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Department of Pathology, University of Chicago Medicine, University of Chicago Medicine, MC6101, Anatomic Pathology, 5841 South Maryland Avenue, Chicago, IL 60637, USA
The common digestive manifestations associated with coronavirus disease-2019 (COVID-19) include anorexia, nausea, vomiting, and diarrhea; the clearance of the viruses in COVID-19 patients with digestive symptoms is usually delayed.
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COVID-19-associated gastrointestinal histopathology is characterized by mucosal damage and lymphocytic infiltration.
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The most common hepatic changes are steatosis, mild lobular and portal inflammation, congestion/sinusoidal dilatation, lobular necrosis, and cholestasis.
Introduction
With the high prevalence of coronavirus disease-2019 (COVID-19), there has been increasing understanding of the pathologic changes associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus can infect multiple organs and cause multiorgan symptoms, causing a wide range of clinical manifestations,
(erythema and papules). A meta-analysis has shown that 17.6% of patients with COVID-19 have GI symptoms, and that viral RNA is detected in stool samples in 48.1% of patients.
Neglecting GI symptoms may sometimes delay a timely diagnosis and may permit the unchecked fecal-oral transmission of the virus. Ulcerative lesions occur in the GI tract in some patients, but only a few studies have described the histopathology of these lesions.
In addition, hepatic injury is a frequent complication of COVID-19 and is associated with the severity of the disease. Studies in patients with COVID-19 have shown the incidence of liver injury ranges from 14.8% to 62%, usually indicated by abnormal alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels accompanied by slightly elevated bilirubin levels.
Gastrointestinal and Hepatic Manifestations of 2019 Novel Coronavirus Disease in a Large Cohort of Infected Patients From New York: Clinical Implications.
Pathologic findings in the GI tract and liver come mostly from autopsies or postmortem biopsies but may include pathologic examination of GI biopsies obtained premortem by GI endoscopy. This review summarizes the pathologic changes in the digestive system and liver associated with COVID-19, including the injuries induced by SARS-CoV2 infection of GI epithelial cells and the systemic immune responses.
Esophageal Pathology
Although the clinical manifestations of COVID-19 are usually dominated by respiratory symptoms, some patients may lack symptoms and imaging features of COVID-19 pneumonia but only show GI symptoms.
Two case reports have shown esophageal bleeding and multiple round herpetic-like erosions and ulcers by endoscopy in patients with GI symptoms, and SARS-CoV-2 RNA was detected in these esophageal lesions.
At the autopsy, two necrotic ulcers were detected at the hypopharynx (Fig. 1A, B). Histopathology showed full-thickness inflammatory cell infiltration with thinning of the pharyngeal wall at the level of the ulcer center (Fig. 1C, D).
Meanwhile, in the presence of cells positive for SARS-CoV-2 spike protein subunit 1, histologic examination showed moderate lymphocytic infiltration in the esophageal mucosa (Fig. 1E–H),
consistent with the histopathological features of viral esophagitis.
Fig. 1Macroscopic examination of fresh (A) and fixed (B) hypopharynx, with two necrotic ulcer (white arrows in A). (C) Histopathology of ulcer in hypopharynx. (D) Inflammatory infiltration of the muscle layer with necrosis and degeneration of the skeletal muscle fibers (E–H). Moderate lympho-monocytic infiltration in esophageal mucosa (E––anti-CD68; F––anti-CD3; G––anti-CD20; H––positive for SARS-CoV-2 spike subunit 1, black arrows).
(Porzionato A, Stocco E, Emmi A, et al. Hypopharyngeal Ulcers in COVID-19: Histopathological and Virological Analyses - A Case Report. Frontiers in immunology. 2021;12:676828. https://doi.org/10.3389/fimmu.2021.676828)
The appearance of GI symptoms in patients with COVID-19 seems to indicate disease progression, as GI symptoms are more common in severe and critically ill patients, and are associated with an increased risk of adverse outcomes.
Interestingly, other case-control studies had previously shown that the presence of GI symptoms was associated with longer illness duration, a trend toward lower ICU admissions, and lower mortality,
A multicenter study showed that ulcers were the most common lesions observed in upper GI endoscopy in patients with COVID-19, with the lesions sometimes accompanied by active bleeding.
retrospectively analyzed the abdominal imaging findings of 412 patients with COVID-19, and a variety of abnormalities were observed. Bowel-wall abnormalities were found on 13 computed tomography (CT) images (31%), which were associated with intensive care unit (ICU) admission. Pneumatosis or portal venous gas was observed in four abdominal CT images obtained in patients in the ICU. Unusual yellow discoloration of the bowel was observed in three cases and bowel infraction in two cases. Pathologic examinations revealed ischemic enteritis, with patchy necrosis and fibrin thrombi in arterioles. Amarapurkar and colleagues
also reported a case of hemorrhagic enteritis associated with COVID-19. Histopathology revealed extensive transmural hemorrhages with many congested and dilated blood vessels, and fibrin thrombi were occasionally observed in capillaries.
