The severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) appeared in December 2019 in Wuhan province, China has become a worldwide pandemic affecting millions of people worldwide and inducts greater waves of the outbreak in comparison with than the prior outbreaks of SARS-CoV and the Middle East respiratory syndrome-related coronavirus (MERS-CoV) [1,2]. The number of cases in both infected patients and mortalities are rising rapidly because neither specific effective antiviral therapies nor vaccine have been identified yet . The clinical features of coronavirus disease 2019 (COVID-19) are similar to SARS, and MERS and dominant symptoms are fever, dyspnea, and coughing. All age groups can be infected, particularly the elderly and those with underlying disease. Most of the patients have mild disease. However, some COVID-19 patients need intensive care, such as critical oxygen deprivation and intubation with mechanical ventilation [4–6]. Because of the contagious and pathogenic nature of COVID-19, a better understanding of clinical features and manifestations and pathogenesis mechanisms of COVID-19 may improve the prevention and treatment program of diseases.
It has been previously revealed that SARS-CoV can infect livers and lead to liver cell impairment . In the case of COVID-19, although the lung is considered a main organ of involvement, several studies have been reported liver test abnormalities and injuries in COVID-19 patients with severe disease [4,8,9]. Recently Chen et al. showed that more than half of patients of COVID-19 have several liver function tests abnormalities, and it shows the patients can also have different degrees of liver dysfunction. Detecting SARS-CoV-2 RNA in stool and blood samples, abnormal levels of aspartate aminotransferase (AST), and alanine aminotransferase (ALT) implicates the possibility of liver cell infection with the virus . However, the viral titer was relatively low, and pathological analysis of a patient who died from COVID-19 did not recognize viral inoculation in the liver tissue [11,12].
In addition, binding to the angiotensin-converting enzyme 2 (ACE2) is a receptor, and the expression of ACE2 in cholangiocytes may explain liver injury by COVID-19 . SARS-CoV-2 can spread to many organs with high expression of the ACE2 cell receptor. According to the recent study, the ACE2 expression on type II alveolar cell and bile duct cells makes these cells available for virus infection [7,14].
Furthermore, the possibility of liver cell infection with the virus is mentioned. Moreover, liver injury mechanisms in patients with COVID-19 might result from liver dysfunctions induced by different drugs and systemic inflammation prompt by cytokine storm or hypoxia-related to pneumonia . Most of the infected patients have been treated with antipyretic agents for fever, like acetaminophen. Many patients have a history of using antiviral drugs, indicating that significant liver damage could also be drug-related . However, more experiments are required to reveal the mechanisms responsible for liver injury. Although the clinical and cause of liver injury by COVID-19 still is mostly unclear, in this study, we assess how the liver is affected by COVID-19 using available evidence in this field.
Taxonomy of coronaviruses
The Nidovirales order includes four subfamilies: Arterividae, Roniviridea, Mesoniviridae, and Coronaviridae. Coronaviridae family is consists of two subfamilies Coronavirinae and Torovirinae. Moreover, Coronavirinae contains four genera, including Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. For the classification of coronavirus family members, features such as virion structure, genomic replication strategies, genomic similarities, physicochemical and genomic properties, and viral infection pathogenesis are considered . Coronaviruses are zoonotic viruses, meaning they can be pathogenic to humans and animals . The alphacoronavirus and betacoronavirus can be carried by mammals, whereas gammacoronavirus and delta coronavirus are found mainly in birds [17,19]. Coronaviruses can be pathogenic in wild and domestic animals such as dogs, chickens, and civets .
So far, human coronavirus 229E and human coronavirus NL63 have been identified as Alphacoronavirus, and human coronavirus HKU1, SARS-CoV, human coronavirus OC43, and MERS-CoV have been identified as betaviruses, which can lead to disease in humans (Fig. 1) [6,21].
However, another coronavirus has recently been identified in the betacoronavirus that is pathogenic to humans . This virus named SARS-CoV-2  first identified in December 2019, in Wuhan city, China , and the virus that leads to a disease called COVID-19 .
Virology and life cycle of coronaviruses
Coronavirus has an enveloped virion with 80–120 nm in diameter, and its nucleocapsid is helical . Coronavirus genomes are single-stranded RNA with positive polarity, and the genome size 27–32 kb is the largest genome among RNA viruses . The genome's characteristic structure is determined as follows: 5′-leader-UTR-replicase-S-E-M-N-3′-UTR-poly(A) tail .
In general, coronaviruses have four main structural proteins that contain: envelope protein (E), spike protein (S), membrane protein (M), and nucleocapsid protein (N). Moreover, there is a homodimer protein called hemagglutinin-esterase, found in some betacoronaviruses . E Protein is a small protein with three domains called the N-terminal domain (NTD), a long α-helical transmembrane domain, and a C-terminal hydrophilic domain . E protein acts as an ion channel . It has multiple functions, participates in the assembly, viral pathogenesis, and release process of the virus , and with the help of the M protein, can lead to the formation of virus-like particles . M protein is a high amount in the virion, which is consists of three transmembrane domains. This protein is involved in the assembly, membrane curvature, and forms the viral envelope [31,32]. N protein, which is a phosphoprotein , contains the NTD, the C-terminal domain and, a region named RNA-binding domain and all of which in various coronaviruses can bind to viral RNA genome .
Coronaviruses generally replicate in the cytoplasm . S glycoprotein is required to bind the coronaviruses virion to specific receptors on the cell surface and comprise two subunits S1 and S2. The binding takes place through the region known as the receptor-binding domain, which is located in S1 , and the virus enters is induced through endocytosis . The virus membrane fusion with the host cell membrane is carried out by the S2 protein . Two overlapping open reading frames (ORFs) form the replicas gene ORF1a and ORF1b and then translated into two polyproteins, pp1a and pp1ab. These polyproteins, which are processed by proteases, are 16 nonstructural proteins . After processing nonstructural proteins, many of them form replication and transcription complex (RTC) . After the RTC complex is formed, several subgenomic RNAs (sgRNAs) are produced by the discontinuous procedure . sgRNAs expression produces the virus's structural proteins that form the capsid structure and assemble in the cytoplasm . The endoplasmic reticulum-Golgi intermediate compartment is the assembly and budding site for coronaviruses. Finally, Coronavirus released occurs through exocytosis of the infected cell .
