Hepatology Communications, VOL. 0, NO. 0, 2020

Liver Care and Surveillance: The Global
Impact of the COVID-19 Pandemic
Hidenori Toyoda,1 Daniel Q. Huang,2,3 Michael H. Le,4 and Mindie H. Nguyen

4

As social distancing and strict stay-at-home orders have been instituted to slow the spread of coronavirus disease 2019
(COVID-19), unintentional outcomes among those with chronic diseases including screening for the lethal hepatocellular carcinoma (HCC) may be occurring. We aimed to describe the changes in liver care before and after COVID-19
restricted access to health care. We obtained data on the number of liver clinic visits, abdominal ultrasound, computed
tomography, and magnetic resonance imaging using electronic query or clinic registry at three medical centers in the
United States, Japan, and Singapore for the following periods: February 1 to March 14, 2018, 2019, and 2020; andMarch 15 to May 1, 2018, 2019, and 2020. We performed trend analysis using logistic regression. In total, 14,403
visits were made to the liver clinics at the three centers: 5,900 in 2018, 5,270 in 2019, and 3,233 in 2020. Overall,there were no significant changes in the distribution of males and females between February 1 and May 1 from 2018
to 2020, but there was a lower proportion of seniors ages 65 years and older (P < 0.001). There were significant
decreasing trends in the total number of liver clinic visits overall (p-trend = 0.038) and in the subanalysis for chronic
hepatitis B, C, and other liver diseases. HCC/cirrhosis visits also dropped from 883 to 538 (39.07% decrease) overall
and 665 to 355 (46.62% decrease) for the US site. In addition, there was a significant decreasing trend in the numberof abdominal ultrasounds (P-trend = 0.004) and computed tomography/magnetic resonance imaging (P-trend = 0.007)
performed overall. Conclusion: Liver clinic visits, hepatoma surveillance, and diagnostic abdominal imaging fell dramatically as social distancing measures were instituted. Care providers must find ways to recall patients for important caremonitoring, including HCC surveillance. (Hepatology Communications 2020;0:1-7).

T

he coronavirus disease 2019 (COVID19) pandemic has claimed 307,296 deaths
globally and 89,420 deaths in the UnitedStates as of May 16, 2020.(1) Worldwide, countries
responded to the pandemic by instituting social
distancing and stay-at-home orders (e.g., UnitedStates) or stay-at-home request (e.g., Japan), to slow
down disease spread. However, unintended consequences of these draconian measures are potentiallyharming others. For example, the American Heart
Association recently reported a 40%-50% decreasein emergency-room visits for stroke and acute myocardial infarction, with the European Union reporting similar findings, while cardiac catherization
labs are reporting a decrease of up to 40% for lifesaving treatment for those in the throes of a myocardial infarction.(2-4) Public health organizations
have reported a decrease in childhood immunizations, to include immunizations for the highly contagious diseases of mumps and measles.(5) Recently,
the American Cancer Society reported a decrease incancer screenings and diagnoses.(6,7)

Abbreviations: COVID-19, coronavirus disease 2019; CT, computed tomography; HCC, hepatocellular carcinoma; MRI, magnetic resonanceimaging; NUH, National University Hospital, Singapore.
Received May 26, 2020; accepted July 8, 2020.
© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver
Diseases. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use
and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modif ications or adaptations are
made.
View this article online at wileyonlinelibrary.com.
DOI 10.1002/hep4.1579

Potential conflict of interest: Dr. Nguyen received grants from Pf izer, Glycotest, Enanta, and Vir. She consults for and received grants from Gilead.
She consults for Novartis, Spring Bank, Janssen, Exact Sciences, Intercept, Eli Lilly, Bayer, Eisai, and Laboratory of Advanced Medicine. Dr. Toyoda
is on the speakers’ bureau for AbbVie, Gilead, and MSD.

1

TOYODA ET AL.

