and pediatric fatty liver disease: Is there interplay?

Anna Di Sessa, Francesca Lanzaro, Sarah arilli, Vittorio Picone, Stefano Guarino, Emanuele Miraglia del Giudice, Pierluigi Marzuillo

Abstract The rapid global spread of coronavirus disease 2019 (COVID-19 ) infection has become a major health issue with higher morbidity and mortality rates. Besides respiratory symptoms, a growing body of evidence indicates a variety of gastrointestinal manifestations including liver involvement. In this regard, several data supported an association between COVID-19 infection and liver injury in adults, while in children there is compelling but currently limited evidence. In particular, patients with COVID-19 have shown a higher risk of liver injury(mainly expressed as increased transaminase levels or hepatic steatosis).Conversely, a greater risk of more severe forms of COVID-19 infection has been observed in subjects with pre-existing chronic liver diseases. The dramatic interplay between COVID-19 and liver damage has been related to the inflammatory pathways chronically active in patients with nonalcoholic fatty liver disease and acutely in those affected by COVID-19 , but other different pathogenic mechanisms have also been supposed. Of note, patients with previous metabolic comorbidities also had a higher risk of severe COVID-19 infection. This emphasizes the pathogenic interrelation of the inflammatory pathways with a dysregulated metabolic milieu in COVID-19 patients. Taking into account the prognostic role of fatty liver in COVID-19 patients and its intrinsic relationship with metabolic abnormalities even in childhood, a strict monitoring of this condition is recommended. We aimed to summarize the most recent evidence regarding the potential interplay between pediatric fatty liver and COVID-19 .

Key Words: COVID-19 ; Children; Adults; Nonalcoholic fatty liver disease

INTRODUCTION

Since late 2019 , the whole world has been suddenly disrupted by the coronavirus disease 2019 (COVID-19 ) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 ). At the beginning of February 2021 , this global acute pandemic produced more than 102 million worldwide confirmed cases and a total number of deaths to 2 .2 million, representing an unprecedented healthcare challenge[1 ].

The pathogenic role of COVID-19 depends on binding of spike viral proteins to angiotensin I converting enzyme 2 (ACE-2 ) receptors facilitating the entry into the target cells[2 -4 ]. Although mainly expressed in the respiratory tract, in particular in the nasopharynx epithelium, these receptors are also located in multiple sites such as the gastrointestinal tract and vascular endothelium[5 -8 ]. Along with clinical respiratory symptoms, growing evidence supported a COVID-19 related gastrointestinal involvement[8 -13 ]. COVID-19 positive adult patients might experience gastrointestinal symptoms due to the presence of ACE-2 receptors in the glandular cells of gastric,duodenal, and distal enterocytes that favor malabsorption, impaired intestinal secretion, and enteric nervous system activation[8 ,9 ,12 ,14 ]. The virus might also affect the liver through a direct viral translocation from gut or by an indirect mechanism involving systemic inflammation, pre-existing liver diseases, or drug-related liver damage[11 ,13 -16 ].

Pediatric COVID-19 reports have shown both a milder course and a better prognosis of the disease in this population, probably due to the special immune response system pertaining to children. Gastrointestinal manifestations of the disease at this age are various and not uncommon, in particular in the early phase of the infection.

Nonalcoholic fatty liver disease (NAFLD) has become the most common worldwide chronic liver disease with an epidemic rate both in adults and children[17 ,18 ]. It has been largely recognized for its close relationship with insulin resistance and other metabolic features leading to an increased cardiometabolic risk from childhood to adulthood[19 -23 ]. Nevertheless, NAFLD pathophysiology is still far from being fully clarified. To date, the “multiple hits” represents the most favored pathogenic hypothesis, including a role for several different factors (e.g., inflammation, oxidative stress, gut axis, mitochondrial dysfunction, diet, hormones, and genetics)[24 ].

HOW CAN COVID-19 AFFECT THE LIVER?

The mechanism underlying the increase of liver enzymes seemed to be different between adult and pediatric patients, but further studies are needed for a better elucidation[25 ] .

In adults, two mechanisms for liver injury have been postulated such as a possible role of ACE-2 receptor binding of the virus to the epithelial cells of the bile ducts or a dysregulated hepatic innate immune response, which represents the most probable hypothesis. No evidence supported the involvement of ACE-2 receptor in pediatric liver injury. Moreover, both interleukin (IL)-6 and IL-10 levels did not significantly differ between infected children with and without elevated liver enzymes[25 ]. Of interest, the presence of a protective mechanism against liver involvement in children accounting for the mild increase of aspartate aminotransferase and/or alanine aminotransferase (ALT) compared to adults has been suggested. Zhouet al[25 ]reported a higher prevalence of liver involvement (expressed as abnormal liver enzymes) in children aged 0 -3 years than in those aged ＞ 3 years, by speculating that this finding might be related to a more pronounced liver immaturity.