Severe acute respiratory syndrome-related coronavirus 2 infections
SARS-CoV-2 binds to its appropriate receptor named human ACE2  at the cellular level in the lung, kidney, heart, and intestine to begin its life cycle in the host body . Patients with COVID-19 disease can transmit the SARS-CoV-2 through droplets in direct contact with people during sneezing and coughing. Incubation time and the disease are 2–14 days, and presymptomatic transmission could be seen . A variety of symptoms such as myalgia, fever, dyspnea, cough, headache, diarrhea, nausea, vomiting, and thrombosis are seen in patients with the COVID-19 disease. However, the essential complications seen in most of these patients are respiratory . Both the upper and lower respiratory system parts can be affected by this virus .
The first site infected by SARS-CoV-2 is the upper respiratory tract , and in most patients, this part of the respiratory system is involved. At this time, the innate immune system begins to respond. Some of the innate immune cytokines, such as CXCL10, elevates, which may be evidence of help for assessing the next stages of the clinical period . Lower respiratory tract infected by this virus, it can lead to pneumonia and induct acute respiratory distress syndrome (ARDS) that can even be fatal . The reason why ARDS causes damage to body organs functions or death in COVID-19 disease is that cytokine storms occur due to increased proinflammatory cytokines and chemokines . In patients with COVID-19, inflammation, and coagulation are seen . COVID-19 can damage the cardiovascular system for several reasons, including a SARS-CoV-2 receptor (ACE2) in the cardiovascular, a systemic cytokine storm, hypoxemia, and respiratory dysfunction . Since the coronaviruses can cross the blood–brain barrier (BBB), therefore, for some reason, the virus can cause neurological complications. Coronaviruses can enter the central nervous system through cells such as monocytes and macrophages; cells in the BBB express SARS-CoV receptors. It is important to note that neurological symptoms have also been observed in patients with COVID-19, which might reflects the presence of SARS-CoV-2 receptors on the neural cells .
Epidemiology of coronavirus disease 2019
As we know, coronavirus disease 2019, which was named to COVID-19, initiates from Wuhan, China, and their first cases reported on 29 December 2019 [48,49]. Since then, 41 570 883 COVID-19 infected cases and 1134 940 deaths worldwide [50,51]. The first cause of people's infection by COVID-19 was their linkage to the local seafood market (Wet market) . After further investigations, the second infection source was considered person-to-person transmission by close contact .
Effects of severe acute respiratory syndrome-related coronavirus 2 on liver
One of the critical roles in the disease infection is binding the virus to the ACE2 as a receptor to enter the host cells. ACE2 expresses in the lungs, heart, kidneys, placenta, and liver [53–56]. Although the expression of ACE2 in cholangiocytes and hepatocytes is low, it has been suggested that cholangiocytes defective may contribute to liver injury [13,57]; however, the exact mechanism is not clear yet. In this regard, the abnormality analysis of COVID-19 patients revealed moderate microvascular steatosis and mild lobular and portal activity, showing the liver damage could be caused by either COVID-19 infection or drug-induced liver injury . Another report has highlighted the role of cytotoxic T cells due to T cells’ overactivation and the initiation of an inflammatory storm that is strongly related to activation of both natural and cellular immunity triggered by COVID-19 infection [40,58].
Indeed, the virus can directly induce proinflammatory signals by Toll-like receptors and T lymphocytes’ activation to apoptosis and necrosis of infected cells . Furthermore, CD4+ T cells promote the activation of B cells and the production of virus-specific antibodies and CD8+ T cells with the ability to kill the infected viral cell in the pulmonary interstitium, can play a significantly vital role in clearing the coronaviruses in infected cells and inducing liver injury . Such a strong response can cause considerable damage to the lungs and the other organs, specifically the liver. Predominantly, 14–53% of hospitalized patients with COVID-19 showed a high AST level, ALT and bilirubin, and usually one to two folds upper than standard limit . These abnormalities are usually mild with rare cases of severe acute hepatitis, and they recover without any special treatment or prolong hospitalization . Nevertheless, liver injury occurs in the 58–78% of death cases from COVID-19; the death of liver failure has not been reported in patients with COVID-19 (Fig. 2) .
There is limited information about the effect of COVID-19 on patients with preexisting liver diseases like chronic hepatitis B virus (HBV) or hepatitis C virus, primary biliary cirrhosis, or nonalcoholic fatty liver disease (NAFLD) . However, the coinfection of COVID-19 with HBV shows high susceptibility to contribute liver damage with more adverse outcomes and death. In this regard, one study has shown patients with HBV infection have a higher frequency of liver cirrhosis, high level of total bilirubin, more severe presentation, and a high mortality rate compared with non-HBV patients . More investigations are needed to realize the hepatic manifestations of COVID-19 in patients with chronic liver disease.
Different concentrations of the liver transaminases, including ALT, AST, and with less proportion gamma-glutamyltransferase (GGT), are usually used as indicators of inflammatory stimuli . Since the liver involves systematic infections, hepatitis and nonhepatitis viral infections could cause acute liver injury . Various studies reported that COVID-19 receptor, ACE2, is present on gastrointestinal cells such as the liver [57,66]. Moreover, SARS-COV-2 can infect the bile duct cells and impair liver function via the upregulation of this receptor [4,13]. Moreover, it shows acute liver injury following raised liver enzymes in blood sample tests [66,67].
Liver injury is defined as ALT and AST higher than three-fold of the upper limit unit (ULN) and GGT higher than two-fold of ULN . On the other hand, liver function abnormalities are defined as increasing the liver enzymes in serum: ALT more than 40 U/l, AST more than 40 U/l, GGT more than 49 U/l, alkaline phosphatase (ALP) more than 135 U/l (Fig. 3) . Transaminitis, which defines as elevated levels of transaminases, is usual among COVID-19 patients with 21–37% [4,70–72]. However, liver injury is not the only cause of aminotransferases elevation, and also, this can be a result of myositis caused by COVID-19 . Recently it is estimated that liver damage in COVID-19 patients may be related to drugs such as antivirals or antibiotics [4,60,73]. Based on Cai et al. investigation of 417 patients with COVID-19 in Shenzhen, China, 318 (76.3%) showed an abnormality in the level of liver enzymes. So actually, these patients were at a higher risk of getting severe COVID-19 disease . In an investigation that studied 148 COVID-19 infected patients in Shanghai, 50.7% (75/148) showed impaired liver function tests (LFTs) .
