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Background and Aims COVID-19 is associated with liver injury and elevated interleukin-6 (IL-6). We hypothesized that IL-6 trans-signaling in liver sinusoidal endothelial cells (LSECs) leads to endotheliopathy (a proinflammatory and procoagulant state) and liver injury in COVID-19. Methods Coagulopathy, endotheliopathy, and alanine aminotransferase (ALT) were retrospectively analyzed in a subset (n = 68), followed by a larger cohort (n = 3,780) of patients with COVID-19. Liver histology from 43 patients with COVID-19 was analyzed for endotheliopathy and its relationship to liver injury. Primary human LSECs were used to establish the IL-6 trans-signaling mechanism. Results Factor VIII, fibrinogen, D-dimer, von Willebrand factor (vWF) activity/antigen (biomarkers of coagulopathy/endotheliopathy) were significantly elevated in patients with COVID-19 and liver injury (elevated ALT). IL-6 positively correlated with vWF antigen (p = 0.02), factor VIII activity (p = 0.02), and D-dimer (p, Graphical abstract

Aim Coronavirus disease (COVID‐19) is characterized by pneumonia with secondary damage to multiple organs including the liver. Liver injury (elevated alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) often correlates with disease severity in COVID‐19 patients. The aim of this study is to identify pathological microthrombi in COVID‐19 patient livers by correlating their morphology with liver injury, and examine hyperfibrinogenemia and von Willebrand factor (vWF) as mechanisms of their formation. Methods Forty‐three post‐mortem liver biopsy samples from COVID‐19 patients were obtained from Papa Giovanni XXIII Hospital in Bergamo, Italy. Three morphological features of microthrombosis (sinusoidal erythrocyte aggregation [SEA], platelet microthrombi [PMT], and fibrous thrombi) were evaluated. Results We found liver sinusoidal microthrombosis in 23 COVID‐19 patients (53%) was associated with a higher serum ALT and AST level compared to those without (ALT: 10‐fold, p = 0.04; AST: 11‐fold, p = 0.08). Of 43 livers, PMT and SEA were observed in 14 (33%) and 19 (44%) cases, respectively. Fibrous thrombi were not observed. Platelet microthrombi were associated with increased ALT (p

The management of hepatic hemangioendothelioma (HHE) may be challenging. We aimed to review a large cohort of children who presented to our centers with symptomatic HHE in the last 16 years. We collected age at presentation, clinical features, histology, diagnostic process, management and outcome. Twenty seven patients (male/female 5/22), median age 13 days (1–1530) presented with hepatomegaly (24/27), cardiac failure (10/27), cutaneous hemangiomas (8/27), fever and anemia (6/27 each), vomiting (5/27), splenomegaly (4/27). The lesion was focal, multifocal, or diffuse in 9 patients of each group. The management included medical treatment (8/27), embolization (8/27), resection (3/27), observation (6/27), transplantation (2/27). After 16 months’ follow-up (30 days–11 years), 23/27 (85%) were alive. Diffuse lesions (4/4), cardiac failure (4/4), type II histology (4/4), age older than 6 months at diagnosis (3/4) predicted mortality (all p

SARS2‐CoV‐2 breakout in Italy caused a huge number of severely ill patients with a serious increase in mortality. Although lungs seem to be the main target of the infection, very few information are available about liver involvement, possibly evocating a systemic disease. Post‐mortem wedge liver biopsies from 48 patients died from severe pulmonary COVID‐19 disease with respiratory failure were collected from two main hospitals in northern Italy. No patient had clinical symptoms of liver disease or signs of liver failure before and during hospitalization; for each of them liver function tests were available. All liver samples showed minimal inflammation features. Histological pictures compatible with vascular alterations were observed, characterized by increase in number of portal vein branches associated with lumen massive dilatation, partial or complete luminal thrombosis of portal and sinusoidal vessels, fibrosis of portal tract, focally markedly enlarged and fibrotic. SARS‐CoV‐2 was found in 15 of 22 samples tested by in situ hybridization method. Our preliminary results confirm the clinical impression that liver failure is not a main concern and this organ is not the target of significant inflammatory damage. Histopathological findings are highly suggestive for marked derangement of intrahepatic blood vessel network secondary to systemic changes induced by virus that could target not only lung parenchyma but also cardiovascular system, coagulation cascade and endothelial layer of blood vessels. It still remains unclear if the mentioned changes are directly related to virus infection or if SARS‐CoV‐2 triggers a series of reactions leading to striking vascular alterations.

