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Glisson's capsule matrix thickness and composition is altered in cirrhotic patients irrespective of etiology [Meeting Abstract]

Llewellyn, J; Fede, C; Theise, N; Stecco, C; Furth, E E; Wells, R G
Background: Glisson's capsule is the layer of connective tissue that surrounds the liver. During fibrosis, mesothelial cells from this layer migrate inwards into the liver and contribute to the myofibroblast population and to the progression of liver fibrosis1. Changes to the capsule itself are less well understood. An increase in capsule thickness in alcoholic cirrhosis and HCV has been reported2. The aim of this study was to characterize the changes in the matrix components of the capsule and to determine whether these correlate with severity of disease or etiology.
Method(s): Human liver samples were collected from autopsies and liver transplants. Collagen, hyaluronic acid and proteoglycans were assessed by immunohistochemistry. Elastic fibers were assessed by Van Gieson staining. Collagen organization was visualized using 3D second harmonic generation imaging.
Result(s): We examined 12 normal samples, 5 mild to moderate steatosis samples and 15 cirrhotic samples from patients with variety of disease etiologies including NASH, PSC, HCV and ethanol induced cirrhosis. Capsule thickness was significantly increased in cirrhotic patient samples compared to normal controls irrespective of the etiology (69.62 +/- 9.99 and 171.269 +/- 16.65 mum mean +/- SEM respectively), but mild to moderate steatosis had no effect on thickness (62.15 +/- 4.97 mean +/- SEM). There was an increase in collagen, hyaluronic acid and elastic fiber deposition. In normal and in mild to moderate steatosis, collagen fiber width significantly decreased in the inner layers of the capsule (outer 5.74 +/- 0.095, inner 4.98 +/-0.099 and outer 5.55 +/- 0.14, inner 4.8 +/- 0.13 nm mean +/- SEM respectively) . This change however is lost in cirrhotic samples and collagen width remains relatively thick (outer 5.69 +/- 0.091, inner 5.3 +/- 0.12 nm mean +/- SEM). 3D collagen organization is also altered in cirrhosis. In the normal human liver, collagen is organized into layered sheets of one orientation with limited overlap between different orientations; however, in cirrhotic samples, this is disrupted and considerable overlap is observed between different fiber orientations.
Conclusion(s): The composition and organization of key matrix components is significantly changed in Glisson's capsule in cirrhotic patients, but not patients with mild to moderate steatosis. These changes likely impact the stiffness and other mechanics of the capsule, particularly its ability to expand in response to changes in liver blood flow. Work is ongoing to characterize capsule mechanics, but the work here makes clear that altered matrix content and organization in cirrhosis is not limited to the parenchyma of the liver. 1. Li Y, Wang J, Asahina K. Proc Natl Acad Sci U S A. 2013;110(6):2324-2329. doi:10.1073/pnas.1214136110 2. Balog S, Li Y, Ogawa T, et al. Hepatology. 2020;71(1):291-305. doi:10.1002/hep.30809
EMBASE:636385691
ISSN: 1527-3350
CID: 5045332

Rappaport, Glisson, Hering, and Mall-Champions of Liver Microanatomy: Microscopic and Ultramicroscopic Anatomy of the Liver Into the Modern Age

Gill, Ryan M; Theise, Neil D
Content available: Author Interview and Audio Recording.
PMCID:8555463
PMID: 34745585
ISSN: 2046-2484
CID: 5050172

Hepatocarcinogenesis: Radiology-Pathology Correlation

Fung, Alice; Shanbhogue, Krishna P; Taffel, Myles T; Brinkerhoff, Brian T; Theise, Neil D
In the background of chronic liver disease, hepatocellular carcinoma develops via a complex, multistep process called hepatocarcinogenesis. This article reviews the causes contributing to the process. Emphasis is made on the imaging manifestations of the pathologic changes seen at many stages of hepatocarcinogenesis, from regenerative nodules to dysplastic nodules and then to hepatocellular carcinoma.
PMID: 34243923
ISSN: 1557-9786
CID: 4965232

Cholangiopathy After Severe COVID-19: Clinical Features and Prognostic Implications

