Funding for the development of this article was received from Salix Pharmaceutical. No personnel from Salix Pharmaceutical participated in the development or publication of this article or the content contained within. Both authors were paid a stipend by Paradigm LTC for consultation and research
1EVERSANA, Berkeley Heights, NJ; Atlanticare/Geisinger, Atlantic City, NJ; Thomas Jefferson University, College of Population Health, Philadelphia, PA
2Professor of Gastroenterology, Epidemiology, and Pathology/Lab Medicine, Robert Wood Johnson School of Medicine, Rutgers University, New Brunswick, NJ
In the current pandemic, it is clear that morbidity and mortality of the coronavirus disease of 2019 (COVID-19) infection disproportionally affect the older adults and those who are immunocompromised and/or have serious comorbidities. One of the largest at-risk groups is that of patients with chronic liver disease, who commonly require periodic serologic tests, radiologic examinations, and surgical biopsy procedures to diagnose and monitor their conditions. However, the heightened concerns for these patients accentuate the need for improved management of the liver to avoid unnecessary diagnostics and preventable hospitalizations, as well as the necessity of limiting invasive measures, changes in medications, and transfer of residents outside the long-term care (LTC) facility to the more urgent, acute cases. Specifically, noninvasive procedures may suffice to confirm a diagnosis of cirrhosis, biopsies may be avoided in cases where they would not be definitive, and advanced imaging procedures may be reserved for cases with high clinical suspicion. Moreover, telemedicine may gather sufficient clinical information to guide treatment without exposing patients to the risks attendant to visits to hospitals and emergency rooms. Thus, for most patients with liver disease, risk/benefit considerations presently favor their receiving safe, effective management in-place in the LTC facility.
Key words: liver disease, COVID-19, long-term care facility, AASLD, encephalopathy, hospitalization
Despite being the largest internal organ, the liver is often overlooked. With the arrival of the coronavirus disease of 2019 (COVID-19), where respiratory conditions tend to be much more in the forefront, it is critical not to forget the liver. In fact, systematic reviews published in the last few months indicate that liver injury is indeed associated with severe COVID-19 symptoms1 and an approximate 3- to 5-fold increased risk of mortality.2 This is why it is important to revisit liver disease management in the context of COVID-19. However, many of these reminders have broad application beyond the immediate concerns related to COVID-19.
Prevalence of Liver Disease
The liver is involved in a range of activities (Figure 1), exposing it to a number of insults and making it an organ more subject to injury. The primary functions of the liver are:
• Bile production and excretion
• Excretion of bilirubin, cholesterol, hormones, and drugs
• Metabolism of fats, proteins, and carbohydrates
• Enzyme activation
• Storage of glycogen, vitamins, and minerals
• Synthesis of plasma proteins, such as albumin, and clotting factors
• Blood detoxification and purification
Given that these injuries can occur over time and be cumulative, it should come as no surprise that a significant number of older adults suffer chronic liver disease (CLD).
CLD affects over 5.5 million patients in the United States,3 of whom more than 600,000 have cirrhosis.4 These are perhaps underestimates due to underreporting as well as changing epidemiologic trends. A majority of patients with CLD and cirrhosis develop hepatic encephalopathy (HE) at some point in their lives, with a substantial impact.5,6
The prevalence of serious liver disease and cirrhosis is increasing due to aging of the population, increased recognition and diagnosis of viral hepatitis, and increases in obesity and diabetes leading to non-alcoholic steatohepatitis (NASH).7 Based on data from the National Health and Nutrition Examination Survey, Kabbany et al reported that, between the periods 1999-2002 and 2009-2012, there was a 2.5-fold increase in prevalence of NASH cirrhosis.8 Moreover, a recent study detected minimal hepatic encephalopathy based on psychometric testing in more than half of patients with cirrhosis of the liver.9
Heidelbaugh and Bruderly have described cirrhosis and chronic liver failure as leading causes of morbidity and mortality in the United States.10 Cirrhosis often is an indolent disease; most patients remain asymptomatic until the occurrence of decompensation, characterized by ascites, spontaneous bacterial peritonitis, HE, or variceal bleeding from portal hypertension. This can mean that the diagnosis was possibly missed prior to admission to the long-term care (LTC) facility.
