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Implications Of COVID-19 On The Liver In Healthy And Diseased States



While lung lesions have been considered as the major damage caused by SARS-CoV-2 infection, liver injury has also been reported to occur during the course of the disease in severe cases.


Recent studies on Covid-19 have shown that the incidence of liver injury ranged from 14.8 – 53%, mainly indicated by abnormal ALT/AST levels accompanied by slightly elevated bilirubin levels.


A case control study of electronic health records of 62.2 million patients (age >18 years) in US has reported that patients with chronic liver disease (CLD) were at significantly increased risk for Covid-19 compared with patients without CLD, with the strongest effect in patients with chronic non-alcoholic liver disease and non-alcoholic cirrhosis, followed by chronic hepatitis C, alcoholic liver damage, alcoholic liver cirrhosis and chronic hepatitis B. Furthermore, patients with Covid-19 and a recent encounter for CLD had a death rate of 10.3% (vs 5.5% among Covid-19 patients without CLD) and hospitalization rate of 41.0% (vs 23.9% among Covid-19 patients without CLD) (1).



Hospitalization and death rates in Covid-19 patients with or without chronic liver disease (CLD) [Adapted from Wang 2021]



Several possible mechanisms of liver injury:


(i) SARS-CoV-2 binds to hepatic cells containing ACE2 receptor leading to active viral replication

SARS-CoV-2 enters cells through the ACE2 molecule, which is abundantly expressed in the liver and, in particular, in bile epithelial cells. Based on this expression, the liver is a potential target for direct infection with this virus [2].


(ii) Covid-19 drug-induced liver injury

An increasing number of drugs, including Remdesivir, was associated with an increase in liver enzymes in one published report. Drugs could activate the endoplasmic reticulum stress pathway in the liver and induce hepatocyte apoptosis through the caspase cascade system and induce inflammatory reactions and oxidative stress by accelerating liver damage [3].


(iii) Localized & Systemic Inflammatory Responses

The massive release of cytokines by the immune system in response to the viral infection can result in a cytokine storm and symptoms of sepsis that are the cause of death in 28% of fatal COVID-19 cases. In these cases, uncontrolled inflammation induces multiorgan damage leading including liver failure. Biomarkers of inflammation, such as C-reactive protein (PCR), serum ferritin, LDH, d-dimer, IL-6, IL-2, are have been found to be significantly elevated in critically ill patients with COVID-19 [4].


(iv) Congestive hepatopathy may occur as a consequence of an acute cardiomyopathy

Cardiomyopathy is a well-described consequence of Covid-19, which was reported in 33% of individuals in one recent study. Thus, the cardiac dysfunction and hepatic congestion from venous outflow obstruction and resulting hypertension and decreased oxygen delivery from an impaired cardiac output contribute to hepatic injury in severe Covid-19 infection [5].


Mechanisms of Covid-19 associated liver injury [Adapted from Zhong 2020]



Hepatoprotective Vitamin & Supplement


1. Vitamin D


Studies have shown that vitamin D could reduce liver inflammation by reducing the secretion of pro-inflammatory cytokines as well as improving adipose tissue oxidative stress and inflammatory parameters. Besides that, vitamin D exert its anti-fibrogenic effect on hepatic cells via vitamin D receptor signaling, inhibiting expression of pro-fibrogenic genes. Furthermore, large numbers of clinical studies documented high incidence of low circulating vitamin D levels in patients with chronic liver disease, establishing the possible influence of low vitamin D levels in the development of liver fibrosis [6].


2. Omega 3


Omega 3 are known to downregulate sterol regulatory element binding protein 1c (SREBP-1c) and upregulate peroxisome proliferator activated receptor which would favour fatty acid oxidation and reduce steatosis. Omega 3 supplementation in some studies has also shown to be effective for liver fat reduction [7].


3. Silybum marianum


The natural compound in silybum marianum, silymarin, has been used traditionally to treat hepatic diseases due to its anti-oxidant, anti-inflammatory and anti-fibrotic activities. Inhibition of cyclooxygenase cycle, leukotrienes, and free radical production contribute to its cytoprotective effects in liver. Improvement in ALT, AST, liver function parameters and liver histology have been seen after consumption of silymarin in patients with liver disease [8].


