Correlation Between Liver Function Tests Abnormalities and Interleukin-6 Serum Levels in Patients With SARS-CoV-2 Infection.

Dear Editors:

We have read with interest the paper by Singh et al reporting a high risk for hospitalizations and mortality in patients with chronic liver disease affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 is frequently associated with elevation in liver function tests, including alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT).1, 2, 3 Vascular endothelium, smooth muscle cells, and cholangiocytes express the angiotensin-converting enzyme 2 receptor, which is used by SARS-CoV-2 to enter the cells, suggesting that liver involvement may be due to direct viral damage. , Singh et al hypothesized drug-induced liver injury, hypoxia, or immune dysfunction as the cause of liver tests abnormalities in patients with chronic liver disease. A contribution of SARS-CoV-2–related systemic hyperinflammation to liver injury is plausible, although this has not been proven so far.

Thus, we collected data on liver tests (ALT; GGT; alkaline phosphatase; total bilirubin) and IL-6 serum levels of 80 hospitalized patients tested SARS-CoV-2 positive (real-time polymerase chain reaction on nasopharyngeal swabs) at the Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome. All patients were treated with antivirals (lopinavir/ritonavir or darunavir/ritonavir) plus hydroxychloroquine; those receiving anti-IL-6 agents or with preexisting chronic liver disease were excluded.

Liver test abnormalities defined as an ALT of >45 IU/L or GGT of >31 IU/L were observed in 25 of 80 (31.2%) and 47 of 80 (58.8%) of patients, respectively. Alkaline phosphatase elevation was present in 4 patients and bilirubin elevation in none.

Higher median serum levels of IL-6 were observed in patients with ALT (157.4 ng/L [60–1019.6 ng/L] vs 21.9 ng/L [8.7–89.1 ng/L]; P < .0001) or GGT elevation (82.6 ng/L [25.9–515.4 ng/L] vs 14.5 ng/L [6.9–33.8 ng/L]; P < .0001; Figure 1 ). Indeed, a significant correlation between IL-6 and ALT (Spearman's coefficient 0.515; P < .0001) as well as GGT (Spearman's coefficient 0.457; P < .0001) was found.

Figure 1

IL-6 median serum levels in patients with abnormal liver tests (upper limit of normal [ULN]: alanine aminotransferase [ALT] 45 IU/L, gamma glutamyl transferase [GGT] 31 IU/L) and in phase 1 (<7 days after symptoms onset) or 2 (>7 or <15 days after symptom onset) patients. Log-transformed data are reported; black bars and boxes indicate median values and interquartile ranges, whiskers the minimum and maximum.

The highest median expression of IL-6 was observed in patients with more severe disease requiring intensive care (355.6 ng/L [172.1–1379.1 ng/L] vs 29.7 ng/L [9.75–82.95 ng/L]; P = .0001). In these subgroup of patients, alterations in liver function tests were also more frequent (ALT 11/17 [64.7%], P = .002; GGT 16/17 [94.1%], P = .0007).

We further explored if there was any difference between IL-6 and liver function tests abnormalities in the early (<7 days after symptoms onset) or late (>7 and <15 days after symptoms onset) phase of SARS-CoV-2 disease. ALT or GGT elevation was more common in phase 2 (ALT > upper limit of normal phase 1: 8/45 [17.8%] vs phase 2: 17/35 [48.6%], P = .004; GGT > upper limit of normal phase 1: 20/45 [44.4%] vs phase 2: 27/35 [77.1%], P = .006). IL-6 median values were also higher in phase 2 than in phase 1 (175.2 ng/L [37.5–989.6 ng/L] vs 21.8 ng/L [9.2–52.6 ng/L]; Figure 1). No case of severe hepatitis or cholestatic injury was observed.

Our data demonstrate a correlation between liver function tests abnormalities and IL-6 serum levels, proving that liver injury follows to the course of the systemic inflammatory response.

SARS-CoV-2 related disease (COVID-19) may evolve through different phases. While in the initial stage, viral symptoms are predominant and a subgroup of patients progresses to pneumonia and hyper-inflammation, characterized by a cytokine storm syndrome with systemic organ involvement. At this stage, IL-6 is overexpressed and has been associated with adverse clinical outcomes.

In our series, circulating IL-6 was elevated in patients with ALT or GGT abnormalities. Furthermore, patients in the late phase of COVID-19 had an increased prevalence of liver tests abnormalities and higher levels of IL-6 compared with those in the early phase. We also found an increased prevalence of AST or GGT elevation and higher IL-6 serum levels in patients requiring intensive care, confirming the association between liver injury, hyperinflammation, and COVID-19 disease severity.

In conclusion, we can argue that liver function tests abnormalities are prevalently owing to liver involvement as an “innocent bystander” in SARS-CoV-2–related inflammatory syndrome, especially in the late phase of COVID-19. Patients with chronic liver disease could be severely affected by this cytokine storm, as supposed by Singh et al. However, the prevalence of SARS-CoV-2 infection among these patients is low and only retrospective data from electronic medical records are available; this factor makes it difficult to conduct specific investigations and, consequently, to draw definitive conclusions.