The exact mechanism linking COVID-19 to pediatric fatty liver remains poorly known[8 ,11 ,25 ] (Figure 1 ). In fact, the low incidence of COVID-19 infection in children and its relatively asymptomatic course at this age make it difficult to better understand the pathophysiology of this concern[8 ,11 ]. To complicate matters, one of the most likely hypotheses supporting the abnormal liver enzymes in adults such as the inflammatory cytokine storm (including IL-6 -and IL-10 ) seemed to not play a central role in pediatric COVID-19 related liver damage[25 ]. In fact, studies in infected children have demonstrated that levels of these cytokines are linked to greater severity of the disease, but no statistical differences of both IL-6 and IL-10 serum concentrations have been detected between patients with and without increased transaminases[25 ].Moreover, the pediatric clinical practice to first give paracetamol for fever management did not exclude the potential link between liver injury (expressed as abnormal transaminase levels) and drug administration[25 ].

However, all these studies suffered from some limitations. The first was relatively small sample sizes. Lack of a more accurate laboratory assessment and of longitudinal data represented another limitation. Finally, lack of previous data about comorbidities or drug administration before the hospitalization needed to be mentioned.

Nevertheless, given the growing amount of data regarding liver involvement during this pandemic, the American Association for the Study of Liver Diseases recommends to regularly monitor the mild increase of transaminase in patients with COVID-19 and (mainly in children) to further evaluate for potential underlying liver diseases because of the uncommon presentation and the current paucity of data at this age[26 ].

FATTY LIVER AND COVID-19

Evidence in adulthood

A large body of evidence has shown an association between COVID-19 and NAFLD in adults (Table 1 ). Findings from adult studies reported that the prevalence of steatosis(mainly detected by ultrasound abdominal scan or computed tomography) in the confirmed COVID-19 cases was significantly higher than in healthy subjects, even after adjustments for gender and age[27 ].

Additional data suggested that male patients aged ＞ 60 years, with higher body mass index, underlying comorbidities, and NAFLD were at higher risk of COVID-19 progression[28 ]. Another study reported no difference in terms of admission to intensive care unit and mortality between NAFLD and non-NAFLD patients.Mortality was associated to male gender (similarly to non-NAFLD patients) and a pronounced inflammatory response (including high ferritin and early weaning score as main predictors). The latter might account for the presence of a dysregulated hepatic innate immune response, one of the most acclaimed mechanisms postulated for liver injury. In addition, NAFLD patients were significantly younger at presentation and showed an increased risk of severe COVID-19 in both genders, specifically in males[29 ].

Interestingly, taking into account the new definition of metabolic-associated fatty liver disease (MAFLD), authors investigated the potential relationship between COVID-19 infection and MAFLD patients[30 -32 ]. MAFLD patients had a greater risk of disease progression, longer viral shedding times, and a higher probability of liver dysfunction from admission to discharge than patients without MAFLD[30 -32 ].Sharmaet al[32 ] found that younger patients (aged ＜ 60 years) with MAFLD showed an increased severity of COVID-19 disease. Overall, a significant association between MAFLD and younger presentation of COVID-19 was found[31 ,32 ].

Notably, as observed in NAFLD subjects, the direct relationship of MAFLD with COVID-19 infection emphasizes the relevance of the metabolic milieu in this viral condition, by pointing out the role of dysregulated hepatic innate immunity to trigger liver damage[29 -32 ]. Moreover, overwhelming evidence supported the association of COVID-19 infection severity (defined as the occurrence of any of the following parameters: arterial PaO2/FiO2 ≤ 300 mmHg, SpO2 ≤ 93 %, ≥ 30 breath per minute) with both NAFLD and/or MAFLD, even after full adjustment for common cardiometabolicrisk factors such as obesity, hypertension, metabolic syndrome, diabetes, and smoking[30 ,33 ]. Hence, this association was found to be independent of metabolic syndrome and/or its components[33 ]. In particular, MAFLD presence in nondiabetic patients was associated with a 4 -fold increased risk of severe COVID-19 , even after adjusting for age, gender, and coexisting comorbidities, and the risk was even higher with increasing numbers of metabolic risk factors[30 ]. Moreover, the presence of intermediate or high fibrosis was also linked to a higher risk of severe COVID-19 , even after adjusting for gender, obesity, and diabetes[34 ].

