (10.2%) were anti-HDV positive. Compared with HBsAg mono-infected, anti-HDV positive patients were more often younger, non-Italians, with a history of drug use, had elevated alanine transaminase (ALT), cirrhosis, or hepatocellular carcinoma (HCC). Compared with Italians, anti-HDV positive non-Italians were younger (42.2% age ≤ 40 years vs. 2.1%; P < 0.001), more often females (males 43.0% vs. 68.6%; P < 0.001) with less frequent cirrhosis and HCC. HDV-RNA was detected in 63.2% of anti-HDV-positive patients, who were more likely to have elevated ALT, cirrhosis, and HCC. Extrahepatic comorbidities were present in 47.4% of anti-HDV positive patients and could affect the eligibility of IFN-containing therapies in at least 53.0% of patients in care. CONCLUSIONS:CHD affects young, foreign-born patients and older Italians, of whom two-thirds had cirrhosis or HCC. Comorbidities were frequent in both Italians and non-Italians and impacted eligibility for IFN.

Background: Porto-sinusoidal vascular disease（PSVD） and portal vein thrombosis（PVT） are causes of portal hypertension characterized respectively by an intrahepatic and a pre-hepatic obstacle to the flow in the portal system. As PVT may be a consequence of PSVD, in PVT patients at presentation, a pre-existing PSVD should be suspected. In these patients the identification of an underlying PSVD would have relevant implication regarding follow-up and therapeutic management, but it could be challenging. In this setting ultrasonography may be valuable in differential diagnosis. The aim of the study was to use ultrasonography to identify parameters to discriminate between PSVD and “pure” PVT and then to suspect PVT secondary to a pre-existing PSVD. Methods: Fifty-three patients with histologically proven PSVD and forty-eight patients affected by chronic PVT were enrolled and submitted to abdominal ultrasonography with elastography by acoustic radiation force impulse（ARFI）. Results: ARFI was higher and superior mesenteric vein（SMV） diameter was wider in PSVD patients than in PVT patients. Thus, a prognostic score was obtained as linear combinations of the two parameters with a good discrimination capacity between PSVD and PVT（the area under the curve = 0.780; 95% confidence interval: 0.690-0.869）. Conclusions: A score based on ARFI and SMV diameter may be useful to suspect an underlying PSVD in patients with PVT and to identify a subgroup of patients to be submitted to liver biopsy.

Adeno-associated virus-based gene therapy (valoctocogene roxaparvovec) is an attractive treatment for hemophilia A. Careful clinical management is required to minimize the risk of hepatotoxicity, including assessment of baseline liver condition to determine treatment eligibility and monitoring liver function after gene therapy. This article describes recommendations (developed by a group of hemophilia experts) on hepatic function monitoring before and after gene therapy. To prevent harmful liver-related effects, gene therapy is contraindicated in patients with uncontrolled liver infections, autoimmune hepatitis, liver stiffness >= 8 kPa, or cirrhosis. Before using gene therapy in patients with liver steatosis or other liver disorders, the risk of liver damage should be considered using a highly individualized approach. Treatment is not recommended in patients with abnormal liver enzymes, including alanine aminotransferase (ALT) at any level above the upper limit of normal (ULN). Therefore, pretreatment assessment of liver health should include laboratory tests, abdominal ultrasound, and liver stiffness measurements by transient elastography (TE). In the first year after therapy, ALT levels should be monitored 1 to 2 times per week to detect elevations >= 1.5x ULN, which may require immunosuppressant therapy. Patients with ALT elevation should receive prednisone 60 mg/d for 2 weeks, followed by stepwise tapering when ALT returns to baseline. ALT monitoring should continue long term (every 3-6 months), along with abdominal ultrasound (every 6 months) and TE (yearly) evaluations. When patients with good liver health are selected for treatment and closely monitored thereafter, ALT elevations can be promptly treated and are expected to resolve without long-term hepatic sequelae.

