COVID-19 And The Pancreas

Another Day, Another Bad Thing About COVID-19

I'm sure you've had enough of COVID-19. Since first being recognized at the end of 2019 as a virulent pathogen, infections with COVID-19 have surpassed 770,000,000 worldwide, resulting in 6,957,216 deaths. It's clear that the virus has turned the world upside down and there doesn't seem to be an end in sight.

The more scientists study the effects of COVID-19 on the human body, the more surprises are found. One particular organ that appears to be deleteriously affected both acutely and potentially forever is the pancreas.

Since the beginning of the pandemic, it was recognized that gastrointestinal manifestations of COVID-19 infection could be problematic. Pathologic examinations of post-mortem COVID-19 patients revealed a substantial viral infiltration in both endocrine and exocrine compartments of pancreatic tissue. Importantly, morphological changes indicative of cell damage were seen as previously had been reported in SARS-CoV (2003). As the pandemic has evolved, many case reports have surfaced demonstrating pancreas damage from COVID-19. The two main pathologic effects on the pancreas are acute pancreatitis and diabetes mellitus.

Acute Pancreatitis

Acute pancreatitis appears to be relatively uncommon in COVID-19 infections although elevated amylase and lipase levels are very common. Point prevalence of true acute pancreatitis was reported as 0.27% in a retrospective cohort study of 11883 cases of hospitalized COVID-19 patients in 2020. Another US study of 1.5 million patients showed that the prevalence was 0.61%. Finally a metanalysis of 11 global studies showed a pooled prevalence of 3.1%.

This much is certain however. It appears to affect mostly women and the median age of patients is 54. A large metanalysis showed that pancreatitis tends to be more severe, with higher incidence of necrotizing pancreatitis (OR 2.40), ICU admissions (OR 4.28) and mortality (OR 5.75). In fact, overall pooled mortality was 18.5%.

Etiology: Direct Cytotoxicity

It is still debatable whether pancreatitis in patients with COVID-19 is related to direct cytotoxic effects of the virus or an epiphenomenon.

Direct cytotoxic effects are certainly quite plausible. SARS-CoV-2 utilizes angiotensin-converting enzyme 2 (ACE-2) receptors to enter human cells and TMPRSS2 for priming. Such proteins are highly expressed in both gastrointestinal luminal cells and pancreatic ductal, acinar and islet cells. In addition, the PLAC8 (placenta-associated 8) gene appears to be very necessary for COVID-19 to enter into cells.

PLAC8 is a highly conserved gene on chromosome 4, implicated in the regulation of multiple cellular processes like autophagy or cell motility. Previous studies have suggested that PLAC8 also plays a prominent role in pancreatic neoplastic transformation. An elegant study showed that PLAC8 overexpression was closely associated with pancreas injury in patients with COVID-19 infection. In addition, if PLAC8 was knocked out, COVID-19 did not infect the pancreas. This strongly suggests that the pathology of COVID-19 is due to more than just the exposure of the host to COVID-19, but due to host genetic factors as well.

Etiology: Cytokine Storm

A broad spectrum of proinflammatory cytokines, such as IL-2, IL-6, IL-7, IL-8, interferon-γ, and Tumor Necrosis Factor α (TNF-α), is released during, in particular severe, COVID-19 infection. Based on current studies, it is reasonable to suspect that these cytokines are released in response to the binding of the virus to ACE2 receptors that are also located in the pancreas. Particular attention should be paid to IL-6, because it is suspected to play a key role in the pathogenesis of pancreatitis as well as acute respiratory distress syndrome (ARDS) that is the most common and most severe clinical manifestation of COVID-19.

The common pathway for injury may well be that the active inflammatory process triggers the coagulation cascade, resulting in thrombosis of pancreatic blood vessels and pancreatic ischemia. In fact, these observations have been supported by the results of experimental studies showing that the inhibition of coagulation reduces the development of pancreatitis clinically.

Diabetes

The relationship between COVID-19 and diabetes is complex. Patients with diabetes have a risk of developing more severe symptoms of COVID-19 infection. In addition, there is newly emerging evidence that COVID-19 causes beta cell injury and the development of diabetes. All of this may well have to do with ACE2 receptor binding.

ACE2 in the pancreas is expressed mainly within the pericytes of pancreatic microvessels and to a lesser extent on the surface of the islets of Langerhans, including pancreatic β cells. ACE2/angiotensin stimulates insulin secretion, reduces insulin resistance, and increases pancreatic β cell survival. Binding of COVID-19 to ACE2 blocks all of that.

Two other possible pathways to pancreas injury are the cytokine storm we discussed above and molecular mimicry. High levels of IL-1β and IL-6 were found to play a determinant role in the β-cell dysfunction observed in patients with COVID-19 in this study . Viral epitopes sharing homologies with amino acid sequences of autoantigens could also lead to the production of cross-reactive antibodies against β-cells, even after the viral infection is cleared.

In any event, histologic and ultrastructural examinations of pancreatic islets from patients with COVID-19 who were newly hyperglycemic revealed mild pancreatic inflammation and altered β-cell structure, displaying characteristic features commonly reported and observed in patients with type 2 diabetes, and detection of viral RNA suggested pancreatic localization of SARS-CoV-2.

A systematic review of 18 studies reported a pooled prevalence of diabetes of 11.5% (95% CI 9.7, 13.4), with pre-existing diabetes being associated with a high risk of severe COVID-19 (relative risk [RR] 2.11; 1.40, 3.19) compared with those without. Adjusted for age, sex, deprivation, ethnicity and geographical region, compared with people without diabetes, the OR for in-hospital COVID-19-related death was 3.51 (95% CI 3.16, 3.90) in people with type 1 diabetes and 2.03 (1.97, 2.09) in people with type 2 diabetes. Male sex, older age, obesity, renal impairment, non-white ethnicity, previous stroke or heart failure all compound the risk of severe COVID-19 in diabetics.

In a large cohort study of more than 629,000 patients, COVID-19 infection was associated with an excess level of new diabetes of 3-5% in the population. Another large metanalysis of more than 40,000,000 patients showed that infection with COVID-19 nearly doubled the risk of diabetes, and patients with severe COVID-19 were at the highest risk especially in the first 3 months of recovery.

Rubino's group has established a global registry of new-onset diabetes due to COVID-19 in an effort to better understand it.

What Does This All Mean?

COVID-19 infection contributes to damage within the pancreas and this is supported by diverse data. The mechanisms involved include direct cytopathic effects of SARS-CoV-2 replication, systemic and local inflammatory responses, and long-term autoimmune damage. Given that the development of autoimmune diseases is often a chronic, long-term process, the true burden of pancreas damage and diabetes remains to be seen. However, a wave of diabetes in the near-future is almost certain.

Yeah, COVID-19 sucks.

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