Ureteral malakoplakia is a rare pathological entity. We report the case of a 54-years-old woman with a single ureteral malakoplakic lesion. Patient presented with history of recurrent urinary tract infections and asymptomatic dilatation of right pelvis. Radiological investigations showed a right lower ureteric filling defect without bladder or kidney involvement. A first uretero-renoscopy allowed an extirpative biopsy, with a histopathologic diagnosis of malakoplakia. Second-look uretero-renoscopy showed only a minute area of hyperemic mucosa that was biopsied and coagulated, showing a residual focus of malakoplakia. At 12-months, imaging and blood test demonstrated reduction of hydronephrosis, serum creatinine recovery and no recurrences.

COVID-19 breakout in Italy has caused a huge number of severely ill patients with a serious increase in mortality. Although lungs seem to be the main target of the infection very few information are available about liver involvement in COVID-19 infection, that could possibly evocate a systemic disease targeting a lot of organs. Since now there are no reports of large series of histological evaluation of liver morphology in this setting. Knowledge of histological liver findings connected to clinical data is crucial in management of this disease. Post-mortem wedge liver biopsies from 48 patients died for COVID-19 infection were available from two main hospitals located in northern Italy, Lombardy; all sample were obtained during autopsies. No patient has a significant clinical complain of liver disease or signs of liver failure before and during hospitalization; for each of them laboratory data focused on liver were available. All liver samples showed minimal inflammation features; on the other side, many histological pictures compatible with vascular alterations were observed, characterized by portal vein braches number increase associated with lumen massive dilatation, partial or complete recent luminal thrombosis of portal and sinusoidal vessels, fibrosis of portal tract, focally severely enlarged and fibrotic. Our preliminary results concerning histological liver involvement in COVID-19 infection confirm the clinical impression that liver failure is not a main concern and this organ is not the target of significant inflammatory damage; histopatological findings are highly suggestive for marked alteration of intrahepatic blood vessel network secondary to systemic alterations induced by virus that could target, besides lung parenchyma, cardiovascular system, coagulation cascade or endothelial layer of blood vessels.

Background: COVID-19 breakout in Italy caused a huge number of severely ill patients with a serious increase in mortality. Although lungs seem to be the main target of the infection very few information are available about liver involvement, possibly evocating a systemic disease. Methods: Post-mortem wedge liver biopsies from 48 patients died for COVID-19 infection were collected from two main hospitals in the north of Italy: all samples were obtained during autopsies. No patient had clinical symptoms of liver disease or signs of liver failure before and during hospitalization; for each of them liver function tests were available. Findings: All liver samples showed minimal inflammation features. Histological pictures compatible with vascular alterations were observed, characterized by increase of number of portal vein branches associated with lumen massive dilatation, partial or complete luminal thrombosis of portal and sinusoidal vessels, fibrosis of portal tract, focally markedly enlarged and fibrotic. Interpretation: Our preliminary results confirm the clinical impression that liver failure is not a main concern and this organ is not the target of significant inflammatory damage. Histopathological findings are highly suggestive for marked derangement of intrahepatic blood vessel network secondary to systemic changes induced by virus that could target not only lung parenchyma but also cardiovascular system, coagulation cascade and endothelial layer of blood vessels. Funding Statement: This work has no financial support. Declaration of Interests: None of the authors declare a conflict of interest Ethics Approval Statement: This work is based exclusively on routine file autoptic material and is ethical approval exempt to use anonymous data. The study followed the Italian general rules used for research related to scientific purposes (official regulations n.72-26 /03/2012).

Various degrees of biliary changes are considered to be part of the histological picture of children with pediatrics autoimmune liver disease (AILD), but the literature is scarce and confusing. We aimed to describe the characteristics of children with AILD (autoimmune hepatitis, AIH, and autoimmune sclerosing cholangitis, ASC) focusing on the prevalence and type of biliary abnormalities on initial biopsy to see whether ASC was predictable on histological ground. The files of children diagnosed with AILD were reviewed. The Ishak score was used to grade inflammation and fibrosis on biopsy; a biliary score was built to grade bile duct injury. Demographic, laboratory and histological features at diagnosis were reported and compared between the two groups (AIH vs ASC). Forty-one patients were diagnosed with AIH (n = 24), ASC (n = 13) and PSC (n = 4) between 2009 and 2018. Twenty-nine patients [F = 76%, AIH = 20, ASC = 9, median age at diagnosis 11.7 (range 2.2–17.8)] were included in the study; 12 (4 with PSC) were excluded. Prevalence of inflammatory bowel disease was higher in ASC group (56% vs 10% in AIH, p