Background/Objectives: Low fasting blood lysosomal acid lipase (LAL) activity is associated with the pathogenesis of metabolic hepatic steatosis. We measured LAL activity in blood and plasma before and after an oral fat tolerance test (OFTT) in patients with metabolic-dysfunction-associated steatotic liver disease (MASLD). Methods: Twenty-six controls and seventeen patients with MASLD but without diabetes were genotyped for the patatin-like phospholipase 3 (PNPLA3) rs738409 variant by RT-PCR and subjected to an OFTT, measuring LAL activity in blood and plasma with a fluorimetric method. Results: LAL activity in blood both under fasting and 4 h after OFTT (0.846 ± 0.309 nmol/spot/h vs. 1.180 ± 0.503 nmol/spot/h p < 0.01) was lower in patients with MASLD compared to controls. These differences were present only in carriers of the PNPLA3 variant. In controls not carrying the PNPLA3 variant, the postprandial increase in blood LAL activity was negatively correlated with that of serum triglycerides (p < 0.05). Extracellular LAL activity in plasma was lower in patients with MASLD (n = 9) compared to controls (n = 8) in the fasting state (p < 0.01) and 4 h post-meal (p < 0.05). The area under the curve up to 6 h of plasma LAL activity was lower in patients with MASLD than in controls (p < 0.05) and correlated negatively with that of triglycerides only in controls (r = −0.841; p < 0.01). Conclusions: Patients with MASLD have reduced LAL activity in blood and plasma both before and 4 h after a meal. In patients with MASLD, the physiological negative correlation between circulating LAL levels and postprandial hypertriglyceridemia is lost.

Mixed cryoglobulinemia vasculitis (MCV) is caused in ~90% of cases by chronic hepatitis C virus (HCVposMCV) and more rarely by hepatitis B virus (HBV) infection, or apparently noninfectious. HCVposMCV develops in only ~5% of patients with chronic hepatitis C (CHC), but risk factors other than female gender have not been identified so far. We conducted a retrospective case control study investigating whether past active HBV infection, defined by hepatitis B surface antigen (HBsAg) seroclearance and anti-core antibody (HBcAb) positivity, could be a risk factor for developing HCVposMCV. The prevalence of HBsAg seroclearance was 48% within 123 HCVposMCV patients and 29% within 257 CHC patients (p=0.0003). Multiple logistic regression including as variables gender, birth year, age at HBV testing, cirrhosis, and hepatocellular carcinoma, confirmed an association of HBsAg seroclearance with HCVposMCV [adjusted odds ratio (OR) 2.82, 95% confidence interval (95% CI) 1.73-4.59, p<0.0001]. Stratification by gender, however, showed that HBsAg seroclearance was associated with HCVposMCV in male [OR 4.63, 95% CI 2.27-9.48, p<0.0001] and not in female patients [OR 1.85, 95% 95% CI 0.94-3.66, p=0.076]. HBsAg seroclearance, and more likely occult HBV infection, is an independent risk factor for HCVposMCV in male CHC patients.

Introduction Radiofrequency thermo-ablation (RFTA) and trans-arterial chemoembolization (TACE) represent effective therapeutic strategies for cirrhotic patients with hepatocellular carcinoma (HCC). It has been proposed that body composition parameters, particularly skeletal muscle index (SMI), may predict outcomes in patients with HCC. However, only few studies investigated the role of visceral (VATI) and subcutaneous adipose tissue index (SATI) on patients' outcomes, and no data are available on the effect of their post-treatment changes in patients with HCC. Aims to investigate the impact of early post-treatment changes in body composition parameters on the overall-survival (OS) of cirrhotic patients with HCC and on the probability of being transplanted. Methods All cirrhotic patients with HCC treated for the first time with TACE or RFTA from 2012 to 2021 were retrospectively enrolled. Early changes of body composition (SMI, SATI and VATI) were extrapolated from abdominal CT scan performed before and one month after treatment and expressed as DELTA, following the formula: (one-month value- pre-procedure value)/ elapsed time. OS and probability of being transplanted were investigated with Fine-Gray multivariate competing risk analysis considering, respectively, LT and HCC progression outside the LT criteria (up-to-seven) as competitive risk events. Results 189 patients were enrolled, 132 undergoing TACE and 57 RFTA. In the multivariate analysis, across the entire population, the early decrease of VATI (DELTA-VATI negative) one month after treatment was associated to a increased risk of death (SHR=1.636; 95.0% CI=1.230-1.979; P=0.018), adjusting for age, MELDNa, Up-to-seven status and DELTA-SMI. In a sub-analysis, conducted considering only patients potentially eligible for LT, the early decrease in SMI (DELTA-SMI negative), but not in VATI was significantly associated to the need for LT (SHR=5.155; 95.0% CI=4.212-6.098; P<0.0001). Conclusions early body composition parameters post-treatment changes are useful in identifying cirrhotic patients with HCC at increased risk of death or need of LT.

