key: cord-0927274-seeg0mgk authors: Tang, Qiuyi; Gao, Lin; Tong, Zhihui; Li, Weiqin title: Hyperlipidemia, COVID-19 and acute pancreatitis: a tale of three entities date: 2022-04-04 journal: Am J Med Sci DOI: 10.1016/j.amjms.2022.03.007 sha: 8950c098250aa6b7b335c30ba306350fb07d609a doc_id: 927274 cord_uid: seeg0mgk Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the ongoing pandemic of coronavirus disease 2019 (COVID-19), which presented as not only respiratory symptoms, but various digestive manifestations have also been recognized, including pancreatic injury and acute pancreatitis (AP). The underlying mechanism is still unclear. Hypertriglyceridemia has become one of the leading causes of AP in recent years and hyperlipidemia is highly reported in COVID-19 cases. The current narrative review aimed to explore the associations between AP, COVID-19 and hyperlipidemia. Substantial cases of COVID-19 patients complicated with AP were reported, while the incidence of AP in the COVID-19 population was relatively low. Hyperlipidemia was common in COVID-19 patients with a pooled incidence of 32.98%. Hyperlipidemia could be a mediating factor in the pathogenesis of AP in COVID-19 patients. Further studies are warranted to clarify the relationship among AP, lipid metabolism disorders and COVID-19. The ongoing pandemic of severe acute respiratory syndrome coronavirus 2 Acute pancreatitis (AP) is the inflammatory disease of the exocrine pancreas characterized by severe abdominal pain and elevated pancreatic enzymes (amylase and lipase), the incidence of which is increasing rapidly in recent years. 3 In published literature, numerous cases of COVID-19 complicated with AP have been reported (Table 1) . However, no robust causative relationship has been established between them. Given the considerable presence of hyperlipidemia in COVID-19 cases, we postulated that hyperlipidemia might play a potential role between COVID-19 and AP. Hence, this narrative review aimed to accumulate evidence on the incidence of hyperlipidemia and AP in the COVID-19 population, and demonstrate whether hyperlipidemia acted as a mediating factor in COVID-19 patients combined with AP. We used "COVID-19" and "acute pancreatitis" as search terms to retrieve related articles in PubMed database. The results of different studies were controversial. An epidemiological study from Spain including 63 We use "COVID-19" and "hyperlipidemia" as search terms to retrieve related articles in PubMed database. Thirty-four papers were reviewed after screening, which reported the incidence of hyperlipidemia in COVID-19 patients ( Table 2) . The incidence of hyperlipidemia ranged from 0.30% to 81.82% in COVID-19 patients among different studies. Potential reasons for the variations could be: 1) Regional factors led to the difference in baseline lipids levels; 2) The definition of hyperlipidemia varied in different studies. An epidemiological study in Iran focusing on COVID-19 patients with diabetes reported that only 49 cases of hyperlipidemia presenting in 16,391 COVID-19 patients (0.30%), however, the incidences of hyperlipidemia in COVID-19 patients from other studies were all much higher than those in the normal population. The aggregated incidence was 32.98% in pooled COVID-19 patients. Hyperlipidemia was commonly presented in critically ill COVID-19 patients and the potential causes for it could be: hemophagocytic lymphohistiocytosis, medication and acute liver injury. 89 For instance, some studies suggested that ARDS patients with COVID-19 experienced a higher rate of propofol-associated hypertriglyceridemia than non-COVID-19 induced ARDS patients, even after adjusting for propofol administration doses. 81 It was reported that the incidence of propofol-associated hypertriglyceridemia was 18%-45% in the non-COVID-19 population, but could be as high as 56.6% in COVID-19 patients. 90 Besides, there was a case report presenting 2 cases of tocilizumab-induced hypertriglyceridemia during the treatment of COVID-19, and one of them developed into AP in the later disease course. It is unclear whether hyperlipidemia leads to deterioration of disease course and prognosis of COVID-19 patients. Previous research has showed that patients older than 50 were prone to have hyperlipidemia, 76 which led to an increased risk of hospital admission (OR=1.8) 78 and disease deterioration (OR=2.15). 91 In addition, previous reviews suggested that patients with hypercholesterolemia had increased risk for COVID-19 and the related complications. 92, 93 However, one study compared between two cohorts, namely COVID-19 patients discharged alive and those that died, and multiple regression analysis showed that hyperlipidemia had a protective effect on reducing the likelihood of death (OR=0.75). 