As has been reported, liver cancer, specifically
hepatocellular carcinoma (HCC), has been on the rise
globally before COVID-19. These findings have beenquite disturbing, as HCC has a high mortality rate inwhich less than 10% of those diagnosed with HCC
are alive at 5 years.(8) Therefore, extensive efforts havebeen undertaken to try to improve HCC surveillanceby focusing on awareness of who is at risk as well as
appropriate screening methods and time intervals.(9-12)This report will briefly describe the experience of
three hospitals located in the United States, Japan,
and Singapore, to illustrate the impact of COVID-19
on liver clinic visits and surveillance for HCC.

Methods

This study was conducted using data from threeclinical sites: Stanford University Medical Center(Palo Alto, CA), Ogaki Municipal Hospital (Ogaki,
Japan), and National University Hospital, Singapore(NUH). We included all patients seen in a liver specialty clinic for follow-up. Patients were identified
through several means that included using electronic
search to obtain the number of patients seen at theliver specialty clinic using ultrasound CPT codes for“hepatoma surveillance,” and/or using a hand searchof all patients seen in the liver specialty clinics for theassigned time periods, identifying those who underwent ultrasound, computed tomography (CT), or amagnetic resonance imaging (MRI) for HCC surveillance. Using a data collection form, we obtained
the number of liver clinic visits, number of abdominal
ultrasounds, and number of abdominal CT or MRI
scans at each study center for the following 1.5-monthtime periods: February 1 to March 14, 2018; March
15 to May 1, 2019; February 1 to March 14, 2019;

Hepatology Communications, Month 2020

March 15 to May 1, 2019; February 1 to March 14,
2020; and March 15 to May 1, 2020. The time periods were chosen to correspond with the beginning ofsocial distancing initiative and orders for 2020, anddata from 2018 and 2019 served as controls. We also
obtained demographic characteristics (age, sex, andrace/ethnicity) and liver disease etiology associatedwith liver clinic visits. To study patients with moreadvanced liver disease, we obtained data for patientswith HCC and/or cirrhosis. The study was approvedby the Institutional Review Board at Stanford
University (Stanford, CA) and was conducted according to the Helsinki Declaration of 1975, as revised in2008.
We used chi-square test to compare demographic
characteristics associated with liver clinic visits among
the different time periods. We performed trend analysis using logistic regression to compare the number of liver clinic visits or abdominal imaging acrosstime periods. Statistical significance was defined witha two-tailed P value less than 0.05. We performed
all analyses using STATA, version 14 (Stata Corp.,
College Station, TX).

Results

During the selected time periods, 14,403 visits weremade to the liver clinics at the three participating
centers (9,345 in Stanford, 3,657 in Ogaki, 1,401 in
Singapore): 5,900 in 2018, 5,270 in 2019, and 3,233
in 2020. Most clinic visits at the Stanford site were
through telemedicine after March 15, 2020, whilemost visits at the Ogaki and Singapore sites continued to be regular in-person visits. Overall (Table 1),
there were no significant changes in the distribution ofmales and females between February 1 and May 1 fromARTICLE INFORMATION:
From the 1 Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan; 2 Yong Loo Lin School of Medicine, National
University of Singapore, Singapore; 3 Division of Gastroenterology and Hepatology, National University Health System, Singapore;
4
Division of Gastroenterology & Hepatology, Stanford University Medical Center, Palo Alto, CA.

ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Mindie H. Nguyen, M.D., M.A.S.
Division of Gastroenterology and Hepatology
Stanford University Medical Center2

Palo Alto, CA 94305
E-mail: mindiehn@stanford.edu
Tel.: 650-498-5691

Hepatology Communications, Vol. 0, No. 0, 2020

TOYODA ET AL.