(1) Background: We investigated, for the first time, whether dietary simple sugar intake affects MELD score changes over time in a cohort of cirrhotic liver transplant candidates. (2) Methods: the MELD score, dietary habits using a 3-day food diary, and visceral adipose tissue index (VATI) measured with CT scan were assessed in 80 consecutive outpatient cirrhotic patients at baseline, after counseling to follow current nutritional guidelines. The MELD score was reassessed after six months and the DELTA-MELD was calculated as the MELD at the second assessment minus the MELD at baseline. (3) Results: Compared with the baseline, the MELD score of cirrhotic patients at the end of the study was decreased, stable, or increased in 36%, 8% and 56% of patients, respectively. In separate multiple linear regression models, DELTA-MELD was positively and independently correlated with the daily intake of simple sugars expressed in g/kg body weight (p = 0.01) or as a percentage of total caloric intake (p = 0.0004) and with the number of daily portions of fruit, added sugar, jam, and honey (p = 0.003). These associations were present almost exclusively in patients with VATI above the median value. (4) Conclusions: In cirrhotic patients with high amounts of visceral adipose tissue the consumption of simple sugars and fructose should be limited to improve their clinical outcome.

Aims Radiomics uses radiological imaging to generate multi-dimensional data, defined as features. The novelty of radiomics is the possible correlation with clinical endpoints, mostly in oncological diseases. We present results of a retrospective study investigating correlations between pretreatment imaging radiomics and clinical outcomes in Patients (Pts.) with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE).

Fibroblast growth factor 21 (FGF-21), previously recognized as a marker of liver damage and a potential drug target in non-alcoholic fatty liver disease (NAFLD), has unclear implications in hepatitis C virus (HCV) infections. This study aimed to investigate the relationship between FGF-21 levels and liver health in patients with HCV undergoing direct-acting antiviral (DAA) treatment. Forty-five patients were assessed for liver stiffness, blood chemistry, and other relevant metrics before and after achieving sustained viral response (SVR), defined as the absence of detectable HCV-RNA after 24 weeks of treatment. Post-treatment, all patients showed a decrease in liver stiffness and improved liver enzyme levels (AST and ALT), alongside an increase in FGF-21 levels. Interestingly, the increase in FGF-21 correlated negatively with liver stiffness but showed no correlation with hepatic steatosis. The observed elevation in FGF-21 levels at SVR following DAA therapy for chronic HCV infection can be attributed to the restoration of hepatic function, including its synthetic capabilities. Specifically, the mitigation of liver fibrosis post-HCV eradication is expected to lead to improvements in liver function, such as enhanced albumin and FGF-21 production. This improvement in synthetic function likely drives the increase in FGF-21 levels, rather than changes in liver fat content. We suggest a potential role of FGF-21 as a marker of fibrosis and hepatic cytotoxicity and as a drug target beyond NAFLD, to be confirmed by additional studies.

Background Liver involvement in adults with acute myeloid leukemia is uncommon. Most of the case reports describe acute liver failure or obstructive jaundice, while acute hepatitis is rarely mentioned. We report a patient with acute myeloid leukemia who presented with clinical, biochemical, and radiological signs of acute hepatitis that totally regressed after chemotherapy. Case presentation A 38-year-old Caucasian man presented with fever, cough, and mild fatigue. Laboratory workup showed anemia, thrombocytopenia, severe leukocytosis, transaminitis, and hyperbilirubinemia. Imaging of the abdomen (ultrasound and magnetic resonance) showed hepatomegaly, splenomegaly, upper limits portal veins diameters, increased thickness of the gallbladder wall, and significant abdominal lymph nodes. Peripheral blood smear and bone marrow evaluation were consistent with acute myeloid leukemia, and liver biopsy showed massive sinusoidal and portal infiltration by leukemic cells. After remission-inducing chemotherapy, there was complete normalization of liver function tests, and liver, spleen, and portal vein size. Conclusions This case highlights the importance of taking acute myeloid leukemia into account as a possible cause of liver damage to make a rapid diagnosis and start appropriate treatment that may lead to hematological remission and hepatic dysfunction resolution.