What to Consider With Regard to Liver Care
Physical examination of patients with cirrhosis may reveal findings that necessitate an evaluation to determine the etiology. Some patients already may have had laboratory or radiographic tests that incidentally uncovered signs of cirrhosis and its comorbidities. No serologic or radiographic test alone can accurately diagnose cirrhosis. It is important to note the correlation between persistently elevated liver function tests and biopsy-proven underlying hepatic disease. Thus, a more targeted serologic work-up is indicated in patients whose liver function test results are persistently abnormal. However, it is equally important to remember that “normal” liver enzymes do not preclude serious liver disease, including cirrhosis. Unnecessary medications and surgical procedures should be avoided in patients with cirrhosis. Referral for liver biopsy should be considered only after thorough, non-invasive serologic and radiographic evaluations have failed to confirm a diagnosis of cirrhosis.10
The American Association for the Study of Liver Diseases (AASLD) has provided some guidance recently for the era of COVID-19.11 This guidance highlights that patients older than 60 years, patients with cirrhosis, those with autoimmune hepatitis on immunosuppressive medications, and pre-transplant and post-transplant patients on immunosuppressive therapy may be among the patients at highest risk for severe illness if infected with COVID-19. Key recommendations from the AASLD guidance are shown in Table 1.
This article continues after the table.
Furthermore, COVID-19 increases the incidence of elevated serum liver biochemistries (AST [aspartate aminotransferase], ALT [alanine aminotransferase], bilirubin) in the range of 14% to 53%.12 These elevated liver biochemistries may reflect a direct virus-induced cytopathic effect and/or immune damage from the provoked inflammatory response. Liver cells may have the same angiotensin converting enzyme-2 receptors as alveoli and gastric cells that allow entry of the virus, thus resulting in damage.13
Notably, some therapeutic agents used to manage symptomatic COVID-19 patients may be hepatotoxic. Working with the consultant pharmacist to evaluate baseline liver status to assess the risks and benefits of these treatments in the face of COVID-19 is increasingly important. For example, a recent review concluded that the effect of hydroxychloroquine on hepatic tissue14 was ambiguous; despite its utility in treating liver infection with protozoa (ie, malaria), it has also been linked to cases of fulminant hepatic failure.15 Also, its combination with azithromycin adds another level of uncertainty, given this antibiotic’s unknown mechanism and delayed hepatotoxicity.16 Thus, the use of these and other emerging COVID-19 therapies will require close monitoring and caution. Knowing each patient’s baseline liver test results is helpful to ensure appropriate treatment. In the current era, ultrasound and other advanced imaging should be avoided unless a clinical suspicion for biliary obstruction, cholangitis, or venous thrombosis is being considered.
The AASLD has made several recommendations regarding liver testing and COVID-19 testing11:
• Consider evaluating patients with liver disease for COVID-19 if they develop new onset encephalopathy or other acute decompensation.
• Conduct serologic testing for hepatitis B and C when assessing patients with COVID-19 and elevated liver biochemistries.
• Regular monitoring of liver biochemistries (serum aminotransferases, bilirubin, alkaline phosphatase, albumin, and prothrombin time) should be performed in all COVID-19 patients.
Of course, establishing the liver function baseline for our LTC patients is an important starting point so that changes can be followed and for appropriate responses. These include mental status changes in patients with cirrhosis that could be the result of HE or worsening of the same due to a new infection.17
Providing “Care Right Where You Are”
Perhaps even more than ever, the phrase, “Care Right Where You Are,” has heightened meaning.18 This is because of the dangers of sending an older adult into the emergency room or hospital and thus increasing their risk of acquiring COVID-19 as well as burdening the health care system.
The AASLD recommends seeing in person only new patients with urgent issues and clinically significant liver disease (eg, jaundice, elevated ALT or AST >500U/L, recent onset of hepatic decompensation).9 Within the skilled nursing facility there is an opportunity for these specialist visits to occur via telemedicine. The COVID-19 emergency funding legislation (H.R.6074)19 waived several of the long-standing restriction to the use of telehealth for Medicare recipients.