Evidence indicates that comorbidities by metabolic diseases such as transplantations, and advanced chronic liver disease, can increase the risk of severing COVID-19 disease and mortality rates [76,77]. Patients suffer from NAFLD show elevation in their liver enzymes and may increase the severity of COVID-19 disease [78,79]. Based on retrospective research that studied 202 confirmed COVID-19 patients by investigating their NAFLD status, it revealed that patients with NAFLD had a higher risk of COVID-19 disease progression . In contrast, in meta-analyze research that studied the effects of comorbidities on COVID-19 severity, liver disease as comorbidity has no relation to the increased risk of the COVID-19 .
According to a retrospective analysis on 115 confirmed COVID-19 patients, they reported the abnormality in the liver function enzymatic indexes, but they stated that liver function is not a significant characteristic of COVID-19 . Regarding liver-related complications of COVID-19 patients, the different prevalence of liver test abnormalities has been reported . Other respiratory viruses like influenza can induce similar elevation of liver function biomarkers that are considered a result of hepatic damage triggered by a viral infection with interactions involving intrahepatic cytotoxic T cells kupffer cells .
Alanine transaminase and aspartate aminotransferase
ALT is a hepatic tissue-specific enzyme that is majorly expressed in the cytoplasm of hepatocytes. Hence, the elevated level of ALT shows the hepatocellular damage  and had sufficient accuracy in predicting COVID-19 patients . AST expresses both in the liver and other tissues, including the pancreas, kidney, heart, and skeletal muscles. So this enzyme is less specific in liver damages diagnosis . ALT is present in the cytoplasm, while AST is present in the cytoplasm and mitochondria . After hepatocellular membrane damage, the permeability will increase and release ALT and AST in the blood . Several studies showed that, following the acute hepatocellular injury caused by a viral infection, hypoxia, and toxic injury, both ALT and AST level could arise thousands of times from normal levels . By an investigation, it has been declared that, since COVID-19 patients showed the abnormal level of liver enzymes in their laboratory assessments and only a small portion of them had underlying liver disease, suggested that the liver damage directly caused by a viral infection .
A retrospective study, by evaluating 1141 confirmed COVID-19 cases, announce that the patients mean leukocyte and lymphocytes were under normal range, C-reactive protein (CRP) levels were elevated, and also there was a mild increase in ALT and AST level besides their typical respiratory manifestations . Based on Lippi et al. Systematic review analysis, following screening 11 relevant articles, they found the higher values of the ALT (1.5 fold) and AST (1.8 fold) in COVID-19 patients. According to another Meta-analyze study that included 21 citations and 3377 total confirmed COVID-19 patients, they recognized several clinical predictors of severe and fatal COVID-19 infection upon laboratory abnormalities investigations. They found that the nonsurvivor group in comparison with the survivor group had more increases in white blood cell (WBC) count, creatine kinase, total bilirubin, IL-6, serum ferritin, and more remarkable decreases in platelet count and lymphocyte count. They also announced the elevated level of ALT and AST in these patient's serum . Consistent with this study, Chen et al. declared that 43 out of 99 COVID-19 patients had increased ALT levels and AST levels based on liver function abnormalities. By a cohort study with 200 confirmed COVID-19 patients, 66 patients had a liver injury. Following laboratory testing, the median urea nitrogen and uric acids, like ALT and AST levels, were beyond normal. The ALT of 56 (28.6%) patients were more than 80 U/l, with a median of 23.5 U/l and the median of AST was 35 U/l. So the AST/ALT ratio was 1.43 for 200 patients. This study suggested that the AST : ALT ratio (AAR) in admission is a crucial prognostic marker and early hospitalization in a potential measure to increase the COVID-19 patients’ survivability . The pattern of liver damaged can be characterized by AAR .
In the context of comorbidities, in a study with 339 included patients, the abnormality in the level of liver enzymes was observed in 96 (28.7%) cases, and 60.7% of the patients had underlying diseases including hypertension, diabetes, cardiovascular disease (CVD), chronic kidney disease (CKD), an autoimmune disease. Two (0.6%) of patients had chronic liver disease as comorbidity. They declared that the survival and dead patients had no evident difference in the ALT level, but comorbidities were more prevalent in the dead group. Although neutrophil counts were significantly increased in dead patients, the counts of monocytes, platelets, and lymphocytes were decreased remarkably in the dead group . A shred of recent evidence indicated that liver dysfunction almost had the same prevalence between survivors (30%) and nonsurvivors (28%) of 710 COVID-19 patients with pneumonia and other comorbidities like acute kidney injury, cardiac injury, hyperglycemia, gastrointestinal hemorrhage were more observed in nonsurvival patients . As mentioned earlier, comorbidities must be considered a significant risk factor in determining the COVID-19 patient's poor outcomes [4,93].
In a study that conducted on 80 individuals that consist of 57 SARS-CoV-2 confirmed and 23 clinically diagnosed cases with 49 (61.25%) females and 31 (38.75%) males, the laboratory findings showed that 14 (17.5%) of patients had elevated level of ALT and in 21 (26.25%) of patients increased level of AST was seen and also males had higher levels of ALT and AST than women . Several studies declared that the proportion of elevated serum AST levels in men was higher than in women. The prevalence of COVID-19-liver dysfunction is more prevalent in men than women and adults than children. These findings revealed the sex differences in COVID-19 disease complications [1,4,61,70,94–98] and older age-related to the higher probability of liver dysfunction in COVID-19 patients .
In COVID-19 patients, ALT and AST's level rises because of liver function abnormalities . This elevation is higher in severe cases compared with mild cases . It means that patients with severe COVID-19 appear to have a higher rate of liver dysfunctions. In comparison with mild ones, the severe cases showed higher plasma levels of d-dimer, lactate dehydrogenase, CRP, procalcitonin (PCT), albumin, AST, and lower lymphocyte counts . A retrospective study on clinical features of 128 confirmed COVID-19 patients, which included 107 nonsevere and 21 severe patients, reported that creatinine and blood urea nitrogen (BUN) of all patients were at the normal range. However, the CRP level was increased in both groups so that elevation was higher in the severe group. ALT and AST were also at normal levels in all patients; however, the sever group showed elevated levels of these enzymes . Acquired data from a large cohort study suggested that most of the COVID-19 patients admitted to the hospital represented liver blood test abnormalities without mechanical ventilation. In contrast with this finding, research following comparing the two mild and sever groups of COVID-19 patients revealed no significant differences in the levels of ALT and AST between the two groups . Overall, laboratory abnormalities, including thrombocytopenia, lymphopenia, leukopenia, elevated CRP levels, are more prominent among severe patients than mild ones .
