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.
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.
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.
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 <0.0001). On liver histology, patients with COVID-19 and elevated ALT had significantly increased vWF and platelet staining, supporting a link between liver injury, coagulopathy, and endotheliopathy. Intralobular neutrophils positively correlated with platelet (p <0.0001) and vWF (p <0.01) staining, and IL-6 levels positively correlated with vWF staining (p <0.01). IL-6 trans-signaling leads to increased expression of procoagulant (factor VIII, vWF) and proinflammatory factors, increased cell surface vWF (p <0.01), and increased platelet attachment in LSECs. These effects were blocked by soluble glycoprotein 130 (IL-6 trans-signaling inhibitor), the JAK inhibitor ruxolitinib, and STAT1/3 small-interfering RNA knockdown. Hepatocyte fibrinogen expression was increased by the supernatant of LSECs subjected to IL-6 trans-signaling.
IL-6 trans-signaling drives the coagulopathy and hepatic endotheliopathy associated with COVID-19 and could be a possible mechanism behind liver injury in these patients.
Patients with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection often have liver injury, but why this occurs remains unknown. High levels of interleukin-6 (IL-6) and its circulating receptor, which form a complex to induce inflammatory signals, have been observed in patients with COVID-19. This paper demonstrates that the IL-6 signaling complex causes harmful changes to liver sinusoidal endothelial cells and may promote blood clotting and contribute to liver injury.
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•Liver injury in patients with COVID-19 is associated with elevated IL-6 and coagulopathy.•Patients with COVID-19 exhibit hepatic endotheliopathy which is associated with liver injury.•IL-6 trans-signaling causes endotheliopathy in liver sinusoidal endothelial cells.
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 < 0.01), whereas SEA was not (p = 0.73). In COVID‐19 livers, strong vWF staining in liver sinusoidal endothelial cells was associated with significantly increased platelet adhesion (1.7‐fold, p = 0.0016), compared to those with weak sinusoidal vWF (2‐fold, p < 0.0001). Sinusoidal erythrocyte aggregation in 19 (83%) liver samples was mainly seen in zone 2. Livers with SEA had significantly higher fibrinogen (1.6‐fold, p = 0.031) compared to those without SEA in COVID‐19 patients.
Conclusions
Liver PMT is a pathologically important thrombosis associated with liver injury in COVID‐19, while SEA is a unique morphological feature of COVID‐19 patient livers. Sinusoidal vWF and hyperfibrinogenemia could contribute to PMT and SEA formation.
The authors present an atypical case of an infant with unremarkable familiar, birth, and neonatal history who developed a mild/benign form of transient cholestasis. At admission, second- and ...third-level assessments were conducted, mitochondrial respiratory chain disorders were excluded. The patient was accurately and promptly diagnosed through a clinically driven genetic test. The genetic analysis evidenced a compound heterozygous mutation c.383A>G (p.Tyr128Cys) of maternal origin and c.835G>A (p.Val279Met) of paternal origin in the TRMU gene associated to transient infantile liver failure, a condition known for its progressive and sometimes fatal prognosis. Biochemical test and patient’s clinical evolution were both good and there was no evidence of liver failure or dysfunction of other organs. This is the first-ever reported case of a patient with a TRMU pathological compound mutation with such good clinical evolution.
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.
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.
Positivity of both immunoglobulin A anti-tissue transglutaminase (TTG) and anti-endomysium antibodies (EMA) has a positive predictive value of nearly 100% for celiac disease (CD). The objective of ...the present study was to evaluate whether patients of any age, with high pretest probability of CD and high titre of anti-TTG and EMA positivity, have a high probability of intestinal damage and may not require the biopsy for final diagnosis.
A retrospective analysis of 412 consecutively referred patients, age range 10 months to 72 years, who underwent small-bowel biopsy for suspicion of CD and positivity to both anti-TTG and EMA, was performed at 4 Italian centers. Biopsies were evaluated independently by 2 pathologists using Marsh modified classification; in cases of dissimilar results, a third pathologist examined the biopsy. The final histological finding diagnosis was expressed as the prevalent or highest score assigned by the pathologist board.