Table 1 Main findings regarding the association between fatty liver disease and coronavirus disease 2019 in adults

Figure 1 Potential mechanisms linking coronavirus disease 2019 to pediatric fatty liver. ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; COVID-19 : Coronavirus disease 2019 .

Evidence in childhood

Compared to adult findings, evidence in children is currently limited but in line with the aforementioned association (Table 2 ). In fact, data from 6 pediatric case-series studies and a review reported that liver involvement, defined as an increase of ALT and/or aspartate aminotransferase, was rare and mild (＜ 2 × ULN)[35 -41 ]. In contrast to adults, Zhouet al[25 ] found no gender difference in children with COVID-19 and elevated liver enzymes.

Pediatric studies examining different variables such as demographic data, clinical and laboratory features, chest imaging results, treatments, and clinical outcomes of the patients with COVID-19 showed a prevalence of possible liver involvement from 6 %to 50 %[25 ,35 -41 ].

A retrospective analysis including eight severe or critically ill patients with COVID-19 (aged 2 mo-15 years) admitted to the intensive care unit of the Wuhan Children’s Hospital reported a mild increase of ALT levels in half of the population, while total bilirubin levels in all patients were normal[36 ]. Similarly, a retrospective study of 20 pediatric patients with COVID-19 infection showed increased ALT levels (＞ 40 U/L) in 25 % of cases[37 ]. A slight prevalence (6 %) of elevated liver enzymes in confirmed-COVID-19 Chinese patients (aged 0 -16 years) was also described in a cohort study[35 ].In addition, it provided evidence for a minor liver involvement compared to adults with COVID-19 (18 %), children with severe acute respiratory syndrome (48 %), and children with influenza A (7 %)[35 ].

It has been observed in children that both critically ill patients admitted to the intensive care unit and mild patients (defined as the presence of upper respiratory symptoms or asymptomatic infection, positive real-time reverse transcription polymerase chain reaction test for SARS-CoV-2 , and no abnormal radiographic and septic presentation) rarely showed abnormal liver enzymes[35 ,36 ]. In these studies, all the patients underwent an antiviral treatment, therefore the possibility that transaminase abnormalities were drug-induced cannot be ruled out[35 ,36 ]. Moreover, it should be noted that the most common symptoms at admission were cough and fever,usually treated with paracetamol, of which an incorrect administration might also influence transaminase levels[41 ].

CONCLUSION

Gastrointestinal symptoms have been largely described in COVID-19 infected patients.Indeed, the wide presence of ACE-2 receptors through the entire gastrointestinal tract has been considered to be responsible for the spectrum of gastrointestinal manifest-ations including abdominal pain, nausea, vomiting, or less commonly fatty liver and acute hepatitis. In particular, liver involvement has been reported both in adult and pediatric affected patients with a higher prevalence in the former population[7 ,42 ,43 ].Several pathogenic mechanisms have been hypothesized to explain liver damage, but its exact pathophysiology is still under debate[42 ,44 ]. First, it could be considered as a consequence of the “cytokine storm” resulting in an aberrant immune system reaction with an excessive inflammatory response, as observed in many affected subjects.Moreover, liver injury might represent a side effect of the administered drugs or a secondary effect of the hypoxia consequent to failure of other organs such as heart and lung. On the contrary, a direct viral effect is unlikely, as supported by the scarce evidence of an increase of the classical markers of biliary tract involvement such as gamma-glutamyl transferase and alkaline phosphatase in affected patients in the face of a large hepatic expression of ACE-2 on cholangiocyte surfaces[6 ,45 ].

Table 2 Main findings regarding the association between fatty liver disease and coronavirus disease 2019 in children

Of concern, liver damage in patients affected by COVID-19 seems to be enhanced by the intrinsic chronic activation of inflammatory pathways in NAFLD, potentially worsening outcomes in subjects with previous coexisting metabolic diseases[7 ,8 ].Moreover, patients with pre-existing chronic liver diseases have been found to be at higher risk to develop more severe forms of COVID-19 infection.

NAFLD expressed as hepatic steatosis and/or elevated liver enzymes represents one of the most common liver abnormalities reported during this pandemic, in particular in pediatric patients[7 ]. Studies reported an overall prevalence of mild liver enzyme increases of almost 25 % in COVID-19 infected children. Although different pathogenic mechanisms than adults have been supposed, further studies are required to better clarify the pathophysiology of abnormal liver enzymes in children with COVID-19 .

The potential prognostic role for NAFLD as well as its intrinsic close relationship with metabolic traits require a close monitoring of fatty liver in these patients.