Letters Section Editor: Stephen J. Lurie, MD, PhD, Senior Editor.
To the Editor: Mildly elevated levels of aminotransferase
have been reported in 23% to 50% of patients with severe acute respiratory
syndrome (SARS). The clinical and pathological significance of this finding,
however, remains unknown.1- 3 We
investigated whether liver dysfunction might reflect disease activity and
have a temporal relationship with other clinical parameters in patients with
We evaluated clinical records, serial blood test results, and chest
radiographs of 54 adult patients with SARS (diagnosed according to US Centers
for Disease Control and Prevention criteria1,4)
but without chronic hepatitis B or C infection, who were admitted to 2 Hong
Kong regional hospitals between March 8 and April 17, 2003. Charts of randomly
selected age- and sex-matched patients with non-SARS community-acquired pneumonia
from Queen Mary Hospital in the same time period were also examined. All patients
with SARS received combination therapy comprising a corticosteroid and either
intravenous or oral ribavirin, beginning a mean of of 3.0 (SD, 1.5) days from
date of admission. All patients were also treated with intravenous cefepime
(2 g 3 times daily) and with either oral clarithromycin (500 mg twice daily)
or azithromycin (500 mg once daily), beginning at admission and continuing
throughout their treatment period, as standard protocol for treatment of severe
community-acquired pneumonia in our institution.
Liver dysfunction was defined as alanine aminotransferase (ALT) level
greater than the upper limit of normal. The time from admission to peak ALT
level was determined for each patient. Serial chest radiographs of the 54
patients with SARS were quantitatively evaluated to provide a daily "chest
x-ray (CXR) score," which reflected the degree of lung involvement. We recorded
the baseline CXR score, the maximal CXR score (worst radiographic disease
severity) as well as the number of days between admission and the day on which
the maximal CXR score was noted.We also recorded the posttreatment CXR score,
obtained either on the last day of assessment or after at least 96 hours of
defervescence together with radiographic evidence of improvement in lung consolidation.
Data were analyzed with the t test, the Spearman
rho correlation, or the Pearson correlation coefficient as appropriate. A P value less than .05 was considered statistically significant.
Our study was approved by a local institutional review board.
Compared with patients with non-SARS community-acquired pneumonia, patients
with SARS had significantly lower initial total leukocyte and lymphocyte counts,
as well as globulin levels, and also had significantly higher initial ALT
levels. (Table 1 and Table 2). Liver dysfunction was found in
29.6% and 75.9% of patients at presentation (before ribavirin treatment) and
during treatment, respectively (P<.001 by χ2 test).
Among patients with SARS, levels of albumin, globulin, bilirubin, aspartate
aminotransferase, and ALT all changed significantly during treatment (Table 2). Time to maximal CXR score (mean
[SD], 7.2 [4.0] days) correlated with time to peak ALT level (mean [SD], 11.6
[6.6] days; r = 0.51, P<.001).
Albumin levels on admission and during time to peak ALT level both had a significant
negative correlation with maximal CXR score (r = −0.39, P = .008; and r = −0.52, P<.001, respectively). Bilirubin levels during time to peak ALT
level correlated with maximal CXR score (r = 0.35, P = .02). Bilirubin and albumin levels during time to peak
ALT level correlated with the posttreatment CXR scores (r = 0.37, P = .008; and r = −0.36, P = .01, respectively).
At the posttreatment assessment, mean levels of albumin and aspartate
aminotransferase had returned to normal, while mean levels of ALT and bilirubin
were still elevated (Table 2).
The mean cumulative dosage and duration of ribavirin treatment were similar
between those who developed liver dysfunction and those who did not (data
The pathological resemblance of SARS to diffuse alveolar injury, as
well as its radiologic resemblance to bronchiolitis obliterans organizing
pneumonia, suggest that the pathogenesis of SARS may involve an immunological
component.1- 3 Given
the clinical and radiological responsiveness of SARS pneumonia to corticosteroid
therapy, our findings of a temporal relationship between liver dysfunction
and pneumonic severity suggest that liver dysfunction in SARS might reflect
an immunological injury to the liver. The temporal relationship between maximal
liver dysfunction and pneumonic severity also suggest that a common pathogenic
mechanism is in action for both organs. We acknowledge that ribavirin may
have also played a role in this relationship. We think that a drug-induced
hepatitis is a less likely explanation for our findings, however, as most
patients had evidence of liver dysfunction prior to therapy. Furthermore,
this would not necessarily explain the correlations that we found between
levels of albumin and bilirubin during time to peak ALT level and the severity
of radiographic disease. While coronavirus causes fulminant hepatitis in mice5,6 and thus it is possible that
coronavirus could directly damage the liver, this is less likely to be the
case in light of the temporal relationship to the steroid-responsiveness of
the lung disease.
Our data, therefore, suggest that liver dysfunction is a distinct abnormality
in patients with SARS, and further suggest a temporal relationship between
clinical disease severity and liver dysfunction in SARS. Since there are no
specific markers for this disease, liver function monitoring may be a useful
adjunct to serial radiographic assessment in the clinical assessment of patients
Acknowledgment: We would like to thank the
doctors, nurses, and medical personnel of Queen Mary and Queen Elizabeth Hospitals
for their dedication and care of SARS patients. We would also like to thank
Kennis To, Fiona Fung, Teresa Tong, June Sun, Colin Ko, and Christina Yan
for data management. Drs W.-M. Wong and J. C. Ho contributed equally to this
Wong W, Ho JC, Hung IF, Ng W, Lam Y, Tam W, Wong BCY, Wong PC, Lai CL, Lam W, Lam S, Tsang KW, Ooi GC, Ho PL, Mok T, Chan J. Temporal Patterns of Hepatic Dysfunction and Disease Severity in Patients With SARS. JAMA. 2003;290(20):2663-2665. doi:10.1001/jama.290.20.2663