This study aimed to ascertain, for the first time, whether serum magnesium (Mg) concentration is affected by the presence of hepatocellular carcinoma (HCC). We retrospectively enrolled consecutive cirrhotic patients with a diagnosis of HCC (n = 130) or without subsequent evidence of HCC during surveillance (n = 161). Serum levels of Mg were significantly (P < 0.001) lower in patients with HCC than in those without (median [interquartile range]: 1.80 [1.62–1.90] mg/dl vs. 1.90 [1.72–2.08] mg/dl). On multivariate logistic regression, low serum Mg was associated with the presence of HCC (OR 0.047, 95% CI 0.015–0.164; P < 0.0001), independently from factors that can influence magnesaemia and HCC development. In a subset of 94 patients with HCC, a linear mixed effects model adjusted for confounders showed that serum Mg at diagnosis of HCC was lower than before diagnosis of the tumor (β = 0.117, 95% CI 0.039–0.194, P = 0.0035) and compared to after locoregional treatment of HCC (β = 0.079, 95% CI 0.010–0.149, P = 0.0259), with two thirds of patients experiencing these changes of serum Mg over time. We hypothesize that most HCCs, like other cancers, may be avid for Mg and behave like a Mg trap, disturbing the body’s Mg balance and resulting in lowering of serum Mg levels.

The Coronavirus Disease (COVID-19) pandemic imposes a high burden of morbidity and mortality worldwide. Several vaccines have been developed to curb the plague and currently represent the most important weapon for this fight. The currently available SARS-CoV-2 vaccines are either lipid nanoparticle/mRNA-based or adenoviral vector vaccines. These vaccines proved effective in preventing severe disease and death in phase-III randomized clinical trials, without significant safety warnings [1Folegatti P.M. Ewer K.J. Aley P.K. et al.Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial.Lancet. 2020; 396: 467-478Abstract Full Text Full Text PDF PubMed Scopus (1767) Google Scholar, 2Polack F.P. Thomas S.J. Kitchin N. et al.Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.N. Engl. J. Med. 2020; 383 (Available from:): 2603-2615Crossref PubMed Scopus (9627) Google Scholar]. This led to worldwide approval and mass administration. Shortly after, a rare syndrome characterized by atypical thrombosis and thrombocytopenia was described [3Greinacher A. Thiele T. Warkentin T.E. et al.Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination.N. Engl. J. Med. 2021; 384: 2092-2101Crossref PubMed Scopus (1564) Google Scholar, 4Umbrello M. Brena N. Vercelli R. et al.Successful treatment of acute spleno-Porto-mesenteric vein thrombosis after ChAdOx1 nCoV-19 vaccine. A case report.J. Crit. Care. 2021; 65: 72-75Crossref PubMed Scopus (16) Google Scholar, 5Lavin M. Elder P.T. O'Keeffe D. et al.Vaccine-induced immune thrombotic thrombocytopenia (VITT) – a novel clinico-pathological entity with heterogeneous clinical presentations.Br. J. Haematol. 2021; 195: 76-84Crossref PubMed Scopus (37) Google Scholar, 6Schultz N.H. Sørvoll I.H. Michelsen A.E. et al.Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination.N. Engl. J. Med. 2021; 384 (Available from:): 2124-2130Crossref PubMed Scopus (1028) Google Scholar]. This syndrome, defined as "vaccine-induced immune thrombotic thrombocytopenia" (VITT) [7Cines D.B. Bussel J.B. SARS-CoV-2 vaccine–induced immune thrombotic thrombocytopenia.N. Engl J. Med. 2021; 384 (Available from:): 2254-2256Crossref PubMed Scopus (356) Google Scholar, 8Afshar Z.M. Babazadeh A. Janbakhsh A. et al.Vaccine-induced immune thrombotic thrombocytopenia after vaccination against Covid-19: a clinical dilemma for clinicians and patients.Rev. Med. Virol. 2021; e2273PubMed Google Scholar], mainly occurred among otherwise healthy adults – mostly women, all vaccinated with SARS-CoV-2 adenoviral vector vaccines [3Greinacher A. Thiele T. Warkentin T.E. et al.Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination.N. Engl. J. Med. 2021; 384: 2092-2101Crossref PubMed Scopus (1564) Google Scholar], with an estimated prevalence of approximately 1 every 100.000 vaccinated adults [9European Medical Agency AstraZeneca's COVID-19 vaccine benefits and risks in context European Medicines Agency [Internet].https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vaccine-benefits-risks-contextDate: 2021Google Scholar]. Cerebral venous thrombosis was the most frequent type of thrombosis reported, with splanchnic thrombosis described only in exceptional cases [5Lavin M. Elder P.T. O'Keeffe D. et al.Vaccine-induced immune thrombotic thrombocytopenia (VITT) – a novel clinico-pathological entity with heterogeneous clinical presentations.Br. J. Haematol. 2021; 195: 76-84Crossref PubMed Scopus (37) Google Scholar]. The pathogenesis, diagnosis, and optimal treatment of VITT are largely unknown. A role for anti-platelet factor 4 (PF4) antibodies in its pathogenesis has been postulated [10Vayne C. Rollin J. Gruel Y. et al.PF4 immunoassays in vaccine-induced thrombotic thrombocytopenia.N. Engl. J. Med. 2021; 385: 376-378Crossref PubMed Scopus (80) Google Scholar], with high uncertainty on the underlying mechanisms, and poor knowledge of the platelet reactivity throughout the disease course. Interim guidance has been developed to aid physicians in treating this syndrome, with anticoagulation and high dose intravenous immunoglobulin (IVIG) currently proposed as first-line therapies [11Gresele P. Marietta M. Ageno W. et al.Management of cerebral and splanchnic vein thrombosis associated with thrombocytopenia in subjects previously vaccinated with Vaxzevria (AstraZeneca): a position statement from the Italian Society for the Study of Haemostasis and Thrombosis (SISET).Blood Transfus. 2021; 19: 281-283PubMed Google Scholar]. Plasma exchange (PE) has been described once as a tentative treatment for patients with refractory VITT [12Patriquin C.J. Laroche V. Selby R. et al.Therapeutic Plasma Exchange in Vaccine-Induced Immune Thrombotic Thrombocytopenia.N. Engl. J. Med. 2021; 385: 857-859Crossref PubMed Scopus (55) Google Scholar], but further confirmation are urgently needed to validate its use. We report a case of severe splanchnic thrombosis caused by VITT in a middle-aged man, successfully treated with PE; we also describe the activation state of circulating platelets during the disease course. A Caucasian 59-years-old man presented to the emergency department complaining of abdominal pain that worsened over five days. The patient received the first dose of the adenoviral vector anti-SARS-CoV-2 vaccine (ChAdOx1 nCoV-19) 8 days prior symptoms onset. His medical history was characterized by well-controlled arterial hypertension and obesity (BMI = 31.8 kg/m2, weight 115 kg), without previous history of venous or arterial thrombosis; he reported two siblings with history of myocardial infarction in their forties. Physical examination showed cutaneous purpura with a blister in the right arm, and diffuse tenderness of the abdomen, without rebound or rigidity; bowel sounds were present, without jaundice or pallor. A graphical representation of the clinical course and laboratory analyses of the patient is reported in Fig. 1. At admission, severe thrombocytopenia was observed (Platelet (PLT) count: 15.000/mm3), along with increased D-dimer (4309 μg/L- reference interval (r.i.) 0-550), low fibrinogen levels (117 mg/dL, r.i. 200-400), and slightly altered INR (1.28). Other laboratory tests were normal. An abdomen computed tomography (CT) showed complete portal vein thrombosis, with partial thrombosis of the superior mesenteric vein; subsequent CT scans excluded other sites of thrombosis, and a suspected diagnosis of VITT was made. Due to the bleeding risk, the patient underwent PLTs transfusion; in accordance with the Italian Society for the Study of Haemostasis and Thrombosis Guidelines [11Gresele P. Marietta M. Ageno W. et al.Management of cerebral and splanchnic vein thrombosis associated with thrombocytopenia in subjects previously vaccinated with Vaxzevria (AstraZeneca): a position statement from the Italian Society for the Study of Haemostasis and Thrombosis (SISET).Blood Transfus. 