TABLE 1. DEMOGRAPHIC CHARACTERISTICS OF THE TOTAL STUDY POPULATION
Variable2018 (2/1/2018-5/1/2018)2019 (2/1/2019-5/1/2019)2020 (2/1/2020-5/1/2020)

n = 5,900

n = 5,270

n = 3,233

P Value
0.043

Age group, years<45

908 (16.17%)

814 (16.25%)

562 (18.11%)

45-55

800 (14.25%)

733 (14.63%)

468 (15.08%)

0.57

55-65

1,597 (28.44%)

1,544 (30.82%)

948 (30.55%)

0.016

65+

2,310 (41.14%)

1,919 (38.30%)

1,125 (36.26%)<0.001

Sex

0.69

Male

3,365 (57.03%)

2,966 (56.28%)

1,822 (56.36%)

Female2,535 (42.97%)

2,304 (43.72%)

1,411 (43.64%)

2018 to 2019 and 2020 (P = 0.69) or in the age group45-55 years (P = 0.57). However, there was a slightincrease in 2020 for the age group less than 45 and55-65 years, but a decrease for seniors ages 65 years orolder (41.14% in 2018, 38.30% in 2019, and 36.26% in
2020; P < 0.001). Table 2 lists the number of patientsseen at each study site and demographic characteristics
associated with liver clinic visits by study center andby time period. The sex distribution remained consistently stable over the study periods at all three centers.
However, while the age distribution remained relatively
stable without significant changes at the Japan andSingapore centers, there was a significant and notable
drop in clinic visits by seniors ages 65 years or older in
the U.S. center (44.94% in 2018, 40.69% in 2019, and37.88% in 2020; P < 0.001). Race/ethnicity data wereavailable for the U.S. sites only, and showed that the
distribution did not differ significantly over time.
Trend analysis of a total number of liver clinic visits for the month of February, March, and April forthe 2018, 2019, and 2020 years showed significant
decreasing trends overall (p-trend = 0.038), for the
U.S. (p-trend = 0.046), and Singapore sites (p-trend =0.026), but not the Japan site (p-trend = 0.103) (Fig. 1).
Fig. 2A-D provides liver disease etiology–specificdata, in which we again found a significant decreasing
trend overall and for the U.S. site, but not the Japansite (p-trend = 0.281) for chronic hepatitis C diagnosis (number of hepatitis C virus visits at the Singapore
site were too few for analysis) (Fig. 2A). For chronic
hepatitis B visits (Fig. 2B), the trend also significantly
decreased for the total cohort (p-trend = 0.003), as
well as for the Japan (p-trend = 0.016), and Singapore(p-trend = 0.001) sites. A similar decreasing trend was
also observed for visits associated with other liver disease at the U.S. site (Fig. 2C). However, there was no

significant decrease in the number of visits for patientswith more advanced disease, namely those with HCC
and/or cirrhosis overall (p-trend = 0.11) or by individual study sites, although there was a non-signficant
decreasing trend at the U.S. site (p-trend = 0.094)(Fig. 2D). Nevertheless, between February 1 to March
14, 2020 and the March 15 to May 1, 2020 period,
the total number of HCC/cirrhosis visits dropped
from 883 to 538 (39.07% decrease) overall, from 665
to 355 (46.62% decrease) for the U.S. site, and 120(26.6% decrease) for the Japan site.
Regarding liver imaging, there was a significant
decreasing trend in the number of abdominal ultrasounds overall (p-trend = 0.004) and at the U.S. site
(p-trend = 0.010), but not the Japan (p-trend = 0.572)
or the Singapore site (p-trend = 0.753) (Fig. 3A). A
similar decreasing trend was also observed for CT/
MRI overall (p-trend = 0.007) and for the U.S. andSingapore sites, but not the Japan site (p-trend =0.838) (Fig. 3B).

Discussion

Although the COVID-19 measures instituted weremeant to stop the spread of COVID-19 and to protect the general public as a whole, the measures appear
to have adversely affected the routine monitoring ofchronic liver disease, to include HCC surveillance. In
this brief report, not surprisingly, we found that clinic
visits for patients with chronic liver disease and surveillance imaging for HCC fell dramatically as thesocial distancing and COVID-19 stay-at-home measures were instituted. In fact, the decrease in clinic visits and screening tests was noted to begin before thestrict implementation of stay-at-home orders but then3

TOYODA ET AL.

