Retrospective analysis of liver function derangement in severe acute respiratory syndrome.

To the Editor:

In March 2003, a hospital outbreak of severe acute respiratory syndrome (SARS) caused by a novel coronavirus (SARS-coronavirus, SARS-CoV) was reported in Hong Kong 1, 2, 3, 4 and cases were subsequently reported globally (5). In this study, we investigated the pattern of hepatic damage as well as the effect of chronic hepatitis B on the clinical outcome of SARS.

This was a retrospective analysis of the patient cohort as reported previously (1). Lamivudine 100 mg daily was prescribed to all chronic hepatitis B patients. Oxygen therapy was given when patients' oxygen saturation fell below 90%. Mechanical ventilation was offered when patients could not achieve 90% oxygen saturation while on 5 L/min oxygen supplement.

Anticoronavirus immunoglobulin (Ig) G antibody was measured by immunoflourescence assay in paired sera samples. Histologic and electron-microscopic examination was performed on the autopsy liver specimens. Liver tissue samples were inoculated onto African green monkey kidney (Vero) monolayers for viral isolation. Reverse transcriptase polymerase chain reaction (RT-PCR) was performed to confirm the presence of SARS-CoV in positive cell cultures (6).

Categorical variables were compared using the chi-squared test and continuous variables using the Mann-Whitney U test. All tests were 2-tailed. Statistical significance was taken as P <0.05.

One hundred and eighteen patients who had hepatitis B surface antigen (HBsAg) results available were studied. Paired serum samples for SARS-CoV serology were available in 113 (96%) patients and all were positive. The baseline characteristics and clinical outcomes of patients are shown in the Table.

Table

Baseline characteristics and clinical outcomes of HBsAg-positive versus HBsAg-negative patients

Baseline Characteristics	HBsAg positive (n = 12)	HBsAg negative (n = 106)	Overall (n = 118)	P Value
	Number (%) or (Range)
Age (years)	38 (21–64)	33 (20–83)	33 (20–83)	0.62
Male sex	9 (75)	46 (43)	55 (47)	0.080
Comorbid illness	2 (16.7)	14 (13.2)	16 (13.6)	1.00
Fever before admission (days)	2.5 (0–4)	3 (0–11)	3 (0–11)	0.099
Hemoglobin level (g/dL)	13.9 (10.3–15.4)	13.5 (6.3–16.6)	13.5 (6.3–16.6)	0.45
Platelet count (× 103/μL)	140 (31–207)	151.5 (14–359)	150 (14–359)	0.54
White blood cell count (× 103/μL)	5.4 (2.8–7.3)	6.7 (1.0–10.9)	4.7 (1.0–10.9)	0.37
Lymphocyte (× 103/μL)	0.8 (0.3–1.3)	0.8 (0.2–6.5)	0.8 (0.2–6.5)	0.72
PT (sec)	11.21 (9.8–17.1)	10.4 (9.0–60.1)	10.5 (9.0–60.1)	0.03
Creatinine (μmol/L)	91 (67–117)	84 (56–1318)	85 (56–1318)	0.26
TB (μmol/L)	8.5 (3–163)	6 (2–266)	6 (2–266)	0.14
TB >50 (μmol/L)	2 (17)	1 (1)	3 (3)	0.021
ALT (IU/L)	106.5 (23–1513)	24.5 (9–199)	25.5 (9–1513)	<0.001
↑ ALT	9 (75)	16 (15)	25 (21)	<0.001
Outcomes
Peak PT (sec)	11.5 (10.5–22.8)	11.1 (9.6–60.1)	11.2 (9.6–60.1)	0.19
Peak TB (mg/dL)	2.0 (1.1–13.5)	1.2 (0.4–22.6)	1.2 (0.4–22.6)	0.008
Peak TB >3.0 (mg/dL)	3 (25)	10 (9)	13 (11)	0.26
Peak ALT (IU/L)	152.5 (35–1513)	107 (19–2940)	116 (19–2940)	0.40
↑ Peak ALT (IU/L)	9 (75)	80 (76)	89 (75)	1.00
Oxygen supplement	8 (67)	59 (56)	55 (47)	0.67
Mechanical ventilation	3 (25)	13 (22)	16 (14)	0.44
Liver failure	1 (8)	0 (0)	1 (0.8)	0.19
Death	2 (17)	7 (7)	5 (8)	0.50

ALT = alanine aminotransferase, HBsAg = hepatitis B surface antigen, PT = prothrombin time, TB = total bilirubin

Two of the 12 chronic hepatitis B patients had liver cirrhosis. Among the patients without cirrhosis, 3 were admitted for chronic hepatitis B flare-up and contracted SARS nosocomially; on admission, 5 patients had elevated alanine aminotransferase levels and 2 patients had normal levels. One patient died of respiratory failure related to SARS and another died of multiorgan failure. Among the survivors, the alanine aminotransferase levels in 6 patients had returned to normal and in 3 other patients had decreased on follow-up.

Among the 106 HBsAg-negative patients, 16 (15%) patients had elevated alanine aminotransferase levels on admission. None of these patients had comorbid illnesses or had taken any medications. Seventy-one percent of patients who had normal baseline levels experienced elevation of alanine aminotransferase during the course of their illness. Clinical outcomes including oxygen requirement, need for intubation, and case fatality rate were not different in patients with normal and elevated baseline alanine aminotransferase levels. No patient developed liver failure. Overall, 66 of 80 (83%) patients who experienced alanine aminotransferase elevation had normalization of alanine aminotransferase levels on discharge and another 10 (13%) patients had decreasing levels on follow-up.

Autopsy was performed in 4 patients, including the 2 chronic hepatitis B patients who died. Specific hepatic lesion, acute hepatitic changes, or hepatic necrosis were not observed. Coronavirus particles were not detected by electromicroscopy. Positive cell culture for SARS-CoV confirmed by RT-PCR was found in 1 patient who had normal alanine aminotransferase levels throughout the admission.

In this study, three-quarters of patients experienced alanine aminotransferase elevation while the levels of the majority had returned normal after recovery. The liver derangement in SARS was likely a nonspecific transient reaction caused by the infection rather than by a direct cytopathic effect of SARS-CoV. The clinical outcomes of chronic hepatitis B patients were not different from those of HBsAg-negative patients, in contrast to the outcomes in a previous report (7). The absence of specific hepatic lesions in hepatitis B virus and SARS-CoV coinfected patients on autopsy supports the lack of influence that SARS has on chronic hepatitis B infection.

In conclusion, we found that chronic hepatitis B virus infection did not influence the clinical outcomes of SARS. Most SARS patients had transient elevation of liver enzyme levels that did not have serious clinical consequences.