2021; 19: 281-283PubMed Google Scholar], the patient started treatment with Dexamethasone (40 mg/die), and IVIG (1 g/kg) for two consecutive days. On day 2, PLTs were 37.000/mm3, and we introduced fondaparinux 2.5 mg/die. On day 4, PLTs levels rose to 77.000/mm3, and fondaparinux was further increased to 7.5 mg/die. An enzyme-immunoassay (EIA) revealed high titre of anti-PF4 antibodies (day 4 – optical density (OD): 1.985), confirmed by functional test [13Guarino M.L. Massimi I. Mardente S. et al.New platelet functional method for identification of pathogenic antibodies in HIT patients, 28.Platelets Taylor and Francis Ltd. 2017; : 728-730Google Scholar]; both tests were strongly reduced in the presence of high concentrations of heparin (100 IU/mL), in accordance with a diagnosis of VITT. On day 5, a new abdomen CT scan showed progression of the splanchnic thrombosis, with complete occlusion of the splenic vein, superior mesenteric vein, and the splenomesenteric confluence; spleen and colon appeared congested and increase in total bilirubin levels (1.4 mg/dL) was also observed. From day 5 to day 8, the platelet count fluctuated between 70.000 and 90.000/mm3. On day 8, flow cytometric analysis of platelet surface receptors expression showed relatively normal levels of the stimulatory receptor glycoprotein (GP)VI and low levels of total integrin αIIb (CD41a) (Fig. 2, panel A and B, respectively), which fluctuated within the normal ranges throughout the clinical course and follow-up; on the contrary, circulating platelets expressed high levels of active integrin αIIbβ3 on their surface (PAC1-FITC median fluorescence intensity (MFI) = 219 -Fig. 2, Panel C), and a high ratio of active/total integrin (0.012) (Fig. 2, Panel D), compared to the levels found among 34 healthy controls (median 97.5, 97.5% Confidence Interval (CI) 68-137, and median 0.004, 97.5% CI 0.002-0.005 respectively). The anti-PF4 quantification assay (EIA) was repeated and confirmed a high antibody titre (OD: 1.782). The patient was considered refractory to treatment, and a rescue-treatment with PE was started on day 8; fondaparinux was also increased to 10 mg. On day 11, PLTs increased to 112.000/mm3, and an abdominal ultrasound (US) revealed partial recanalization of portal and superior mesenteric veins, with complete recanalization of splenic vein. This was accompanied by a reduction of the active integrin αIIbβ3 detected on the surface of circulating platelets (PAC1-FITC MFI = 81). A total of 6 cycles of PE were completed by day 15, when the platelet count reached 215.000/mm3. Contextually, Dexamethasone was tapered during the following days. Another US showed complete resolution of the splanchnic thrombosis on day 19. Platelet count remained stable above 150.000/mm3. In the meanwhile, inherited and acquired thrombophilia (including antiphospholipid syndrome) were excluded. However, on day 14 and day 21 we detected a progressive increase of platelet integrin activation (PAC1-FITC MFI = 136.5 and 183, respectively) and, on day 25, we observed a sudden drop of the platelet count. The patient did not report new symptoms, and his blood exam showed no significant new findings. On day 27, anti-PF4 antibodies levels were strongly reduced (OD:0.910), the functional test became negative, and an abdominal US excluded the recurrence of splanchnic thrombosis. On day 28, the integrin activation status of circulating platelets had decreased again (PAC1-FITC MFI = 97). A whole-body CT scan showed thrombosis of the right subclavian and axillar veins, in which a peripherally inserted central catheter had been placed on day 6. The device was promptly removed, and the patient was closely monitored, without change in therapy. On day 32, an US scan showed complete resolution of the right arm thrombosis, consistent with an increase in PLT count. The patient was discharged on day 39 in good clinical conditions, on treatment with fondaparinux 10 mg/die, prednisolone 25 mg, and is now attending scheduled follow-up visits. PLTs count remained above 170.000/mm3 during follow-up, and we also observed normal levels of PAC1-FITC and active/total integrin ratio. The patient is still treated with fondaparinux and is currently undergoing steroids tapering. No relapsing or new thrombotic events were observed during follow-up.Fig. 2Platelet surface receptor expression during hospital stay and follow-up. Panel A: glycoprotein GPVI; Panel B: integrin CD41a (total integrin αIIb); Panel C: PAC1 (active integrin αIIbβ3); Panel D: active/total integrin ratio.Show full captionLegend: CI = Confidence Intervals; GPVI = Glycoprotein VI; MFI = Median Fluorescence Intensity, PLT = Platelets, r.i.: reference intervals (compared to the levels found among 34 healthy controls).