A study of the evaluation of hepatic enzymes changes and its relation to COVID-19 patients’ prognosis revealed that the risk of transferring patients to the ICU is associated with ALT and AST elevation levels. Moreover, the fatality rate increases with the elevated level of AST . There are significant differences in the laboratory test results between ICU and non-ICU patients so that lactate dehydrogenase, creatine kinase, d-dimer, ALT, and AST enzymes were significantly higher in ICU patients than those of non-ICU patients . Several studies announced that the ALT level rise was found in 14–53% of COVID-19 hospitalized patients [1,4,9,60]. Like an investigation on 125 hospitalized patients with COVID-19 infection in china, about 20% of patients showed varying degrees of elevation in ALT and AST enzymes [4,103].
A study found that the abnormality in AST concentration in subclinical patients is lower than patients with the onset of clinical symptoms . Liu et al. researched the clinical characteristics of 24 asymptomatic COVID-19 infected individuals, announced that ALT and AST's increased levels were uncommon . These findings suggested that this virus may affect several organs such as the liver, heart, and kidney, but more investigations are needed in this area . Although the interaction between existing hepatic dysfunction and COVID-19 has not been evaluated, it is suggested that liver impairment in mild COVID-19 patients is transient and can return to normal function without any specific treatment. Moreover, mild groups show a better prognosis of COVID-19 diseases .
Upon increasing the gastrointestinal wall permeability to infectious particles like viruses, enteric symptoms like diarrhea and vomiting are inevitable. In this way, our digestive system becomes vulnerable to COVID-19 infection . According to a descriptive, cross-sectional multicenter study conducted by Pan et al., upon evaluating 204 confirmed COVID-19 patients, they found that digestive symptoms are common among these patients with a 103 (50.5%) prevalence rate. The elevated ALT level and AST (more than 50 U/l) in COVID-19 patients with digestive manifestations, including lack of appetite, diarrhea, vomiting, and abdominal pain, are higher than those without digestive symptoms. So the patients with gastrointestinal manifestations have more probability of suffering liver impairment, although the mean ALT and AST level were in the normal range . About another research on 95 COVID-19 patients with an emphasize on their gastrointestinal symptoms at the time of admission or during hospitalization; they found that 58 out of 95 patients had gastrointestinal manifestation like diarrhea, anorexia, nausea, and 32.6% of patients developed liver function abnormalities during their remaining in the hospital with an elevated level of bilirubin and ALT or AST as their main relevant features [99,106].
COVID-19 infection can affect pregnant women as well as several studies reported their results in this area. In one investigation that studied nine pregnant women with COVID-19, they found three out of nine had an increase in ALT and AST concentration, and about one of them, ALT, reached 2093 U/l . Another study by Yu et al. on seven pregnant women with COVID-19 disease showed that two (29%) patients had liver function impairment with the increasing level of ALT or AST or both. Systematic review analysis on 108 pregnant women with COVID-19 declared, the early symptoms of infants included dyspnea, vomiting, moaning, increased heart rate, and after that, thrombocytopenia with abnormal liver function were observed . In contrast with these findings, in a study on five pregnant COVID-19 patients, the level of ALT, AST, and total bilirubin were normal, but creatine kinase and albumin were reduced in one and all patients, respectively .
Since pregnant women are more susceptible to respiratory pathogens, they are at a higher risk of COVID-19 infection more than other people, and also existing evidence is not sufficient. More investigation is needed to identify the maternal COVID-19 infection nature .
ALP is one of the bile duct injury enzymes and does not elevate specifically toward COVID-19 infection [4,49]. Although ACE2 is highly expressed on bile duct cells, SARS-COV2 does not cause the bile duct injury . So the cholestatic pattern is rare among COVID-19 patients; the report suggests that ALP remains at an average level .
About the investigation carried out on 417 laboratory-confirmed COVID-19 patients, 318 (76.3%) of patients had abnormal liver function tests, and 90 (21.5%) of patients showed liver injury during hospitalization. Based on the pattern of liver dysfunction results, 20.75% had hepatocyte type, 29.25% showed cholestatic type, and 43.4% were a mixed type. Upon analysis, they found that unlike the elevation in ALT, AST, and GGT levels, the ALP level has not increased, and only in one patient it has been elevated more than 3 × ULN and patients with hepatocyte type or mixed type of liver abnormalities, were at the higher odds of developing severe pneumonia . By the first published cohort report of determining liver biochemistry during hospitalization in America, 60 COVID-19 patients that four (7%) of them had a prior diagnosis of chronic liver dysfunction and 41 (69%) had at least one abnormal liver results of biochemistry analysis. After investigating the liver biochemistry pattern, they found that ALP level was normal and stable in most patients, and only about three (5%) cases showed ALP level two times higher than the limit of normal. Therefore, liver biochemistry was associated with severity and distinct clinical outcomes in COVID-19 patients . Consistent with this, another research on laboratory-confirmed COVID-19 patients showed that the ALP level was normal for these infected cases . Patients with abnormal liver function tests are at a higher risk of progressing to severe pneumonia and ARDS, so they should be evaluated and monitored frequently .
In contrast, based on the Zhang et al. study, they showed the rise in the ALP level in one (1.8%) out of 56 COVID-19 hospitalized patients. Evidence indicates that, based on laboratory assessment results, serum ALP remarkably higher among severe patients than among those with mild disease . Research on 350 COVID-19 patients’ clinical characteristics revealed that ALP was higher in men than in women and was higher in patients over 60 years old than younger patients. According to their findings, ALP was moderately elevated in COVID-19 patients with hypertension than those without hypertension. Their analysis showed that ALP slightly increased in patients with diabetes than patients without diabetes . So comorbidities could be a significant risk factor in the prognosis of COVID-19 diseases.