Faruqui, Saamia; Okoli, Fidelis C; Olsen, Sonja K; Feldman, David M; Kalia, Harmit S; Park, James S; Stanca, Carmen M; Figueroa Diaz, Viviana; Yuan, Sarah; Dagher, Nabil N; Sarkar, Suparna A; Theise, Neil D; Kim, Sooah; Shanbhogue, Krishna; Jacobson, Ira M
INTRODUCTION/BACKGROUND:Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 virus, is a predominantly respiratory tract infection with the capacity to affect multiple organ systems. Abnormal liver tests, mainly transaminase elevations, have been reported in hospitalized patients. We describe a syndrome of cholangiopathy in patients recovering from severe COVID-19 characterized by marked elevation in serum alkaline phosphatase (ALP) accompanied by evidence of bile duct injury on imaging. METHODS:We conducted a retrospective study of COVID-19 patients admitted to our institution from March 1, 2020, to August 15, 2020, on whom the hepatology service was consulted for abnormal liver tests. Bile duct injury was identified by abnormal liver tests with serum ALP > 3x upper limit of normal and abnormal findings on magnetic resonance cholangiopacreatography. Clinical, laboratory, radiological, and histological findings were recorded in a Research Electronic Data Capture database. RESULTS:Twelve patients were identified, 11 men and 1 woman, with a mean age of 58 years. Mean time from COVID-19 diagnosis to diagnosis of cholangiopathy was 118 days. Peak median serum alanine aminotransferase was 661 U/L and peak median serum ALP was 1855 U/L. Marked elevations of erythrocyte sedimentation rate, C-reactive protein, and D-dimers were common. Magnetic resonance cholangiopacreatography findings included beading of intrahepatic ducts (11/12, 92%), bile duct wall thickening with enhancement (7/12, 58%), and peribiliary diffusion high signal (10/12, 83%). Liver biopsy in 4 patients showed acute and/or chronic large duct obstruction without clear bile duct loss. Progressive biliary tract damage has been demonstrated radiographically. Five patients were referred for consideration of liver transplantation after experiencing persistent jaundice, hepatic insufficiency, and/or recurrent bacterial cholangitis. One patient underwent successful living donor liver transplantation. DISCUSSION/CONCLUSIONS:Cholangiopathy is a late complication of severe COVID-19 with the potential for progressive biliary injury and liver failure. Further studies are required to understand pathogenesis, natural history, and therapeutic interventions.
PMID: 33993134
ISSN: 1572-0241
CID: 4876442

Evidence for continuity of interstitial spaces across tissue and organ boundaries in humans

Cenaj, Odise; Allison, Douglas H R; Imam, Rami; Zeck, Briana; Drohan, Lilly M; Chiriboga, Luis; Llewellyn, Jessica; Liu, Cheng Z; Park, Young Nyun; Wells, Rebecca G; Theise, Neil D
Bodies have continuous reticular networks, comprising collagens, elastin, glycosaminoglycans, and other extracellular matrix components, through all tissues and organs. Fibrous coverings of nerves and blood vessels create structural continuity beyond organ boundaries. We recently validated fluid flow through human fibrous tissues, though whether these interstitial spaces are continuous through the body or discontinuous, confined within individual organs, remains unclear. Here we show evidence for continuity of interstitial spaces using two approaches. Non-biological particles (tattoo pigment, colloidal silver) were tracked within colon and skin interstitial spaces and into adjacent fascia. Hyaluronic acid, a macromolecular component of interstitial spaces, was also visualized. Both techniques demonstrate interstitial continuity within and between organs including within perineurium and vascular adventitia traversing organs and the spaces between them. We suggest that there is a body-wide network of fluid-filled interstitial spaces that has significant implications for molecular signaling, cell trafficking, and the spread of malignant and infectious disease.
PMID: 33790388
ISSN: 2399-3642
CID: 4830922

The histopathologic characteristics of the gastrointestinal system in SARS-COV-2 infected patients who underwent biopsy or resection [Meeting Abstract]

Ahmed, S; Hoskoppal, D; Lin, L; Suarez, Y; Liu, W; Cho, M; Thomas, K; Guzzetta, M; Hajdu, C; Theise, N; Jour, G; Sarkar, S; Cao, W
Background: In addition to respiratory distress, GI symptoms have been reported in COVID-19 patients at various stages of the disease. Among the GI symptoms that have been reported, diarrhea, nausea, vomiting, abdominal pain and GI bleeding were often seen. Age and comorbid conditions such as obesity, HTN, DM and/or CAD have been considered as risk factors for COVID-19 patients for severe disease. GI manifestations in COVID-19 patients appeared to act as a sign for a serious condition. The virus has been identified in the stool and in rectal swabs of some infected patients, even after a negative nasopharyngeal test. There is a lack of reports on pathological alterations of the GI tract in COVID-19 infected patients.
Design(s): 16 PCR confirmed COVID-19 patients (11 males and 5 females) were included in the study. Biopsy or resection specimens were taken from the esophagus (4), stomach (6), small intestine (5), appendix (3), colon (5) and gallbladder (3). Clinical information including demographics, comorbidities, GI symptoms, related laboratory tests were collected. Histopathologic evaluation was performed and correlated with clinical properties.
Result(s): The age of the patients ranged from 10 to 84 years old, with an average of 47 years. Eight (50%) patients had at least one comorbid condition, two patients (12.5%) had prior history of cancer, and six patients had no significant medical history. Abdominal pain and GI bleeding were the most common presenting symptoms. Histologically, acute and chronic inflammation was seen in 14 of 16, and 15 of 16 cases, respectively. Eight cases showed severe acute inflammation with ulceration. The mucosal changes included nonspecific reactive change, hypermucinous, atrophic/ischemic changes, and necrosis, were indiscriminately noticed in these cases. Four cases showed intraepithelial lymphocytosis. Viral like inclusions were found in four cases. Microthrombi were identified in 5 cases with an average patient age of 60 years. Notably, microthrombi were seen in about 5 out of 8 (62%) patients with comorbidities. The patients with microthrombi had a higher D dimer test value than those without thrombus. Three patients died shortly after operation, and two of them showed microthrombi in the tissue specimens.
Conclusion(s): Acute and chronic inflammation were indiscriminately seen in these cases. Microthrombi were dominantly found in aging patients with comorbidities, suggesting microthrombi in the GI tract may be a histologic indication for severe COVID-19 patients with GI symptoms
EMBASE:634717313
ISSN: 1530-0307
CID: 4857062