Three hundred ninety-six patients (96.1%) had histological findings consistent with CD (grade 2 and 3a, 3b, or 3c of modified Marsh classification). An anti-TTG ratio ≥ 7 was able to identify with the 3 assays used (Celikey, anti-TTG immunoglobulin A, EuTTG) all of the patients with significant mucosal damage (Marsh ≥ 2) independent of age and sex; specificity and positive predictive value were 100%. An anti-TTG ratio >20 was more specific (99.8%) for identification of patients with villous atrophy (Marsh 3 a, b, or c).
Patients with positivity of anti-TTG ≥ 7-fold cutoff, confirmed by positivity to EMA, have a high-degree probability of duodenal damage. In selected conditions, a duodenal biopsy may be avoided and a confirmed greatly positive anti-TTG result could be the basis to prescribe a gluten-free diet.
We describe the case of a patient with a clinical and molecular diagnosis of Beckwith-Wiedemann Syndrome (BWS) and a clinical, radiologic and histologic diagnosis of colon isolated hypoganglionosis. ...BWS is a genetic multisystem disorder characterized by generalized and lateralized overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycemia and predisposition to embryonal tumors (Brioude et al., Nat Rev Endocrinol 1998; 14:229-249). Hypoganglionosis of the colon is a condition that clinically resembles Hirschsprung's disease and it is part of a group of numerous and heterogeneous conditions that are defined 'Variants of Hirschsprung's disease' (Friedmacher and Puri, Pediatr Surg Int 2013; 29:855-872). To the best of our knowledge, the association of BWS with Hirschsprung's disease has been observed only in one patient, an infant with hypoglycemia (Shah et al., BMJ Case Rep 2020; 13:e235121). We suppose that dysganglionosis could be rare comorbidity of BWS. We suggest to put particular attention to patients affected by BWS who develop early severe constipation taking into account the possibility to study them at radiologic and histologic levels to show the possible evidence of Hirschsprung's disease variants.
Objectives:
We performed a retrospective case control study to evaluate the histological characteristics of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) positive pediatric patients ...undergoing laparoscopic exploration for acute abdomen symptoms. To our knowledge this is the first study that analyzes histopathological characteristics of abdominal tissues in SARS‐CoV‐2 children.
Study design:
We enrolled 8 multisystem inflammatory syndrome in children (MIS‐C) patients and 4 SARS‐CoV‐2 positive patients who underwent intestinal resection versus 36 control appendectomies from 2 pediatric tertiary referral centers between March 2020 and July 2021. Surgical resection samples were evaluated on several histological sections focusing on general inflammatory pattern and degree of inflammation. Peculiar histological features (endotheliitis and vascular thrombosis) were semi‐quantitatively scored respectively in capillary, veins, and arteries.
Results:
All SARS‐CoV‐2 related surgical samples showed thrombotic patterns. Those patterns were significantly less frequent in SARS‐CoV‐2 negative appendectomies (P = 0.004). The semi‐quantitative score of thrombosis was significantly higher (P = 0.002) in patients with SARS‐CoV‐2 related procedures.
Conclusions:
Our results showed that SARS‐CoV‐2 can cause thrombotic damage in abdominal tissues both in the acute phase of the infection (SARS‐CoV‐2 related appendectomies) and secondary to cytokine storm (MIS‐C).
Purpose
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.
...Methods
We collected age at presentation, clinical features, histology, diagnostic process, management and outcome.
Results
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
< 0.01). Histology showed type 1 lesion in 3/8, type 2 in 3/8, and type 3 in 2/8 with foci of angiosarcoma.
Conclusion
Most patients with symptomatic HHE can be managed successfully with a combination of medical, radiological and surgical treatments. Patients with diffuse lesions, late presentation, cardiac failure and type II histology have a poor outcome.
Level of evidence
Diagnostic level IV. Therapeutic level IV.
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