key: cord-0046164-pl6qsojf
authors: Wang, Yijin; Lu, Fengmin; Zhao, Jingmin
title: SARS-CoV-2 infection in liver-Author’s reply
date: 2020-06-23
journal: J Hepatol
DOI: 10.1016/j.jhep.2020.06.028
sha: 2d61772e5f502087e31fa5de401db0dbeca9fa9e
doc_id: 46164
cord_uid: pl6qsojf

nan

We appreciated the thoughtful comments regarding hepatic impairment by SARS-CoV-2 infection.

Our study focused on COVID-19 related liver enzyme abnormality, other than acute liver injury.

Although SARS-CoV-2 could infect liver, it is not a hepatotropic virus that featured by inducing pronounced hepatitis, even fulminant hepatitis. In keeping with this, abnormal liver function tests during the course of COVID-19 are common and primarily limited to aminotransferases, while clinically severe acute liver injury is rare [1, 2] . This also explained the concern of mild transaminases elevation and well-preserved other parameters, such as lactate, glucose and INR, which is more likely blamed for direct virus infection.

Refer to biochemistry parameters, the median GGT in our both groups were in normal range and there were no significant differences in levels of TBiL, DBiL, or ALP, suggesting cholangiocytes are unlikely the target sites. AST was recently reported to highly correlate with ALT and reflects disease severity throughout the COVID-19 course, whereas the correlation with markers of muscle injury was weak [3] . Meanwhile, we noted that the median CK was still in normal range in abnormal aminotransferases group, and the frequency of elevated CK were comparable between two groups (17.86 % vs. 13.51%, p=0.89), indicating elevated CK and abnormal transaminases might not a causal relationship. Leakage of albumin from blood vessel due to severe vasculitis was usually accompanied by hydrothorax or ascites as a consequence. However, the albumin reduction in COVID-19 patients was usually in a mild manner, other than the consequence of systematic damage. Taken together, these aberrant blood variables should be predominantly derived from hepatic impairment.

We stated SARS-CoV-2 directly contributing to cytopathy based on the ultrastructural findings of conspicuous mitochondria swelling, endoplasmic reticulum dilatation, glycogen granule decrease, and impaired cell membrane. Apoptotic and bi-or multi-nucleated syncytial hepatocytes were also signs of viral direct effect [4, 5] . Previous studies demonstrated coronaviruses exerted extensive cytopathic effect through apoptosis via a caspase-dependent pathway [4, [6] [7] [8] . The 'corona-like' particles definitely indicated characteristic of coronavirus particles, but not cholesterol crystals, which are normally in a form of high-electronic dense, structurelessness, and inhomogeneity. Hepatocytes manifested no megamitochondria with linear crystalline inclusions, cristae loss, or increased matrix electrondensity, which is against NAFLD [9] [10] [11] . The reported autolytic microscopic modifications in liver include the cytoplasm intrasinusoidal extension, membrane lysis, and early signs of karyolysis at 24h after decease [12] , none of which were observed in our biopsies as our biopsies were acquired in one hour. Clathrins are generally located at the plasma membrane of synapses and play a role in synaptic vesicles reconstitution [13] . Clathrin processes variable morphology including multiple coated buds forming on endosome, distinctive from typical coronavirus.

In light of the low percentage of hepatocytes expressing ACE2, but not absolute absence, it is not surprisingly that SARS-CoV-2 is capable of causing liver injury directly. On the other hand, there exist wide discrepancies between ACE2 distribution and that of infected organs, as well as between the organ symptomatology and ACE2 expression levels [14, 15] . For instance, ACE2 expression in the respiratory tract is only moderate compared with that in intestinal epithelia, but respiratory symptomatology is substantially more severe than intestinal [14, 15] . It is therefore assumed that viral direct effect in liver might not operate absolutely through ACE2 expression, and other receptors could not be excluded. Alternatively, the finding of up-regulated ACE2 expression in hepatocytes in cirrhotic liver inspired us to speculate that SARS-CoV-2 infection might induce compensatory hyperplasia of hepatocytes, which are possibly derived from highly expressed ACE2 cholangiocytes [16] . This procedure might result in a higher ACE2 expression in regenerative hepatocytes and facilitate viral infection in turn.

We acknowledge that fatty liver disease, DILI, sepsis and multiple organ dysfunction syndromes (MODS) could not be ruled out involved in liver damage in setting of COVID-19, but our clinical and pathological findings do not favor these possibilities as thoroughly described in the paper.

Firstly, the prevalence of transaminases abnormality was up to 23.5% even in context of mild cases, precluding the role of COVID-19 related comorbidities. Secondly, despite of steatosis, both biopsied cases had neither NAFLD nor other metabolic syndromes. The pathological features of no obvious eosinophil infiltration, cholestasis, fibrin deposition, vasculitis, granuloma, massive central necrosis, or interface hepatitis did not comply with DILI. Thirdly, only 7 of 64 (10.9%) cases had sepsis and other severe comorbidities, which apparently not explain the high rate (41.0%) of liver enzyme abnormality in our cohort. Additionally, the liver pathology in our septic case showed no pathological hallmark of sepsis, suggesting sepsis seemed not a main insult. All in all, our data fully support a direct role of SARS-CoV-2 in COVID-19 related hepatic impairment.

In conclusion, we believe SARS-CoV-2 is capable of infecting liver and is a crucial factor for liver dysfunction through a series of robust evidences, though other factors could not be fully excluded.

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