SIH is a multifactorial complication, and there appear to be many risk factors linked to it. Although the available findings may not suffice to cover certain aspects of SIH in detail, we have classified the possible risk factors into three categories: host factors, environmental factors, and viral factors. Host factors point to a group of individual-oriented variables, such as age, gender, pre-existing diseases, and liver markers, while environmental and viral factors embrace dietary habits, unhealthy behavior, drugs, mutations, coinfection, etc. (Fig. 4).

As a multifactorial complication, the development and severity of SIH are considered to be relatively dependent on host-oriented, environmental, and viral risk factors, which can influence the outcome of the disease in COVID-19 patients

The general health of a host is a conclusive criterion that determines an individual’s capacity to control and eliminate any infection in the body. Vigorous general health status can reinforce the immune system’s protection against COVID-19 and SIH. We assume that aging, male sex, and pre-existing medical conditions such as hypertension, liver and heart diseases, diabetes, chronic kidney disorders, obesity, chronic obstructive pulmonary disease (COPD), brain and nervous system conditions, dementia, a history of stroke, cancer, and blood disorders are among the most important culprits that can exacerbate the morbidity of COVID-19 (Table 1) [47].

It is difficult to accurately determine the age distribution of COVID-19 patients. However, it is assumed that aging influences the pathophysiology of the disease in several ways, and adults older than 65 years are more prone to SIH [1, 48]. There are also reports that neonates infected with SARS-CoV-2 have lower chances of experiencing liver injury, implying that SIH might correlate with immunopathological factors and that immature adaptive immunity may be more advantageous in this context [49]. From the perspective of science, there are two types of aging systems termed chronological age and biological age. Chronological age, aka phenotypic age, is calculated merely based on the number of years that have passed since a person’s birthday, whereas biological age, aka epigenetic age, is defined on the basis of DNA methylation patterns and takes into account a collection of more factors, including nutrition, lifestyle, genetics, and diseases to display a more accurate picture of our overall body age. It is believed that the coexistence of underlying diseases is more likely to be seen in elderly people either chronologically or biologically. Furthermore, pulmonary stem cells undergo aging-induced degradation over time, which highlights the possibility of respiratory failure and developing SIH via hypoxic hepatitis [1, 50]. In addition, levels of ACE-2 and TMPRSS-2 expression are apparently higher in elderly individuals, explaining why aging is correlated with a higher risk of serious illness. Interestingly, analysis of epigenetic clocks and telomere shortening in two groups of people, including patients with severe and non-severe COVID-19, revealed that an increasing age acceleration occurs during the initial phases of the disease. Although this phenomenon can be partially reversed in later phases, SARS-CoV-2 infection might expedite biological aging, which on a larger scale, unfavorably affects whole-body organs, including the liver [51].

It has also become clear that the risk of developing SIH is probably sex-biased [48]. According to epidemiological studies, males constitute up to 75% of all COVID-19 deaths, with three times the odds of being admitted to the ICU and a mortality rate at least 15% higher than that of females. Males showed a higher risk of organ dysfunction that may involve the liver when infected with SARS-CoV-2. It appears that higher expression levels of ACE-2 in men, sex-specific immunological differences driven by sex hormones, and the X chromosome can be the potential culprits to blame. Moreover, lifestyle and behavioral differences between females and males might be a case as well, because the latter exhibit greater tendencies for smoking, drinking, and irresponsibility toward wearing face masks, frequent handwashing, staying at home, etc. [52, 53].