The GI pathology of SARS-CoV-2 infection had been verified in autopsy and biopsy studies. Liu and colleagues
observed alternating segmental dilatations and stenoses of the small bowel at the autopsy of a patient with COVID-19, associated with SARS-CoV-2 replication in GI mucosa.
Another report described GI alterations in patients with COVID-19 as characterized by lymphoplasmacytic infiltration in the lamina propria of the GI tract.
Coagulative necrosis, micro-hemorrhages, microthrombi, and vascular congestion had been found in the colonic mucosa, suggesting ischemia is one mechanism of injury. Such lesions have been found to be positive for COVID-19 by immunohistochemistry.
Duodenitis may also occur in critically ill patients with COVID-19, with endoscopic manifestations of diffuse bleeding, mucosal edema, and severe inflammation with erosions. Intracytoplasmic and intranuclear inclusions consistent with a viral infection were identified in duodenal crypts.
In addition, as both ACE2 and TMPRSS2 are expressed in the enteric nervous system, gut sensory-motor functions may be affected in susceptible patients with COVID-19.
Among patients hospitalized with COVID-19, the prevalence of acute pancreatitis is 0.27%. COVID-19-associated acute pancreatitis is more frequently associated with severe systemic disease and multi-organ complications.
SARS-CoV-2 can cause hepatic injury via direct binding to ACE2 receptors in cholangiocytes and hepatocytes, antibody dependent enhancement of infection, systemic inflammatory response syndrome, inflammatory cytokine storms, ischemia/reperfusion injury, and adverse events due to drug therapy.
Findings in autopsies or postmortem biopsies of patients with coronavirus disease-2019
The main liver findings in patients with COVID-19 are shown in Table 2 and are illustrated in Fig. 2A–E. The most common histopathological changes associated with SARS-CoV-2 are hepatic steatosis, mild lobular and portal inflammation, congestion/sinusoidal dilatation, lobular necrosis, and cholestasis.
Histopathological and virological features of lung, heart and liver percutaneous tissue core biopsy in patients with COVID-19: A clinicopathological case series.
Fig. 2Histology of liver changes in patients with COVID-19. (A) Steatosis. (B) Mild portal activity. (C) Mild lobular activity. (D) Mild sinusoidal dilatation with increased lymphocytic infiltration. (E) Focal centrilobular hepatic necrosis. (F) Portal arteriolar muscular hyperplasia (left arrow) and hyalinosis of a smaller branch of portal arteriole (right arrow).
([A] Zhao CL, Rapkiewicz A, Maghsoodi-Deerwester M, et al. Pathological findings in the postmortem liver of patients with coronavirus disease 2019 (COVID-19). Human pathology. Mar 2021;109:59-68. https://doi.org/10.1016/j.humpath.2020.11.015 (Ref. 43); [B, C] Chornenkyy Y, Mejia-Bautista M, Brucal M, et al. Liver Pathology and SARS-CoV-2 Detection in Formalin-Fixed Tissue of Patients With COVID-19. American journal of clinical pathology. May 18 2021;155(6):802-814. https://doi.org/10.1093/ajcp/aqab009 (Ref. 55); [D, E] Tian S, Xiong Y, Liu H, et al. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. Jun 2020;33(6):1007-1014. https://doi.org/10.1038/s41379-020-0536-x (Ref. 50); [F] Lagana SM, Kudose S, Iuga AC, et al. Hepatic pathology in patients dying of COVID-19: a series of 40 cases including clinical, histologic, and virologic data. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. Nov 2020;33(11):2147-2155. https://doi.org/10.3389/fimmu.2021.676828)
which may be related to high BMI, as well as hypoxia and shock induced by COVID-19-related complications. It is well documented that shock and hypoxia can lead to lipid accumulation in hepatocytes and cause liver injury.
showed moderate microvesicular steatosis and mild lobular and portal activity, indicating the injury could have been caused by either SARS-CoV-2 infection or drug-induced liver injury. In another study of 48 postmortem liver biopsies performed on patients with COVID-19, the histologic assessment also revealed microvesicular and macrovesicular steatosis (54%), mild portal inflammation (66%), and lobular inflammation (50%).
described gross findings of hepatic fibrosis in two patients. Histologically, macrovesicular steatosis was the most common finding, involving 30 patients (75%). Mild lobular necroinflammation and portal inflammation were present in 20 cases (50%) each.
congestion, steatosis and minimal-to-mild portal inflammation were the most common findings, whereas lobular inflammation was not prominent. Conversely, Yurdaisik and colleagues
reported mild sinusoidal dilatation and focal macrovesicular steatosis in postmortem liver biopsies of four patients. There was mild lobular lymphocytic infiltration, which was insignificant in portal areas; the same findings were reported in another pathologic study.
Histopathological and virological features of lung, heart and liver percutaneous tissue core biopsy in patients with COVID-19: A clinicopathological case series.
mainly in centrilobular areas (zone 3) and without evident inflammatory cellular infiltration. This pattern is consistent with acute ischemic injury. More severe changes such as confluent necrosis
Other histopathological changes frequently described in patients with COVID-19 include the proliferation of the intrahepatic bile ducts and the presence of intra-canalicular bile plugs, consistent with cholestasis.