Providing the right care in the LTC setting means that while the COVID-19 restrictions exist, the additional option of patients receiving telemedicine services to avoid leaving the facility should be utilized. As importantly, it means establishing the diagnosis of liver disease and treating hepatic complications appropriately. Whether it involves adjustments needed secondary to the impact of COVID-19 or conditions of hepatitis or HE, treating these conditions correctly, and in timely fashion, can prevent an avoidable emergency room visit or hospitalization. Opportunities exist for liver care to be rendered in the LTC facility for our LTC patients. Perhaps it has never been more important to avoid emergency room visits or visits to crowded settings like the hospital for our highly vulnerable LTC patients. It all starts with thinking of liver diseases and potential complications like HE.
The heightened concerns for patients with liver disease accentuate the need for improved management of the liver to avoid unnecessary diagnostics and preventable hospitalizations. Moreover, telemedicine may gather sufficient clinical information to guide treatment without exposing patients to the risks attendant to visits to hospitals and emergency rooms. For most patients with liver disease, risk/benefit considerations presently favor their receiving safe, effective management in-place in the LTC facility.
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2. Singh S, Khan A. Clinical characteristics and outcomes of COVID-19 among patients with pre-existing liver disease in United States: a multi-center research network study. Gastroenterology. May 3, 2020. doi:10.1053/j.gastro.2020.04.064
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8. Kabbany MN, Conjeevaram Selvakumar PK, Watt K, et al. Prevalence of nonalcoholic-associated cirrhosis in the United States: an analysis of National Health and Nutrition Examination Survey data. Am J Gastroenterol. 2017;112(4):581-587. doi:10.1038/ajg.2017.5
9. Bale A, Pai C, Shetty S, et al. Prevalence of and factors associated with minimal hepatic encephalopathy in patients with cirrhosis of liver. J Clin Exp Hepatol. 2018;8(2):156-161. doi:10.1016/j.jceh.2017.06.005
10. Heidelbaugh JJ, Bruderly M. Cirrhosis and chronic liver failure: part I. Diagnosis and evaluation. Am Fam Physician. 2006;74(5):756-762.
11. American Association for the Study of Liver Diseases (AASLD). Clinical Insights for Hepatology and Liver Transplant Providers During The COVID-19 Pandemic. April 7, 2020. Accessed June 5, 2020. https://www.aasld.org/sites/default/files/2020-04/AASLD-COVID19-ClinicalInsights-4.07.2020-Final.pdf?_zl=tDVd6&_zs=FQn7h1
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13. Magrone T, Magrone M, Jirillo E. Focus on receptors for coronaviruses with special reference to angiotensin-converting enzyme 2 as a potential drug target - a perspective. Endocr Metab Immune Disord Drug Targets. April 27, 2020. doi:10.2174/1871530320666200427112902
14. Boeckmans J, Rodrigues RM, Demuyser T, Piérard D, Vanhaecke T, Rogiers V. COVID-19 and drug-induced liver injury: a problem of plenty or a petty point? Arch Toxicol. April 8, 2020. doi:10.1007/s00204-020-02734-1
15. Makin AJ, Wendon J, Fitt S, Portmann BC, Williams R. Fulminant hepatic failure secondary to hydroxychloroquine. Gut. 1994;35(4):569-570. doi:10.1136/gut.35.4.569
16. Martinez MA, Vuppalanchi R, Fontana RJ, et al. Clinical and histologic features of azithromycin-induced liver injury. Clin Gastroenterol Hepatol. 2015;13(2):369-376.e3. doi:10.1016/j.cgh.2014.07.054
17. Hagerty D, Rustgi V, Stefanacci R. Hepatic encephalopathy in LTC residents: missing a potential cause of change in mental status in patients with cirrhosis. Ann Longterm Care. 2020;28(1):e18-e27.
18. Manzi J, Saffel D. Care right where you are: treating in place to avoid an emergency department visit or hospitalization. Caring for the Ages. 2020;21(4):6-7,8. doi:10.1016/j.carage.2020.04.005
19. Coronavirus Preparedness and Response Supplemental Appropriations Act, HR 6074, 116th Cong, (2019-2020). Accessed June 9, 2020. https://www.congress.gov/bill/116th-congress/house-bill/6074