A study that assessed the first COVID-19 patient's laboratory features, a 58-year-old man in Australia, revealed that the blood examinations showed lymphopenia, and CRP reached its high level on admission day 6. Moreover, ALP comes its peak level with 210 U/l on admission day 12 ; the clinical features in this study were consistent with previous research [4,110]. Based on a systematic review analysis with a total of 9889 confirmed COVID-19 patients of 57 included studies, the liver damage was more common among severe cases than mild patients, and the ALP level was higher in severe COVID-19 patients than in mild ones. However, this increase was observed only in seven cases. Finally, The combined analysis revealed that the risk of liver injury is 2.07 times higher in severe patients than no-severe ones . Similar to these findings, A retrospective, a single-center study on 148 COVID-19 patients consists of 73 females and 75 males found that 55 (37.2%) of the infected cases showed an abnormality in admission and 4.1% had elevated level of ALP. About 45 patients with routine liver function tests, 48.4% showed abnormalities in liver indexes enzymes, 4–11 days after admission. 18 patients had an elevated bilirubin level, and reached their peak in 4–11 days after admission. They pronounced that liver injury was more common among men, but its mechanism is unclear. They also suggested that the patients with higher inflammatory biomarkers, including CRP and PCT, showed more liver injury, maybe the results of the immune response toward virus infection . In concordant with this, According to a case report study of a patient with COVID-19 infection, his laboratory investigations demonstrated Transaminitis with an elevated level of ALP (144 IU/l) and hyperbilirubinemia with a CRP level of 299 mg/l .
Although the abnormal liver function tests are common among COVID-19 patients , based on further evidence mentioned previously, changes in the ALP level in these patients do not follow the same trend and showed fluctuated levels in different assessments.
GGT is a less specific liver function index and is a biomarker of cholangiocyte injury [9,113]. This enzyme is present in the cell membrane of many tissues, including the liver, pancreas, intestine, the proximal renal tubule, and spleen. The crucial origin of serum GGT is the liver. In the liver, GGT is located on biliary epithelial cells and the apical membrane of hepatocytes. The entrance of GGT into the blood may occur as a result of releasing the membrane-tied GGT or the death of biliary epithelial cells .
Several studies announced the elevated level of GGT in COVID-19 patients. Zhang et al. research declared the increased levels of GGT in 30 (54%) of 56 patients during their hospitalization. Consistent with this, the abnormality in the GGT level of more than 3 × ULN, was observed in the study conducted on 318 COVID-19 inpatients during their hospitalization; they also indicated that patients who had higher abnormalities in GGT, AST, ALT, and total bilirubin (TBIL) level, showed higher probability to progress to severe COVID-19 cases. In addition, the increase in ALT and GGT were frequent, while the elevated level of AST and TBIL was less frequent (Table 1). So liver function abnormalities can be a predictor for the poor prognosis of the COVID-19 disease . In an investigation by enrolling 135 COVID-19 patients, they conducted dynamic liver function tests monitoring and analysis on three groups of mild, severe, and dead patients. They revealed that the GGT levels in dead patients were significantly higher in comparison with two other groups. So they concluded that the higher levels of GGT indicate the worsening outcomes in COVID-19 patients .
Table 1 -
Biochemical and hematological biomarkers of coronavirus disease 2019.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; LDH, lactic dehydrogenase.
In contrast, in the study conducted by Wei et al., a total of 597 COVID-19 patients in three groups of mild (394), severe (171), and critical (32) were enrolled. Following clinical laboratory analysis, the lymphocytes and CD8+ T cells decreased in all three groups, and the levels of WBCs and CRP increased gradually during disease progression. However, the changes in GGT levels were not in evidence .
His laboratory test results revealed the elevated levels of bilirubin and protein in serum about a COVID-19 laboratory-confirmed patient who suffered from end-stage liver cirrhosis related to hepatitis B thrombocytopenia, leukocytosis, lymphopenia and, prolonged prothrombin time. The AST and GGT levels were moderately elevated, but AST and ALP remained at their normal levels. COVID-19 patients with preexisting decompensated cirrhosis appear to be more disposed to higher complications and mortalities than patients with only COVID-19 disease . In another investigation with 148 COVID-19 patients in China, 37.2% of patients had liver function abnormalities at admission. Following the liver function tests analysis, 26 (17.6%) of patients had increases in GGT levels. While the proportion of patients with elevated levels of AST, ALT, TBIL, and ALP was 21.6, 18.2, 6.1, and 4.1%, respectively .
In an investigation of 156 cases with COVID-19 diagnosis, 64 out of 156 patients had elevated transaminases levels. This group of patients showed elevated levels of GGT compared with patients with a normal range of transaminases. So the COVID-19 infection is a pivotal cause of liver impairment, and monitoring should be continued until the viral clearance . The same trend was observed in a study on 63 confirmed COVID-19 patients. The laboratory features revealed that the GGT level was elevated in 21 (33.3%) of patients, and the inflammatory indexes, including CRP, erythrocyte sedimentation rate (ESR), and ferritin, were increased in severe or worsen cases. They also showed a hyperimmune inflammatory state by an elevated level of IL-6 . Regarding a research study on 273 COVID-19 patients, in two groups of patients who suffered from image progression on chest computed tomography (CT) and who had imaging progression-free on chest CT. Upon liver function analysis, they declared that GGT levels were remarkably higher among patients with image progression on chest CT in comparison with patients without chest CT image progression .
Li et al. conducted a study On 83 laboratory-confirmed COVID-19 patients in two groups of CVD and non-CVD, with 42 and 41 patients, respectively. They found that CVD patients showed elevated levels of GGT compared with non-CVD COVID-19 patients. Moreover, they suggested that CVD could be an essential risk factor for the rapid and poor prognosis of COVID-19 disease .
Approximately all the liver damage reports about COVID-19 patients found the abnormality in the blood liver enzymes tests with different degrees , so liver function tests should be ordered routinely to evaluate relative hepatic injury in COVID-19 patients . Overall, unlike the indications that COVID-19 infection might influence the liver functions abnormalities, and Since little is known about the effect of COVID-19 infection on liver function [105,124], more investigation and mechanistic studies need to corroborate the COVID-19 pathogenic mechanism and to determine the potential consequences of these patients based on liver function abnormalities .
As a glycolytic enzyme, lactic dehydrogenase (LDH), made of four polypeptide chains. These polypeptides encoded by separate M and H genes exist in various types in human tissues and neoplasms. LDH is a pivotal enzyme in changing pyruvate to lactate under anaerobic conditions . Because of the five different combinations of polypeptide subunits, LDH has five isoforms. LDH is released from necrotic cells. Several preclinical models investigating the hypoxic tumor microenvironment role, a correlation between high tumor volume, a high percentage of necrosis, high tumor LDH expression, and high serum LDH levels were demonstrated. LDH overexpression ensures a competent anaerobic/glycolytic metabolism and a reduced dependence on oxygen under hypoxic conditions in the tumor cells .