Moreover, patients with chronic liver diseases (CLDs) are more likely to exhibit a critical form of COVID-19. Liver dysfunction, if not caused by SARS-CoV-2 itself, might be a result of different conditions, including alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic or end-stage cirrhosis, and liver transplant complications. These states are among the significant preceding factors that can remarkably increase the severity of COVID-19 accompanied by hepatonecrosis [54,55,56]. COVID-19 patients with liver dysfunction, HCC, or cirrhosis experience a greater degree of injury to the liver. Such a complex medical history, along with higher hepatic expression of ACE-2 and TMPRSS-2 in critically ill patients, may generate immune system defects, coagulation disorders, renal failure, systemic inflammation, and hepatic encephalopathy [16, 40, 57, 58]. Reportedly, the lethal combination of cirrhosis and SARS-CoV-2 infection has a poor prognosis, and the mortality rate in this group of patients is fourfold higher (32%) than that in patients without cirrhosis (8%) [59]. Moreover, comorbidity of COVID-19 and diabetes is also another condition that pooled data from manifold meta-analyses have proposed as a risk factor for extrapulmonary complications of COVID-19. It has been observed that diabetic mice express higher levels of ACE-2 in their renal cortex, liver, and pancreas, a finding that might be generalizable to humans and suggest a higher possibility of developing SIH in diabetic patients with COVID-19. In addition, with respect to findings that report three-year lasting hyperglycemia after recovery from SARS-CoV-1 infection and the belief that pancreatic islets are also able to express ACE-2 receptors, it is worth considering that SARS-CoV-2 might deal a transient or permanent damage to beta cells as well. Moreover, diabetes has been reported as a causative agent for (a) lymphocytopenia, (b) overexpression of FURIN, and (c) elevation of IL-6 production, which are associated with increased susceptibility to infection, more effective internalization of SARS-CoV-2, and higher chances of cytokine storm, respectively [60].

Environmental factors, such as air pollution, regional temperature, relative humidity, solar radiation, geographical features, economy, culture, and general hygiene, can affect the pattern of COVID-19 pathophysiology through four interconnected ways: (a) causing a secondary health condition or triggering a pre-existing one to relapse, (b) weakening the immune system, (c) allowing the virus to survive and spread, and (d) promoting behaviors that increase the chances of infection [61].

Unhealthy dietary habits such as the consumption of excessive carbohydrates and saturated fatty acids result in the accumulation of intrahepatic fat, which signals the incidence of NAFLD and NASH. The clinical implications of NAFLD range from an asymptomatic condition with a trace of fat accretion (> 5%) to more advanced challenges, such as a health-threatening state of steatosis that may end in NASH, liver fibrosis, cirrhosis, hepatitis, and hepatocellular cancer. The combination of SARS-CoV-2 infection and NAFLD foretells a poor prognosis that may give rise to SIH in COVID-19 patients [62, 63].

It is also crucial to bear in mind that adequate intake of micronutrients and minerals such as iron, selenium, zinc, copper, as well as vitamins A, B family, and C should be among the principal priorities of people’s regimen. Foodstuff containing these materials interacts with different nuts and bolts of metabolism in the body and plays a pivotal role in the process of energy production. They also actively participate in counteracting oxidative reactions within organs, leading to the inhibition of inflammation and cellular stress. In addition, the intake of dietary fiber is highly recommended for the production of short-chain fatty acids, which modulate cytokine secretion and regulate the migration of immune cells. A nutrient-rich diet accompanied by essential micronutrients, minerals, and vitamins is essential for the body’s repair, maintenance of immune system robustness, and overall health, potentially resulting in a milder phenotype of respiratory distress and SIH in COVID-19 patients [45].

Lifestyle affects the quality of general health to a massive extent. A history of consistent healthy behaviors boosts innate and adaptive immunity. Low levels of physical activity have been confirmed to be a solid cause of high blood cholesterol, cardiovascular diseases, obesity, and immune-related issues. Moreover, smoking, alcohol addiction, drug abuse, overeating, and impaired sleep have also been reported to increase the rate of morbidity and mortality associated with CLDs in COVID-19, mostly by exaggerating the release of inflammatory cytokines and acute-phase proteins [7, 64,65,66,67,68].

It also appears that drugs have their own share of influence on the development of SIH, and regular monitoring along with precautionary measures should be taken to ensure that the functionality and general status of the liver in patients with COVID-19 remain optimum. Drug-induced hepatopathy is the third leading cause of liver damage after viral hepatitis and ALD/NAFLD/NASH [40]. Reports indicate that it can result in SIH after two weeks of hospitalization and drug intake. Some antiviral drugs make COVID-19 patients prone to MOF and liver injury, which addresses the potential risk of drug hepatotoxicity during the course of medication [69] (Fig. 5). Chloroquine, lopinavir/ritonavir, ribavirin, favipiravir, remdesivir, and tocilizumab are broadly prescribed candidates whose majority of metabolism is performed in the liver [70]. The literature warn that chloroquine and hydroxychloroquine can result in acute liver failure, and their use in patients with pre-existing liver diseases should be cautiously administered [57]. Furthermore, in a recent meta-analysis, the pooled incidence of drug-induced liver injury was reported to be 25.4% among COVID-19 patients, and those for whom lopinavir/ritonavir was administered, this rate (37.2%) was almost two and a half times higher than that of patients treated with remdesivir (15.2%) [71]. On the other hand, there is evidence that remdesivir, as well as systemic corticosteroids or antifungal agents, can cause elevation of aminotransferases. Ribavirin, an active agent against a wide range of RNA viruses, has also been reported to correlate with hemolysis and hepatotoxicity following cessation of its use. Moreover, COVID-19 patients who take acetaminophen to alleviate their fever are at risk of hepatic damage or even liver failure if they overdosed (Table 2) [40, 57].