94 Another study carried out cluster analysis in a large cohort of 12,066 COVID-19 patients, and the results showed that hyperlipidemia had no significant effects on COVID-19 prognosis. 95 It is widely acknowledged that gallstones and alcohol intake are two major causes of AP followed by hypertriglyceridemia (HTG) and others. HTG has been a major cause of AP over the last decade and accounts for about 10% of total AP worldwide. 96, 97 Especially in East Asia, HTG has become the second leading cause of total AP and the incidence of HTG-AP could reach up to 15-25%. [98] [99] [100] HTG is one of the predominant subtypes of hyperlipidemia, and it has been reported to deteriorate disease severity, progression, and outcomes of AP. A meta-analysis of 15 studies compared 1,564 HTG-AP patients to 5,721 AP cases with other etiologies, the results showed that the occurrence of renal failure, respiratory failure, shock, and mortality was significantly higher in HTG-AP patients. 101 A retrospective study classified AP patients into a normal triglyceride group or mild HTG (<200 mg/dL) group, a moderate HTG (200-749 mg/dL) group, and a severe HTG (>750 mg/dL) group, and demonstrated that higher serum triglyceride level was independently associated with a more severe disease course of AP. 102 Previous studies suggested that the potential mechanisms of the deteriorating effects of HTG on AP may lie in the accumulation of free fatty acid and thereafter, activation of inflammatory response in the pancreas. 103 Free fatty acid has been reported to cause the increase in the levels of inflammatory mediators, such as TNF-alpha, interleukin-6, interleukin-10, which might strengthen the systemic inflammatory response and local pancreatic injury. Moreover, in vitro experiments also presented that free fatty acid had direct cytotoxic effects on acinar cells and vascular endothelial cells. When it comes to the causes of AP in the COVID-19 population, some studies suggested that SARS-CoV-2 could cause pancreatic injury and AP directly. Angiotensin-converting enzyme 2 (ACE2) is widely expressed in human vascular endothelium, respiratory endothelium, and other cell types, which is thought to be a primary mechanism of SARS-CoV-2 entry and infection. 104 An inflamed/injured endothelium promotes neutrophilia and systemic inflammatory cascades, leading to involvement of multi-organs. A review concerning the role of endothelium in COVID-19 suggested that endothelial cells were a crucial link between SARS-CoV-2 and host immune responses and thus may serve many roles in determining the disease severity and mortality in COVID-19. 105 Receptor proteins of SARS-CoV-2 including ACE2 were also highly expressed in the epithelial cells of gastrointestinal tract, so do the pancreatic duct epithelium, pancreatic acinar cell, and islet cell. SARS-CoV-2 could infect the gastrointestinal epithelial cells through the gastrointestinal tract and spread into the pancreas. This hypothesis was supported by a few studies, one study showed the existence of SARS-CoV-2 in gastrointestinal tract epithelium, and RNA of the virus could be detected by real-time reverse transcriptase polymerase chain reaction from feces. 106 Furthermore, SARS-CoV-2 was also isolated from pancreatic pseudocyst tissue. 107 However, this hypothesis was not validated by robust evidence and it is unable to explain the relatively low incidence of AP in COVID-19 patient in some large epidemiological researches. 47, 48 Taking into consideration of the high incidence of hyperlipidemia in COVID-19 patients, we hypothesized that hyperlipidemia could also be a mediator in the pathogenesis of pancreatic injury and AP in COVID-19 patients besides direct virus infection. The detrimental effects of HTG mentioned above should also exist in COVID-19 patients combined with AP. To support the hypothesis, we wondered whether the incidence of AP was higher in patients with hyperlipidemia compared to patients without hyperlipidemia in the COVID-19 population. However, no well-designed study has yet to report the related data, we thereby retrospectively collected the information of all case reports of AP with COVID-19 ( Table 1) . From the retrospective analysis, the levels of total triglycerides and total cholesterol increased slightly in COVID-19 patients complicated with AP, which suggested that hyperlipidemia may be the reason for the occurrence of AP. (1) A small portion of COVID-19 patients presented with acute pancreatitis, but the underlying mechanism was still unknown. (2) The occurrence of hyperlipidemia was high in the COVID-19 population. (3) In general population, hyperlipidemia has become one of the major causes of AP. 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