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Legend: CI = Confidence Intervals; GPVI = Glycoprotein VI; MFI = Median Fluorescence Intensity, PLT = Platelets, r.i.: reference intervals (compared to the levels found among 34 healthy controls). VITT is a rare adverse event of viral vectored SARS-CoV-2 vaccines. Most cases occurred in young adults (typically <60 years old), particularly women, without overt risk factors or known thrombophilia [14Schultz N.H. Sørvoll I.H. Michelsen A.E. et al.Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 Vaccination.N. Engl. J. Med. 2021; 384 (Available from:): 2124-2130Crossref PubMed Scopus (366) Google Scholar]. In our case, three major remarks should be made: first, the epidemiology and natural history of VITT is still largely unknown (our case occurred in a middle-aged man, and the thrombosis involved an uncommon and extensive vein district); second, refractory VITT may be treated effectively with PE, as previously described in a recent case series [12Patriquin C.J. Laroche V. Selby R. et al.Therapeutic Plasma Exchange in Vaccine-Induced Immune Thrombotic Thrombocytopenia.N. Engl. J. Med. 2021; 385: 857-859Crossref PubMed Scopus (55) Google Scholar]; third, knowledge on the platelet activation state during the course of the disease is urgently needed and may help to understand what causes VITT, its evolution, and what treatments may be useful. Beyond that, the mechanisms underlying VITT are still largely unknown [15Rzymski P. Perek B. Flisiak R. Thrombotic thrombocytopenia after covid-19 vaccination: In search of the underlying mechanism [Internet]. Vaccines. Multidisciplinary Digital Publishing Institute.https://www.mdpi.com/2076-393X/9/6/559/htmDate: 2021Google Scholar]. Similar platelet signaling patterns have been reported among patients with COVID-19-related thrombosis and VITT, suggesting that common mechanisms may be involved [16Kowarz E. Krutzke L. Reis J. et al."Vaccine-Induced Covid-19 Mimicry" Syndrome:Splice reactions within the SARS-CoV-2 Spike open reading frame result in Spike protein variants that may cause thromboembolic events in patients immunized with vector-based vaccines.PREPRINT (Version 1) available at Research Square. 2021; https://doi.org/10.21203/rs.3.rs-558954/v1Crossref Google Scholar, 17Apostolidis S.A. Sarkar A. Giannini H.M. et al.Signaling through FcγRIIA and the C5a-C5aR pathway mediates platelet hyperactivation in COVID-19. bioRxiv Prepr Serv Biol [Internet] Cold Spring Harbor Laboratory.https://www.biorxiv.org/content/10.1101/2021.05.01.442279v1Date: 2021Google Scholar]. A recent report demonstrated that the different binding properties of anti-PF4 antibodies detected in VITT and heparin-induced thrombocytopenia patients could explain why in the former, but not in the latter, antibodies do not need heparin to crosslink the FcγIIA receptor and activate platelets [18Huynh A. Kelton J.G. Arnold D.M. et al.Antibody epitopes in vaccine-induced immune thrombotic thrombocytopenia.in: Nature [Internet]. Nature Publishing Group, 2021: 1-7https://www.nature.com/articles/s41586-021-03744-4Google Scholar]. Alternatively, one could envisage that the nucleic acids contained in the vaccines promote the antibody crosslinking since previous reports showed that nucleic acids can bind PF4 [19Jaax M.E. Krauel K. Marschall T. et al.Complex formation with nucleic acids and aptamers alters the antigenic properties of platelet factor 4.Blood. 