Rectal SWAB SARS-COV-2 testing and histologic findings in the small intestine of 18 autopsy patients [Meeting Abstract]

Lin, L; Ahmed, S; Thomas, K; Guzzetta, M; Hoskoppal, D; Cho, M; Suarez, Y; Liu, W; Hajdu, C; Theise, N; Jour, G; Sarkar, S; Cao, W
Background: Digestive symptoms are often seen in COVID-19 patients with poor outcomes. The Viral RNA is mostly positive in the stool of these patients, and has a longer delay before viral clearance. However, its diagnostic value and significance for guiding clinical treatment remain unknown. And the pathologic alterations in the GI tract in COVID-19 patients have not been well defined. We evaluated rectal swab SAS-CoV-2 test and histopathologic changes in the small intestine in autopsy patients.
Design(s): 18 autopsy cases with confirmed SAS-CoV2 infection were included. Nasal, bronchial, and rectal swab SARS-CoV-2 PCR were performed at the time of autopsy. Clinical information included demographics, comorbidities, presenting symptoms, related laboratory tests were collected. Histopathologic evaluation was performed and correlated with clinical properties.
Result(s): 83% (15/18) of patients were male. Median age is 50 years. 7/18 (38.9%) patients had diarrhea in addition to cough, fever and other symptoms. Except in one case, all patients had underlying comorbidities of diabetes, hypertension and /or obesity. In the small intestine, acute inflammation was not seen in any cases. 5/18 displayed mild and one showed moderate chronic inflammation. Hypermucinous change was found in six patients but not associated with diarrhea. 3 cases had microthrombi identified in the sections. Notably, obviously increased D dimer in lab tests were noticed in all patients. Postmortem 17/17 (100%) nasal, 18/18 (100%) bronchial and 7/16 (43.8%) rectal swabs showed SARS-CoV-2 PCR positivity. 3 of 7 (42.9%) patients with diarrhea are positive in rectal swab for SARS-CoV-2.
Conclusion(s): There are no specific COVID-19 changes in the small intestine. More investigations are needed, especially on tissues from different locations of the GI tract. Data from rectal swab testing suggests that it is not ideal for diagnosing COVID-19, guiding treatment, or predicting small intestinal pathology
EMBASE:634717542
ISSN: 1530-0307
CID: 4857032

Clinical and Intestinal Histopathological Findings in SARS-CoV-2/COVID-19 Patients with Hematochezia [Case Report]