Hepatology Communications, Month 2020

TABLE 2. PATIENT DEMOGRAPHIC CHARACTERISTICS BY STUDY SITE
Variable2018 (2/1/2018-5/1/2018)2019 (2/1/2019-5/1/2019)2020 (2/1/2020-5/1/2020)

P Value

Stanfordn = 3,990

n = 3,430

n = 1,925—<45

535 (14.44)

465 (14.67)

295 (16.43)

0.13

45-55

445 (12.01)

405 (12.78)

225 (12.53)

0.62

55-65

1,060 (28.61)

1,010 (31.86)

595 (33.15)

0.001

65+

1,665 (44.94)

1,290 (40.69)

680 (37.88)<0.001

Age group, years

Sex

0.79

Male

2,275 (57.02)

1,945 (56.71)

1,110 (57.66)

Female1,715 (42.98)

1,485 (43.29)

815 (42.34)

EthnicityWhite

1,600 (46.85)

1,265 (44.15)

775 (46.69)

0.075

Black

95 (2.78)

75 (2.62)

35 (2.11)

0.36

Hispanic

980 (28.70)

850 (29.67)

490 (29.52)

0.67

Asian

660 (19.33)

615 (21.47)

315 (18.98)

0.052

Pacific Islander/ Native

80 (2.34)

60 (2.09)

45 (2.71)

0.42

n = 1,326

n = 1,281

n = 1,050—<45

280 (21.12)273 (21.31)

235 (22.38)

0.73

45-55

259 (19.53)

258 (20.14)

199 (18.95)

0.77

55-65

325 (24.51)

313 (24.43)

259 (24.67)

0.99

65+

462 (34.84)

437 (34.11)

357 (34.00)

0.89

Ogaki
Age group, years

Sex

0.44

Male

714 (53.85)

659 (51.44)546 (52.00)

Female612 (46.15)

622 (48.56)

504 (48.00)

n = 584

n = 559

n = 258—

NUH
Age group, years<45

93 (15.92)

76 (13.60)

32 (12.40)

0.327

45-55

96 (16.44)

70 (12.52)

44 (17.05)

0.106

55-65

212 (36.30)

221 (39.53)

94 (36.43)

0.482

65+

183 (31.34)

192 (34.35)

88 (34.11)

0.514

Sex

0.989

Male

376 (64.38)

362 (64.76)

166 (64.34)

Female208 (35.62)

197 (35.24)

92 (35.66)

accelerated as the stay-at-home orders were more forcefully enforced. The decreasing trend was observed forboth sexes, all race/ethnicity (in the United States), andall liver disease etiologies studied, including patientswith HCC and/or cirrhosis, although p-trend for thispopulation at the U.S. site was only trending toward
statistical significance. Indeed, between the February 1
to March 14, 2020 and the March 15 to May 1, 2020
period, there was a 40% decrease in the number of
HCC/cirrhosis visits overall, almost 50% at the U.S.
site, and about 25% at the Japan site. In Japan, the rangeof the number of patients seen in Japan decreased from
1,326 patients seen in 2018, 1281 patients were seen in2019 while only 1050 patients were seen in 2020.

4

A recent informal Gallup poll found that over 80%
of patients were afraid to go to the hospital due tofears of contracting COVID-19.(13) To overcome thisfear, the American College of Cardiology has started
a campaign, CardioSmart, in which they use social
media and local news stations to let people know that
it is safe to come to the hospital if one is sick.(14)Given the lethality of HCC, we must also findways to reach out to patients to bring them in for
their surveillance. In fact, a delay of just a few months
in HCC surveillance may be catastrophic for patients,
given that the doubling time for HCC tumor volume is 85.7 days.(15) Therefore, any delay may resultin either more aggressive treatment than would have

Hepatology Communications, Vol. 0, No. 0, 2020

TOYODA ET AL.

FIG. 1. Trends in total number of liver clinic visits.