In spite of significant improvements, availability, and deeper knowledge of many tools of investigation in liver transplanted patients (US, angiography, cholangiography, CT, and MRI), liver biopsy maintains a central role in the diagnosis and management of early and late postsurgery complications. Information arising from liver biopsy interpretation may be crucial for clinical decisions and therapy arrangements, but, to reach this goal, tissue samples must be representative, processed properly, and carefully evaluated by committed pathologists in order to discover significant histological pictures. Continuous and detailed communications between hepatologists and pathologists are necessary to obtain correct diagnostic details from this unique powerful procedure. Biochemical liver tests are associated with poor sensitivity and specificity in the diagnosis of graft dysfunction and usually provide only limited information about the target and the severity of graft damage. Moreover protocol scheduled liver biopsies are able to detect the early and asymptomatic stages of many diseases, occurring late after transplant and in some cases allow an early treatment that may avoid or delay graft injury and graft loss. Detailed and updated knowledge of the histological alterations observed in liver samples may improve the understanding of the post-transplant diseases that could improve post-transplant care and the final outcome.

Objectives 2012 European Society of Pediatric Gastroenterology, Hepatology and Nutrition guidelines allow to establish a celiac disease diagnosis without duodenal biopsy in symptomatic pediatric patients with antitissue transglutaminase (anti-tTG) titers >10 times the upper limit of normal. For some years now, new chemiluminescence immunoassays have been made available: it is important to establish the clinical performance of anti-tTG and to determine the cut-off best suited to predict Marsh ≥2 to avoid gastrointestinal endoscopy not only in children, but also in the adult population. Methods A total of 2565 patients performed duodenal biopsy from July 2012 to September 2016; we selected all the patients who had undergone QUANTA Flash anti-tTG immunoglobulin A (IgA) within -3 months of duodenal biopsy and before the start of gluten-free diet. A total of 827 patients fulfilled the criteria for selection. Results Using a cut-off of 20 chemiluminescent unit (CU; area under the curve: 0.995), sensitivity, specificity, positive, and negative predictive value were 98.2%, 98.4%, 97.9%, and 98.6%, respectively. For the correlation with Marsh ≥2, in the pediatric population, positive predictive values (PPV) were 92.1%, 99%, and 100% at 200 CU (10×), 560 CU (28×), and 1000 CU (50×), respectively. In the adult population PPV was 94.2%, 98.2%, and 100% at 200 CU (10×), 350 CU (15×), and 400 CU (20×). Conclusions Sensitivity, specificity, positive, and negative predictive value of QUANTA Flash h-tTG IgA were excellent. The cut-off providing an optimized PPV for histological lesions compatible for celiac disease (Marsh ≥2) for the QUANTA Flash h-tTG IgA is 350 CU (15×) in adult and 560 CU (28×) in children.

Background: Although the neurotrophin-inducible gene vgf is expressed in mammalian neurons and endocrine cells, limited data is available in man. Aim: The objective of the study was to map proVGF peptides in human endocrine cells during development, adulthood, hyperplasia, and tumors. Methods: Antisera were generated against peptides related to internal cleavage or cleavage-amidation sites (rat proVGF422–430 and human proVGF298–306-NH2) and the proVGF C-terminal ending (human proVGF607–615). Developing and normal adult endocrine cells, hyperplastic endocrine lesions (thyroid, parathyroid, lung, and stomach), and 120 tumors (102 endocrine) were studied. Immunogold electron microscopy was performed on normal adult pancreas and gut, and Western blotting was performed on extracts of control tissues and endocrine tumors. Results: proVGF fragments were revealed in developing pituitary, gut, pancreas, and adrenal medulla from 10 gestational weeks, in normal adult pituitary and adrenal medulla, pancreatic glucagon, and insulin cells and gut serotonin cells, in hyperplastic thyroid calcitonin cells, lung P cells, gastric enterochromaffin-like cells, and gastrin cells, and in 88 of 102 endocrine tumors. At electron microscopy proVGF immunoreactivity was restricted to electron-dense granules. Western blotting revealed large molecular weight forms and cleavage fragments in both control tissues and tumor extracts. Conclusions: proVGF-related peptides are present in endocrine cells early during development and adulthood and increase in hyperplasia and tumors, and proVGF fragments could be novel diagnostic tools for endocrine cells and related lesions, including tumors.