Histopathological and virological features of lung, heart and liver percutaneous tissue core biopsy in patients with COVID-19: A clinicopathological case series.
noted alterations of vascular structures, both acute (thrombosis of portal and sinusoidal vessels, luminal ectasia) and chronic (fibrous thickening of vascular wall or phlebosclerosis, and abnormalities of the portal intrahepatic vasculature). Lagana and colleagues
Portal arterioles were abnormal (Fig. 2F) in nine cases (22.5%), including arteriolar muscular hyperplasia, hyalinosis of the vessel wall, and fibrinoid necrosis with endothelial apoptosis. These findings strongly suggest marked derangement of the intrahepatic blood vessel network secondary to systemic changes induced by the viral infection.
Other uncommon histologic changes include histiocytic hyperplasia in the portal tract,
Histopathological and virological features of lung, heart and liver percutaneous tissue core biopsy in patients with COVID-19: A clinicopathological case series.
showed in 22 COVID-19 autopsies (18 with comorbidities and 4 without comorbidities), that the incidence of macroscopic parenchyma congestion, histologic sinusoidal congestion, steatosis, and inflammatory infiltrate were similar between the two groups.
In another postmortem study, patients with COVID-19 (n = 8) were compared with controls (n = 4). Minimal to focal mild portal tract chronic inflammation (P < 0.05) and mild focal lobular activity (P = 0.06) were more frequently observed in COVID patients.
compared postmortem liver biopsies between 43 patients with COVID-19 versus normal controls (n = 12). Dilated sinusoids with congestion (P < 0.01), lobular inflammation (P < 0.01), steatosis (P = 0.02), and sinusoidal erythrocyte aggregation (P < 0.01) were more frequently observed in patients with COVID-19.
Pathology of liver biopsies in living patients with coronavirus disease-2019
Although findings at autopsy are often “contaminated” by terminal iatrogenic changes, liver biopsies performed in patient's premortem likely present more specific pathologic findings. Such findings include mild portal inflammation, scattered hepatocyte apoptosis, ground-glass hepatocytes consistent with cytoplasmic accumulation of fibrinogen,
In another study of 2 patients without significant lung disease, acute hepatitis, prominent bile duct damage, foci of centrilobular necrosis, and endothelitis were identified, although some of these changes may be due to post-transplant changes in one of the patients.
Clinical Characteristics and Outcomes of Coronavirus Disease 2019 Among Patients With Preexisting Liver Disease in the United States: A Multicenter Research Network Study.
Hepatic dysfunction was significantly higher in patients with preexisting liver disease, especially in patients with cirrhosis and this was associated with poor outcomes.
Clinical Characteristics and Outcomes of Coronavirus Disease 2019 Among Patients With Preexisting Liver Disease in the United States: A Multicenter Research Network Study.
patients with NAFLD had a higher risk of disease progression (P < 0.0001) and longer viral shedding (P < 0.0001) than those without NAFLD. Postmortem liver biopsies in one of these patients showed microvesicular steatosis with overactivation of T cells. However, other autopsy and biopsy studies only showed histologic findings consistent with shock liver
Moreover, among the infiltrating T cells, there is an enrichment of T cells that are reactive to SARS-CoV-2, suggesting that the vaccine-induced cells can contribute to hepatic inflammation. In a cohort of 16 patients who presented with hepatic dysfunction after vaccination, 10 underwent liver biopsy. All showed portal inflammation (60% of which was graded as moderate or severe).
In a case report of an 86-year-old man who died of acute renal and respiratory failure after receiving the first dose of the BNT162b2 mRNA COVID-19 vaccine, the autopsy showed stenosis and sinus dilatation in the liver.
In summary, the most common histologic changes associated with SARS-CoV-2 in the liver are steatosis, mild lobular and portal hepatitis, congestion with sinusoidal dilatation, lobular necrosis, and cholestasis. Hepatocyte apoptosis, vascular pathology with or without thrombosis, histiocytic hyperplasia, and Kupffer cells hyperplasia may also occur.
Clinics care points
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GI symtoms due to involvement by COVID-19 are non-specific. Diagnosis may be facilitated by exclusion of other etiology and positive COVID test.
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Pathologically GI involvement is mainly characterized by lymphocytic infiltration of the mucosa.
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In patients with hepatic involvement, non-specific portal and/or lobular lymphocytic infiltration, mild steatosis, and rarely, spotty necrosis may be pathologic findings.
References
Aiyegbusi O.L.
Hughes S.E.
Turner G.
et al.
Symptoms, complications and management of long COVID: a review.
Gastrointestinal and Hepatic Manifestations of 2019 Novel Coronavirus Disease in a Large Cohort of Infected Patients From New York: Clinical Implications.
Histopathological and virological features of lung, heart and liver percutaneous tissue core biopsy in patients with COVID-19: A clinicopathological case series.
Clinical Characteristics and Outcomes of Coronavirus Disease 2019 Among Patients With Preexisting Liver Disease in the United States: A Multicenter Research Network Study.
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