FIG. 2. (A) Trends in liver clinic visits by etiology, HCV (data too few for NUH). (B) Trends in liver clinic visits by etiology, HBV.
(C) Trends in liver clinic visits by etiology, other liver disease (data unavailable for NUH). (D) Trends in liver clinic visits in advanced
patients, HCC, and/or cirrhosis. Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus.

5TOYODA ET AL.

Hepatology Communications, Month 2020

FIG. 3. (A) Trends in the number of abdominal ultrasounds performed. (B) Trends in the number of CT/MRI performed over time.

possibly been needed or the potential for no longer
being eligible for curative treatment. In addition to
decreased hepatoma surveillance ultrasound, there wasalso a decreasing trend for CT/MRI, which was evenmore concerning, as these are usually performed for
diagnostic purposes. Using the telehealth platform
may be one way of directly linking with patients, toassure them that they are safe coming to the hospital and that the need to for continual follow-up of
their liver cancer is vitally necessary. However, given
the average age of patients with HCC, the use ofsocial media may not be as effective, so sending lettersthrough the postal system may be a necessary means
to reach the patients. As seen in our report, the agegroup with most pronounced decrease in the number

6of clinic visits was those of seniors 65 years or older.
Elderly patients may have a more limited capability
with technology which may impair their use of telehealth. Elderly patients may also be more fearful about
COVID-19 exposure based on reports of higher mortality within the elderly as reported by the media andthe Center for Disease Control and Prevention.(16)Another important observation from our study isthe heterogeneity of observations among the study
sites. Some of these may be due to cultural differences
and some may be due to differences in the local government’s response to COVID-19 and subsequentmorbidity and mortality. These findings were most pronounced at the U.S. site, where when shelter-in-place
was ordered by local government, all regular in-person

Hepatology Communications, Vol. 0, No. 0, 2020

TOYODA ET AL.

clinic visits were discontinued almost immediately
replaced by almost exclusively telemedicine clinics. In
the U.S., the first COVID-19 death was only reported
on March 1, 2020, but the death toll quickly rose to 40
on March 13, 2020, and over 87,000 on May 16, 2020,
prompting extended government lock-down orders in
the area of the U.S. study site of this report. Although
Japan reported the first COVID-19 death earlier on
February 13, 2020, the death toll has risen to only
725 as of May 16, 2020. Although the government ofJapan has closed school since early March 2020 andhas requested citizens to stay home, the government
has not ordered a severe shelter-in-place order, and thismay explain the less severe drop in health care visits at
the Japan center. Singapore has a small population andhas reported only 21 COVID-19 deaths as of May 16,
2020, although it has more confirmed cases than Japan(26,891 vs. 16,237). Singapore shifted its public healthresponse level to “enhanced preparedness” on February
7, and on April 7, instituted “circuit breaker” measuresthat included closure of nonessential services and social
distancing measures.(17) We also recognize that patients
may have been seen at another clinic during our study
time, and therefore would not have been counted in ourstudy. However, due to the restrictions of the pandemic
as noted, we feel it is highly unlikely that a patient
would go to another clinic or would have been able tobe seen at another clinic. We also used internal controls
as a means of controlling for this potential phenomenon and did not see such a pattern. Finally, although
we were not able to provide outcome data with ourstudy, we have highlighted an area that requires study
to determine the effects of delaying HCC surveillance.
When future pandemics happen, health care will bebetter prepared to identify areas that need to continue
to function, so as not to increase morbidity and mortality as an unintended consequence.

which by trying to avoid one disease, patients succumb
to another potentially preventable disease.

Summary

Due to the stay-at-home measures that have been
instituted as a means of stopping the spread of COVID19, liver care for patients with chronic liver disease has
been suboptimal, and HCC surveillance has incurred adramatic drop. Given the lethality of HCC, health care
workers must find effective ways to reach out to patientsto provide assurance that it is safe to come for their HCC
testing so that we do not see an increase in mortality, in

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