A general flowchart visualizing possible mechanisms and outcomes related to drug hepatotoxicity and their association with the progression of SIH in patients with COVID-19; (1) Drugs may interact with particular receptors and cause a detrimental response or suppress/shut down a crucial function. (2) Drugs can cause different types of hypersensitivity reactions (HSR). (3) Drugs may trigger certain cascade reactions that affect regulatory systems. (4) Drugs might also interfere with transcription and replication processes

Authors’ perspective: It appears that people in hot or sultry weather tend to wear face masks for a shorter period of time since the warmth is already irritating, and a physical obstacle such as face masks makes breathing even harder. On the other hand, people in cold weather are more likely to gather in groups so that the heat generated by their bodies keeps them warm. In addition, most people are likely to keep doors and windows closed to protect themselves against the low temperature outside, which results in the reduction of air velocity, accumulation of viral particles in the room, and increasing the likelihood of spreading infection. Air pollution and exposure to hazardous chemicals due to habitation in metropolitan areas or engagement in particular occupations are other reasons that might contribute to the onset of various health complications, such as cancer, or re-emergence of pre-existing diseases. These conditions can directly or indirectly affect the susceptibility of individuals to COVID-19, accelerate the progression of liver pathogenesis, and define new epidemiological patterns of the pandemic on larger scales.

The influence of viral factors, such as different variants, viral load, coinfection, virulence, and the tropism of SARS-CoV-2 are all of great importance and relevance to our research agenda. Since the onset of the SARS-CoV-2 pandemic, research and healthcare organizations have been dealing with an avalanche of mutations that have affected numerous biological aspects of the virus. The mutation frequency appears to be directly related to the level of virus circulation and spread, allowing it to evolve and develop competitive traits, such as enhanced virulence potency, new tropism tendencies, higher contagiousness, and more robust capabilities of evasion from neutralizing antibodies. These characteristics may set the milestones for the formation of vast waves of new outbreaks that can rapidly overtake the whole world [1, 73].

Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) results revealed that patients with lower quantification cycle (Cq) values within the first 20 days of hospitalization experienced two temporary periods of elevated ALT and AST levels, indicating that a higher viral load in the early phase of the illness correlates with a higher risk of experiencing SIH. Moreover, SARS-CoV-2 RNAemia has been observed to be linked to a greater chance of MOF development [74,75,76,77].

It also has been reported that hospitalized patients with COVID-19 show different levels of disease severity in the presence of other viral or bacterial pathogens. Coinfection with two viruses is a common event with a spectrum of diverse possibilities. SARS-CoV-2 coinfection with influenza, HBV, human hepatitis C virus (HCV), and human immunodeficiency virus (HIV) have been observed in clinical cases, suggesting that they might contribute to SIH or accentuate a challenge for misdiagnosis. It has been documented that a mixed infection of SARS-CoV-2 and adenoviruses may increase the risk of hypoxia, ARDS, and lymphopenia. SARS-CoV‐2/HIV coinfection has also been reported to be more invasive owing to immune deficiency. In addition, it has been demonstrated that SARS-CoV-2 can cause lymphopenia and trigger the reactivation of the Epstein-Barr virus (EBV) and HBV, thus remarkably increasing the morbidity and mortality rates associated with MOF and liver involvement [16, 78]. Moreover, interactions between SARS-CoV-2 and Mycobacterium tuberculosis signify the possibility of malignant hypoxic liver injury and other challenging outcomes with poor prognosis, particularly in the elderly [79].