LDH is typically located in small amounts in most active organs. Thus, the high level of this enzyme may indicate unusual conditions .
LDH is a major enzyme in glucose metabolism present in tissues throughout the body and catalyzes pyruvate to lactate. It is released from cells upon damage to their cytoplasmic membrane. Previous studies showed that LDH could be used as an indicator of lung diseases [128–130]. In a study on Epstein–Barr virus (EBV), researchers found that EBV infected B cells had more LDH transcripts than the uninfected B cells . Increases in the production of LDH in hypoxic conditions have been reported [132,133].
Findings of recent studies revealed that LDH is positively associated with CRP and negatively with lymphocytes. An increase in CRP and decreased lymphocytes were observed in severe cases during the 14-day observation period. LDH is not only a metabolic but also an immune surveillance prognostic biomarker. Its elevation has a bad prognosis in immunosuppressive patients. LDH increases the production of lactate, leads to enhancement of immune-suppressive cells, including macrophages and dendritic cells, and inhibition of cytolytic cells, such as natural killer cells and cytotoxic T-lymphocytes .
LDH is an inflammatory predictor in many pulmonary diseases, such as obstructive disease, microbial pulmonary disease, and interstitial pulmonary disease . In a recent study, COVID-19 patients treated in the ICU had a higher level of LDH and CRP than those not treated in the ICU .
A large reservoir of SARS-like bat coronavirus can efficiently use the human ACE2 receptor for docking, replication, and entry. ACE2 expresses in human alveolar cells and intestinal epithelial cells. The binding force change is caused by the mutation of SARS-CoV-2 .
This fact may partly explain the high prevalence of severe COVID-19 in patients with hypertension. LDH has been recognized as a marker for severe prognosis in various diseases like infections. In severe cases, the high LDH level in COVID-19 suggested that LDH may be associated with lung injury and tissue damage .
The SARS-CoV-2 uses the ACE2 to attack the host system . SARS-CoV-2 has a genome; the sequence of 82% similar to SARS-CoV but can bind to cells more efficiently than the 2003 strain of SARS-CoV.
The cell entry receptor, ACE2, is widely expressed across the human body . ACE2 expression in the cell clusters of cholangiocytes is predominantly higher than hepatocytes. It has been concluded that SARS-CoV-2 may directly bind to ACE2 positive cholangiocytes without any hepatocytes bindings. Cholangiocytes are responsible for maintaining liver physiology, and disruption of these cells can cause hepatic injury .
Older age, leukocytosis, and high LDH level were reported to be risk factors associated with in-hospital death in previous studies . Hyperglycemia is correlated with increased mortality in COVID-19 patients. The localization of ACE2 expression in the pancreas in SARS leads to islets damage, resulting in hyperglycemia; this finding suggests that hyperglycemia may also be an indicator of severe COVID-19.
The LDH can causes lactate formation from pyruvate and pyruvate from lactate. In aerobic conditions, lactate converts into pyruvate with lactate dehydrogenase enzyme and enters the tricarboxylic acid cycle. Since tissue oxygenation is disturbed, the hypoxic environment is formed. In anaerobic conditions, lactate formation increases from pyruvate; coronavirus can create an anaerobic environment by disrupting tissue oxygenation . Energy production in the hypoxic environment is achieved through anaerobic glycolysis. A vicious cycle continues, and lactate production continues to increment as the hypoxic and acidic environment increases. In addition, elevated lactate levels increase the release of proinflammatory cytokines and oxidative stress .
Patients with elder age, hypertension, and high LDH levels need regular observations and also prompt interventions to prevent the development of severe COVID-19. Male patients with underlying diseases like heart injury, hyperglycemia, and high-dose corticosteroid may have a high risk of fatality . Yuan et al. in a study showed that COVID-19 mRNA clearance ratio was identified significantly related to the decline of serum creatine kinase and LDH levels, suggesting that constitutive decrease of LDH or creatine kinase levels probably predict a favorable response to the course of COVID-19 infected patients.
In humans, the activity and release of a large body of inflammatory mediators and markers of cell damage such as lactate dehydrogenase have been evaluated as prognostic and monitoring tools for disease development, activity, and progression in respiratory diseases .
Elevated LDH is a prognostic factor for ARDS diagnosis, while both leukocyte count and elevated LDH should be measured for mortality prognosis . Early identification of COVID-19 patients at risk of exacerbation to severe disease will lead to better management and optimal medical resources .
CRP is a nonspecific acute-phase protein induced by IL-6, IL-1, and IL-17 in the liver and a sensitive biomarker of inflammation, infection, and tissue damage. CRP expression level increases rapidly and significantly during acute inflammatory responses. The elevation of CRP in isolation or combination with other markers may reveal bacterial or viral infections [128–130]. CRP is synthesized by hepatocytes during infectious processes, assisting in eliminating cell debris from necrosis and apoptosis and facilitating phagocytosis through its action as an opsonin .
Serum levels of CRP may increase over a short period, especially in the presence of an acute stimulus, such as an infection. In the first few hours, this increase may reach 1000 times the normal value [145–147]. CRP comes from its reaction to antibodies against C-polysaccharide of Streptococcus pneumoniae. Serum CRP concentrations increase in situations responsible for a systemic inflammatory response syndrome in patients without and are strongly associated with mortality in different populations of patients without cirrhosis in the ICU . Although CRP is a sensitive but nonspecific systemic marker of inflammation, it also rises in other situations, including trauma, burns, myocardial infarction, and cancer .
CRP is produced because of the increased synthesis of proinflammatory cytokines to activate the immune response. Therefore, serum CRP level has been often used as a laboratory marker of inflammation. A few studies indicated that CRP is a predictive factor for disease progression in MERS-CoV and H1N1-infected patients .
CRP concentration mainly uses an inflammation marker for early diagnosis of pneumonia, and patients with severe pneumonia had high CRP levels . It is an important index for the diagnosis of severe pulmonary infectious diseases. Matsumoto's study showed that CRP levels and the largest lung lesion diameter increased as the disease progressed. CRP levels can be used as an indicator of lung lesions and disease severity. This suggests that in the early stage of COVID-19, CRP levels could reflect lung lesions and disease severity .
CRP is a nonspecific marker of inflammation and directly participates in the host defense against infection. The levels of N and S specific IgM and IgG were evaluated for correlations with CRP levels in non-ICU patients. As the disease progressed, the increase of S-IgG positively correlated with the decrease of CRP in non-ICU patients .