Cho, Margaret; Liu, Weiguo; Balzora, Sophie; Suarez, Yvelisse; Hoskoppal, Deepthi; Theise, Neil D; Cao, Wenqing; Sarkar, Suparna A
Gastrointestinal (GI) symptoms of SARS-CoV-2/COVID-19 in the form of anorexia, nausea, vomiting, abdominal pain and diarrhea are usually preceded by respiratory manifestations and are associated with a poor prognosis. Hematochezia is an uncommon clinical presentation of COVID-19, and we hypothesize that older patients with significant comorbidities (obesity and cardiovascular) and prolonged hospitalization are susceptible to ischemic injury to the bowel. We reviewed the clinical course, key laboratory data including acute-phase reactants, and drug/medication history in 2 elderly male patients admitted for COVID-19 respiratory failure. Both patients had a complicated clinical course and suffered from hematochezia, acute blood loss, and anemia which led to hemodynamic instability requiring blood transfusion around day 40 of their hospitalization. Colonoscopic impressions were correlated with the histopathological findings in the colonic biopsies that included changes compatible with ischemia and nonspecific acute inflammation, edema, and increased eosinophils in the lamina propria. Both patients were hemodynamically stable, on prophylactic anticoagulants, multiple antibiotics, and antifungal agents due to respiratory infections at the time of lower GI bleeding. Hematochezia resolved spontaneously with supportive care. Both patients eventually recovered and were discharged. Elderly patients with significant comorbid conditions are uniquely at risk for ischemic injury to the bowel. This case report highlights hematochezia as an uncommon GI manifestation of spectrum of COVID-19 complications. The causes of bleeding in these COVID-19 associated cases are likely multifactorial and can be attributed to concomitant etiologies based on their age, multiple comorbid conditions, prolonged hospitalization compounded by lung injury, and hypoxia precipitated by the virus. We hypothesize that rather than a direct viral cytopathic effect, ischemia and hypoperfusion may be unleashed due to the cytokine storm orchestrated by the virus that leads to abnormal coagulation profile. Additional factors that may contribute to ischemic injury are prophylactic use of anticoagulants and polypharmacy. There were no other causes to explain the brisk lower GI bleeding. Presentation of hematochezia was followed by hemodynamic instability that may further increase the mortality and morbidity of COVID-19 patients, and prompt consultation and management by gastroenterology is therefore warranted.
PMCID:8077654
PMID: 33976619
ISSN: 1662-0631
CID: 4867392

Clinical stage molecule PT150 is a modulator of glucocorticoid and androgen receptors with antiviral activity against SARS-CoV-2

Theise, Neil D; Arment, Anthony R; Chakravarty, Dimple; Gregg, John M H; Jacobson, Ira M; Jung, Kie Hoon; Nair, Sujit S; Tewari, Ashutosh K; Thurston, Archie W; Van Drie, John; Westover, Jonna B
PT150 is a clinical-stage molecule, taken orally, with a strong safety profile having completed Phase 1 and Phase 2 clinical trials for its original use as an antidepressant. It has an active IND for COVID-19. Antiviral activities have been found for PT150 and other members of its class in a variety of virus families; thus, it was now tested against SARS-CoV-2 in human bronchial epithelial lining cells and showed effective 90% inhibitory antiviral concentration (EC90) of 5.55 µM. PT150 is a member of an extended platform of novel glucocorticoid receptor (GR) and androgen receptor (AR) modulating molecules. In vivo, their predominant net effect is one of systemic glucocorticoid antagonism, but they also show direct downregulation of AR and minor GR agonism at the cellular level. We hypothesize that anti-SARS-CoV-2 activity depends in part on this AR downregulation through diminished TMPRSS2 expression and modulation of ACE2 activity. Given that hypercortisolemia is now suggested to be a significant co-factor for COVID-19 progression, we also postulate an additive role for its potent immunomodulatory effects through systemic antagonism of cortisol.
PMCID:7738205
PMID: 33305659
ISSN: 1551-4005
CID: 4735512

Keratin 19 and mesenchymal markers for evaluation of epithelial-mesenchymal transition and stem cell niche components in primary biliary cholangitis by sequential elution-stripping multiplex immunohistochemistry

Paulsen, John David; Zeck, Briana; Sun, Katherine; Simoes, Camila; Theise, Neil D; Chiriboga, Luis
Multiplexed immunohistochemical techniques give insight into contextual cellular relationships by offering the ability to collect cell-specific data with spatial information from formalin-fixed, paraffin-embedded tissue sections. We established an automated sequential elution-stripping multiplex immunohistochemical assay to address two controversial scientific questions in the field of hepatopathology: 1) whether epithelial-to-mesenchymal transition or mesenchymal-to-epithelial transition occurs during liver injury and repair of a chronic liver disease and 2) if there is a stromal:epithelial relationship along the canals of Hering that would support the concept of this biliary structure being a stem/progenitor cell niche. Our 4-plex assay includes both epithelial and mesenchymal clinical immunohistochemical markers and was performed on clinical human liver specimens in patients with primary biliary cholangitis. The assay demonstrated that in each specimen, co-expression of epithelial and mesenchymal markers was observed in extraportal cholangiocytes. In regard to possible mesenchymal components in a stem cell niche, 82.3% ± 5.5% of extraportal cholangiocytes were intimately associated with a vimentin-positive cell. Co-expression of epithelial and mesenchymal markers by extraportal cholangiocytes is evidence for epithelial to mesenchymal transition in primary biliary cholangitis. Vimentin-positive stromal cells are frequently juxtaposed to extraportal cholangiocytes, supporting an epithelial:mesenchymal relationship within the hepatobiliary stem cell niche. Our automated sequential elution-stripping multiplex immunohistochemical assay is a cost-effective multiplexing technique that can be readily applied to a small series of clinical pathology samples in order to answer scientific questions involving cell:cell relationships and cellular antibody expression.
PMID: 32998669
ISSN: 2046-0236
CID: 4617662