2013; 122: 272-281Crossref PubMed Scopus (122) Google Scholar]. All these hypotheses, however, still need confirmation in vivo, and insights on platelet activation during VITT course are urgently needed. In our case, the median fluorescence intensity of PAC1-FITC (that binds active αIIbβ3 on platelets), and the ratio of active/total integrin followed the thrombotic evolution mediated by anti-PF4 antibodies. Thus, we postulate that platelet integrin activation could represent a promising tool to diagnose and monitor the progression of VITT. This case underlines the high uncertainty surrounding our knowledge of VITT, particularly regarding risk factors, clinical presentation, and treatment, as for COVID-19 [20Romiti G.F. Talerico G. Embracing the uncertainty: an important lesson from COVID-19.J. Gen. Int. Med. 2021; : 1-3https://doi.org/10.1007/s11606-021-06809-2Crossref Scopus (9) Google Scholar]. While VITT is a rare event, and further studies are required to confirm our findings on PE efficacy and platelet reactivity, we believe that granular reporting of VITT cases is helpful to inform clinical practice and tackle the burden of VITT during this vaccination campaign. This case contributes to expand the knowledge on VITT and PE approach and suggests that flow cytometric analysis of integrin activation could be used to improve the surveillance of vaccinated individuals and the diagnosis of suspected VITT. SB received a research grant from MSD, outside the scope of this study. We thank the patient, who reviewed the manuscript, for giving his consent to publication. We thank Prof. Antonio Angeloni, Dr. Shafii Bafti Mahnaz, Dr. Martina Di Palma and the Immunohematology and Transfusion Medicine Unit of Policlinico Umberto I, Sapienza University of Rome, Italy for their involvement in the case management.

Rectal prolapse is a disorder in which the rectum protrudes from the anal canal. Solitary rectal ulcer may coexist. Both conditions have been associated with chronic constipation and excessive straining during defecation. Rectal prolapse has been rarely reported in women suffering from anorexia nervosa. Lack of rectal support because of loss of ischiorectal fat has been proposed as one of the possible mechanisms in this condition, together with chronic constipation and abuse of laxative. We report the case of an anorexic woman with a severe rectal prolapse and bleeding requiring urgent Altmeier's procedure. Surgery was complicated by dehiscence of the anastomosis and volvulus, requiring ileostomy and laciniae debridement. Pathological analysis of all the surgical samples taken from different abdominal sites highlighted changes in the visceral adipose tissue consisting in nodular aggregates of small adipocytes dispersed in a myxoid matrix surrounding blood vessels within abundant fibrosis. The morphologic features resemble those observed in primordial fetal fat and are comparable to those observed in cancer associated cachexia. The diffuse myxoid degeneration of visceral adipose tissue may play a role in the pathogenesis of rectal prolapse in patients with anorexia nervosa. Besides starvation, the mechanism sustaining myxoid degeneration of the adipose tissue is not entirely clear. Whenever possible improving nutritional and clinical conditions should be ideal before any surgical approach.

Sustained virological response (SVR) obtained with interferon (IFN) or with direct-acting antivirals (DAAs) is commonly followed by response of hepatitis C virus (HCV)-associated mixed cryoglobulinemia vasculitis (MCV), but relapse of MCV despite SVR has been reported in several patients after DAAs and rarely after IFN. Since relapses could have been overlooked in studies with IFN, we retrospectively compared the outcomes of MCV in SVR patients treated with DAAs (n = 70) or IFN (n = 39) followed-up, respectively, for 30.5 (range 11-51) or 48 months. Groups were comparable for demographics and clinics and response rates of MCV were similar (92% and 86%); however, DAA-treated patients less efficiently reduced cryoglobulins (P = .006) and circulating B-cell clones (P = .004), and had more frequently relapses of MCV (18% vs 3%, P = .028) and need for rituximab therapy (P = .01). Although largely inferior on an intention-to-treat basis, IFN may be superior to DAAs on clinico-immunological outcomes possibly owing to its antiproliferative activity.