Recommendation:


(i) Powerlife Vitamin D3: Anti-inflammatory and anti-fibrotic

Dosage: Healthy adults - 1 capsule/day

Vitamin D deficiency – 2 capsules / day


Powerlife Vitamin K2D3: Better option for patient with comorbidity of heart/kidney/bones (NOT for individual taking warfarin)

Dosage: 2 capsules/day


(ii) Powerlife Essential Omega 3 / Powerlife Asta Omega: Improve liver function

Dosage: Healthy adults – 1 softgel/day ; Liver disease patients - 2 softgels/day


(iii) Powerlife Hepapho: Hepatoprotective effect

Dosage: Liver disease patients: 1 capsule/day






Close monitoring on Covid patient liver profile is essential, as well as keeping a healthy liver during this pandemic.




References:

1. Wang Q, Davis PB, Xu R. COVID-19 risk, disparities and outcomes in patients with chronic liver disease in the United States. EClinicalMedicine. 2021 Jan;31:100688. doi: 10.1016/j.eclinm.2020.100688. Epub 2020 Dec 22. PMID: 33521611; PMCID: PMC7834443.

2. Chai X., Hu L., Zhang Y., Han W., Lu Z., Ke A. Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection. BioRxiv. 2020;2020 doi: 10.1101/2020.02.03.931766.02.03.931766.

3. Vitiello, A., La Porta, R., D’Aiuto, V. et al. The risks of liver injury in COVID-19 patients and pharmacological management to reduce or prevent the damage induced. Egypt Liver Journal 11, 11 (2021). https://doi.org/10.1186/s43066-021-00082-y

4. Lozano-Sepulveda SA, Galan-Huerta K, Martínez-Acuña N, Arellanos-Soto D, Rivas-Estilla AM. SARS-CoV-2 another kind of liver aggressor, how does it do that? Ann Hepatol. 2020 Nov-Dec;19(6):592-596. doi: 10.1016/j.aohep.2020.08.062. Epub 2020 Aug 25. PMID: 32858226; PMCID: PMC7445466.

5. van Deursen VM, Damman K, Hillege HL, van Beek AP, van Veldhuisen DJ, Voors AA. Abnormal liver function in relation to hemodynamic profile in heart failure patients. J Card Fail. 2010 Jan;16(1):84-90. doi: 10.1016/j.cardfail.2009.08.002. Epub 2009 Sep 26. PMID: 20123323.

6. Keane JT, Elangovan H, Stokes RA, Gunton JE. Vitamin D and the Liver-Correlation or Cause?. Nutrients. 2018;10(4):496. Published 2018 Apr 16. doi:10.3390/nu10040496

7. Parker HM, Johnson NA, Burdon CA, Cohn JS, O'Connor HT, George J. Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol. 2012 Apr;56(4):944-51. doi: 10.1016/j.jhep.2011.08.018. Epub 2011 Oct 21. PMID: 22023985.

8. Gillessen A, Schmidt HH. Silymarin as Supportive Treatment in Liver Diseases: A Narrative Review. Adv Ther. 2020 Apr;37(4):1279-1301. doi: 10.1007/s12325-020-01251-y. Epub 2020 Feb 17. PMID: 32065376; PMCID: PMC7140758.

9. Ao ZH, Xu ZH, Lu ZM, Xu HY, Zhang XM, Dou WF. Niuchangchih (Antrodia camphorata) and its potential in treating liver diseases. J Ethnopharmacol. 2009 Jan 21;121(2):194-212. doi: 10.1016/j.jep.2008.10.039. Epub 2008 Nov 17. PMID: 19061947.

10. Ogutu FO, Makori SI, Maringa CW, Lemtukei D, Okiko G, Luvita S. Wheat Grass: A Functional Food. Food Science and Quality Management, 2017; 65: 33–38

11. Zhong, P., Xu, J., Yang, D. et al. COVID-19-associated gastrointestinal and liver injury: clinical features and potential mechanisms. Sig Transduct Target Ther 5, 256 (2020). https://doi.org/10.1038/s41392-020-00373-7



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