CRP was a widely used biochemical indicator for inflammation, reflecting the acute severe systemic inflammatory response caused by a viral infection. In a recent study, COVID-19 patients treated in the ICU had a higher level of LDH and CRP than non-ICU patients .
Previous studies suggested that excessive immune response played an essential role in the pathogenesis of severe influenza or SARS, and IL-6 and CRP may link to the excessive immune response .
Chronic inflammation is critical in the pathogenesis of atherosclerosis. Biomarkers such as oxidized LDLs, IL-6, and high sensitivity CRP can reflect an ongoing inflammatory process [154–156]. SARS-CoV-2 may infect lymphocytes, particularly T lymphocytes. So this damage leads to the malfunction of the immune system . The CRP concentration in COVID-19 patients is significantly lower. Most of the severe COVID-19 patients presented an elevated CRP level . It is found that the pathologic basis for the COVID-19 pneumonia are advanced diffuse alveolar damage and superimposed bacterial pneumonia in some patients. For treating severe and critical COVID-19 patients, antibiotic therapy may be crucial [159–161]. However, it has been shown that the CRP level was significantly lower in the infected patients with MERS-CoV .
Recent studies have revealed that elevated CRP is strongly associated with metabolic syndrome. Recent evidence implicates adipose tissue as a major regulator of chronic low-grade inflammation in patients with metabolic syndrome. Adipose tissue produces proinflammatory cytokines, such as tumor necrosis factor and IL-6, 3, 5, 7, 8, which are produced by adipose tissues, considered an essential source IL-6 production, the primary inducer of the CRP production [163–167].
In patients who did not survive, a continuous increase in CRP level or lymphopenia until death is observed . Patients with elevated CRP levels have a more significant proportion of comorbidity and dyspnea .
WBC count with differential and CRP can act as clinical markers of host inflammatory responses. These markers provide critical information to the clinician and help decide diagnosis and treatment strategy . Several studies have indicated that CRP is feasible and accurate at differentiating pneumonia from acute bronchitis [170–172].
Liver damage in patients with coronavirus infections might be directly caused by liver cells’ viral infection . Both SARS-CoV-2 and SARS-CoV bind to the ACE2 receptor to enter the target cell , where the virus replicates and subsequently infects other cells in the upper respiratory tract and lung tissue. Pathological studies in patients with SARS confirmed the liver's presence, although the viral titer was relatively low .
SARS-CoV-2 attacks the alveolar epithelial cells via ACE2. ACE2 is the ACE of isozyme, mainly distributed in cardiovascular, kidneys, testes, lung and colon, and other organizations . ACE2 by generating Ang 1–7 has anti-inflammatory and antiproliferation effects [175–177]. When SARS-CoV-2 binds to the ACE2 receptor on alveolar epithelial cells’ surface, the ACE2 expression in alveolar epithelial cells is downregulated. Then the increased expression of Ang II leads to the inflammatory response [11,178], and inflammatory factors such as CRP will be elevated.
Around 7–14 days after the initiation of symptoms, clinical manifestations of the disease arise. The inflammatory markers and cytokines increase systematically, known as a ‘cytokine storm’ . Higher CRP has been related to the bad prognosis of COVID-19 diseases, like ARDS development , higher troponin-T levels and myocardial injury, and death .
In 1995 Breimer suggested that bilirubin might protect specific diseases resulting from oxidative damage . Then, bilirubin has the potential capacity to tolerate oxidative damage . So, all kinds of serum bilirubin, such as total bilirubin, direct bilirubin, and indirect bilirubin, play protective roles in CVDs. Several investigations indicated that bilirubin's high antioxidative characteristics could mainly show its protective effects [184–187].
Bilirubin is primarily considered to be a toxic waste product, but recent studies showed that it could be an immunomodulatory metabolite. Through intracellular signaling and transcriptional control mechanisms, bilirubin affects those immune cell functions that regulate cell proliferation, differentiation, and apoptosis. During the pathogenesis of viral hepatitis, the heme degradation pathway is disrupted, resulting in changes to average bilirubin concentrations. These alterations have been previously studied mainly as a consequence of the infection .
Indirect bilirubin is a metabolic end-product of heme breakdown in the reticular-endothelial system and is recognized as a powerful antioxidant cytoprotectant . Bilirubin protects against oxidative stress by inhibiting NADPH oxidase's action that increases superoxide production [190,191]. Bilirubin can quickly clear up peroxyl radicals, singlet oxygen, hydroxyl radicals reactive nitrogen varieties [192,193]. Bilirubin may have anti-inflammatory attribution and work as the major antifibrogenic agent through heme oxygenase-1 . Indirect bilirubin may play a role in reducing oxidative stress, inflammation, and preventing the progression of liver fibrosis .
Patients with severe COVID-19 have higher bilirubin levels compared with those with milder forms . Old age, higher serum lactate dehydrogenase, C-reactive protein, the coefficient of variation of red blood cell distribution width, BUN, direct bilirubin, and lower albumin are associated with severe COVID-19 . Significantly, in a study, moderately higher bilirubin levels within the range considered normal were related to decreasing the risk of respiratory disorders and mortality . ICU patients show higher respiratory rate, higher levels of random blood glucose, bilirubin, PCT, creatine, aspartate transaminase, troponin I, ferritin, d-dimers, C-reactive protein, IL-2R, IL-6, and IL-8 than non-ICU patients . Dani et al. reported that bilirubin exerted a detrimental effect on lung surfactant surface tension properties in the hyperbilirubinemia resulting from acute lung injury [198,199]. Valdes-Dapena et al., eight described the lungs of 16 preterm infants who died of respiratory distress syndrome in which bilirubin metabolites caused yellow staining of pulmonary hyaline membranes. These findings are attributed to hyperbilirubinemia and mechanical ventilation. Lung damage resulting from mechanical ventilation could enhance plasma efflux containing bilirubin across damaged capillary and alveolar walls. The deposition of bilirubin in the damaged lungs can change its plasma levels . Experimental studies using animal models support a protective effect of increased bilirubin against respiratory injury by environmental stressors .
Serum albumin is the most abundant protein in plasma. Albumin can bind to drugs, long-chain fatty acids, bilirubin, bile acids, endotoxin, and hormones, modulating their biologic activity, distribution, and clearance. Moreover, albumin has antioxidant properties as it binds to highly toxic reactive metal species. Albumin also inhibits inflammatory mediators, such as TNF-α and C5a. Albumin can inhibit inflammation through several mechanisms [199,202]. It inhibits TNF-α expression directly through transcription downregulation and indirectly by preserving cellular glutathione and protecting cells against oxidant-mediated injury, which is a trigger for inflammatory responses. TNF-α downregulation by albumin inhibits the activation of proinflammatory NF-kB pathway and recruitment of leukocytes, further limiting inflammation [203,204].
Serum albumin is a multifunctional protein known to interact with a range of exogenous and endogenous compounds [199,205]. It is predominately present in the extracellular space, with high concentration being reported in the skin, guts, muscles, and secretions . There is a complicated relationship between the inflammation and albumin level in the extracellular matrix under various physiological and pathological conditions. The earlier studies showed that the stressed and inflamed cells increase albumin's uptake [71,199,207].
Changes in albumin's biochemical structure and decreased availability of the reduced form may be associated with its impaired oxidative function, altered transport role, and short half-life in medical conditions, including chronic inflammatory states and liver disease .
According to an analysis, increased C-reactive protein and low albumin levels are indicators associated with a low-grade COVID-19 infection . Albumin is the most intuitive index of the nutritional status of the body. When albumin decreases, the body loses resistance to the virus, leading to disease progression. Elevated C-reactive protein is an important inflammatory index in addition to abnormal blood coagulation function . Studies have shown that lymphocytes are the main target of viral infections. Viral infections involve damage to the immune system, which presents a decrease in the absolute number of lymphocytes .
Luo et al. showed that patients with positive CT findings were older and had a higher chance of developing fever; the higher level of lymphocytes, CRP, ESR, and LDH; lower level of WBC, neutrophil, and albumin . This finding indicates that there is a positive correlation between the systemic inflammation level and radiographic characteristics.
Based on a piece of evidence, more than half of the patients had hypoalbuminuria. In addition, the continuous decrease in the serum albumin level was observed in those progressed to critical illness. Hypoalbuminemia is linked to the poor clinical outcome for hospitalized patients. Decreased prealbumin level in severe patients indicates the damage of the liver [213,214].
Coronavirus has a strong affinity for ACE2 receptors located in multiple human cell types, including lung AT2 cells. ACE2 is partly responsible for mediating inflammation, which could explain the occurrence of diarrhea. The binding efficiency is considered stronger for SARS-CoV-2 than the SARS-CoV-1, which could indicate its high transmission rate. The virus's binding to intestinal epithelial cells also shows the possibilities of fecal–oral transmission, although it is unconfirmed for SARS-CoV-2 [75,215,216]. The pathophysiology behind hypoalbuminemia is thought to be secondary to increased capillary permeability, decreased protein synthesis, decreased half-life of serum albumin, decreased serum albumin total mass, increased volume of distribution, and increase expression of vascular endothelial growth factor .
The synthesis of inflammation factors, such as C-reactive protein, ferritin, TNF-α, interleukin family factors , requires albumin, and even muscle consumption protein . Therefore, the patient's albumin level and calf circumference will reduce .
The majority of severe COVID-19 patients have a deficient level of albumin. The liver activity in COVID-19 patients is correlated with CRP (a marker of inflammation) .
Refractory patients have a higher level of neutrophils, AST, LDH, C-reactive protein, and lower platelets and albumin levels compared with general patients . Another study also showed that the LDH level is significantly elevated in severe patients compared with mild patients, while prealbumin, another liver synthetic function indicator, is significantly decreased . Being male, severe and critical condition, expectoration, muscle ache, decreased albumin, decreased lymphocytes, older than 60, occupation, CVD, dyspnea, chest tightness, fever, bilateral pneumonia, reduced hemoglobin, increased ALT, increased AST, increased LDH, damaged patients . Levels of potassium, albumin, and lymphocytes increase persistently after treatment .
There is a relation between albumin levels in the blood and ACE2 receptor expression in the cells. ACE2 receptors could be crucial in mediating the virus infection, so albumin therapy of COVID-19 patients could help.
According to the Global Burden of Disease, about 2 million deaths happen annually due to liver cirrhosis and its complications, hepatocellular carcinoma, and viral hepatitis . It has been reported that liver disease is the 16th highest cause of morbidity globally; cirrhosis is a final stage of the chronic liver that is triggered by various agents, including viral infections and chronic alcohol use [224,225]. The WHO aims to the elimination viral hepatitis up to 2030 by focusing on testing, treatment, immunization against HBV, preventing mother to child transmission, blood safety, and harm reduction and the number of new cases and related mortality should be decreased by 90 and 65%, respectively [226,227].
Given the fact that liver disease and CKD patients are high risks to COVID-19 , there is limited information about the effect of COVID-19 on patients with preexisting liver diseases such as chronic HBV or HCV, primary biliary cirrhosis, or NAFLD . However, the coinfection of COVID-19 with HBV shows high susceptibility to contribute liver damage with more adverse outcomes and death. In this regard, one study from china showed a 53-year-old man with HBV-related cirrhosis, portal hypertension, and ascites died of irreversible multiple organ dysfunction syndromes 48 days after the onset of the illness though receiving intensive support . Another report has shown that patients with HBV infection have a higher frequency of liver cirrhosis, high level of total bilirubin, more severe presentation, and a high mortality rate than non-HBV subjects .
In summary, the liver's cells can be infected by SARS-COV-2 through ACE-2 receptors on the liver and lungs, heart, kidneys, and placentae. Subsequently, SARS-COV-2 infection may increase the levels of several biochemical and hematological biomarkers such as ALT, AST, LDH, GGT, and total bilirubin.
All in all, given the cirrhotic poor immune function and worst outcomes, treatment should be maintained according to guidelines, including continuing systemic therapies, but consider least expose to medical staff is required for severe patients with COVID-19 and preexisting liver diseases. Thereby further studies are needed to understand more about the hepatic manifestations of COVID-19 in chronic liver disease and improve the clinical management and more stringent preventive measures for this group of patients.
Copyright/Ethics statement: All figures and tables in this study are original.
Authors’ contributions: S.S. and A.F.: Conceptualized and designed the review, interpretation of data for the work, and final approval of the version to be published. S.A., M.K., M.Z., A.Z., T.L., A.T., and P.S.: Collected data and wrote the article. A.R., A.K., A.Z., and B.A.: Supervised the collection of the data and wrote the article. All authors reviewed and approved the article.
Conflicts of interest
There are no conflicts of interest.
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