Am. J. Trop. Med. Hyg., 71(2), 2004, pp. 125-128
Copyright © 2004 by The American Society of Tropical Medicine and Hygiene
SEQUENTIAL CHANGES OF SERUM AMINOTRANSFERASE LEVELS IN PATIENTS WITH SEVERE ACUTE RESPIRATORY SYNDROME
KENG-LIANG WU,
SHENG-NAN LU,
CHI-SIN CHANGCHIEN,
KING-WAH CHIU,
CHUNG-HUANG KUO,
SENG-KEE CHUAH,
JIEN-WEI LIU,
MENG-CHIH LIN,
HOCK-LIEW ENG,
SHUN-SHENG CHEN,
CHUAN-MO LEE, AND
CHAO-LONG CHEN
Division of Hepato-Gastroenterology, Department of Internal Medicine, Division of Pulmonary and Critical Care, Department of Internal Medicine, Division of Infectious Disease, Department of Internal Medicine, Department of Pathology, Department of Neurology, and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China
 |
ABSTRACT
|
Severe acute respiratory syndrome (SARS) is a newly emerging infectious disease. To describe the hepatic injury caused by this disease, we report the sequential changes of serum transaminase in probable SARS patients during a hospital outbreak in southern Taiwan. From April to June, 2003, 52 probable SARS patients were hospitalized. Serial serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were retrospectively analyzed and hepatitis B surface antigen (HBsAg) was also evaluated to correlate with the progression of this disease. Fifty-three percent of the patients had abnormal liver function during hospitalization. More than 70% of abnormal transaminase levels were mildly elevated. Most elevated levels were noted during the second week after onset of fever. Neither transaminase elevation nor HBsAg was related to the prognosis of SARS, and only advanced age was an independent predictor of poor outcome. Our study suggested that coronavirus causing SARS might induce liver damage.
|
INTRODUCTION
|
Severe acute respiratory syndrome (SARS) is an emerging infectious disease that first manifested in humans in China in November 2002, and has subsequently spread worldwide. At present, it has affected more than 33 countries and regions all over the world, infected 8,089 people, and killed 774 patients by September 26, 2003.1
A new virus, the SARS-associated coronavirus, has been identified as the causal agent.2–5 Most coronaviruses cause either respiratory or enteric disease, and may be transmitted by the fecal-oral route. The clinical, radiologic, and other laboratory findings at the initial presentation regarding SARS have been previously described.2,6–10
Mildly elevated aminotransferase levels (indicating liver damage) or liver dysfunction at the later stages of disease were noted in some patients with SARS,2,6,7,10 and chronic infection with hepatitis B virus was reported to be an important independent risk factor of severity in SARS.11 However, sequential changes in serum aminotransferase levels are still unclear. There was an outbreak of SARS in southern Taiwan between April and June 2003. Herein we describe the sequential changes in serum aminotransferase levels and retrospectively analyze the correlation between abnormal serum aminotransferase levels, hepatitis B surface antigen (HBsAg) carrier status, and the progression of SARS.
|
MATERIALS AND METHODS
|
Between April 25 and June 5, 2003 we identified 52 probable SARS patients whose symptoms met the Centers for Disease Control and Prevention (CDC) (Atlanta, GA) definition of March 17, 2003 in our medical center in southern Taiwan. All cases were diagnosed clinically by a Committee for SARS Diagnosis in this hospital, based on the patients’ clinical symptoms and the ruling out of common bacterial and viral pathogens that cause pneumonia. On the basis of the criteria for SARS that had been established by the CDC, our case definition was fever (temperature >38°C), a chest radiograph (a plain radiograph of the thorax) showing evidence of consolidation with or without respiratory symptoms (e.g., cough or shortness of breath), and a history of exposure to an index patient suspected to have SARS or direct contact with a person who became ill after exposure to an index patient.12 Aspartate aminotransferase (AST, upper limit of normal [ULN] = 37 units/L), alanine aminotransferase (ALT, ULN = 40 units/L), and creatine kinase (CPK, ULN = 130 units/L) levels were checked within two days after the onset of fever in 52 patients and sequentially assessed and analyzed during hospitalization. Day 1 was defined as the day of onset of fever. The clinical end point was the need for care in an intensive care unit, death, or both. We used univariate analysis to compare patients who reached the end point and those who did not, and also analyzed clinical and laboratory variances between patients with normal ALT levels and abnormal ALT levels by an unpaired Student’s t -test, or chi-square test, as appropriate. A P value < 0.05 was considered to indicate statistical significance. Serial AST and ALT data were available for 48 cases. Four patients were excluded because two patients had no data on serum aminotransferase levels and two patients had extremely abnormal serum aminotransferase levels due to shock and hypoxemia. Results of testing for HBsAg were available for only 38 patients. All of these patients received the medical protocol therapy, i.e., patients received broad spectrum antibiotics and a combination of ribavirin and prednisolone as an empirical treatment. Intravenous methylprednisolone at high dosages was used in patients with respiratory distress or progressive consolidations as detected in their chest radiograph.13 A pulse oximeter reading was obtained if the patient had dyspnea. Eight patients carriers of were hepatitis B virus, including one with cirrhosis, but no alcoholism was noted in these patients.
|
RESULTS
|
Fifty-two patients (20 men and 32 women) with a mean ± SD age of 45 ±20 years old (range = 21–84) were included in this retrospective study. There were 16 medical care workers, 14 relatives of hospitalized patients, and 22 patients. Forty-two patients might have been exposed to an index patient or ward in our hospital. The other 10 patients were transferred from other hospitals. The incidence of abnormal AST and ALT levels in patients with SARS was 53%. The distribution of serum aminotransferase levels is shown in Figure 1
. Most patients showed mild elevation of these levels. Seventy percent of the abnormal AST levels and 77% of the abnormal ALT levels were mildly elevated (1–2.5 times the ULN, 41–100 units/L). Only 3.8% of the patients had ALT levels greater than 200 units/L (five times the ULN). Based on the available data, the sequential changes in median serum aminotransferase levels are shown in Figure 2. Slightly elevated AST and ALT levels occurred during the second week after the onset of fever. There was no correlation between serum aminotransferase levels and muscle damage (CPK levels). There was no significant difference in the percentage of abnormal AST and ALT levels in patients who died or needed intensive care and in those who did not. Advanced age was an independent predictor of adverse outcomes. Eight patients were positive for HBsAg among 38 cases with available results. Only one patient with liver cirrhosis progressed to respiratory failure, and other seven patients had a self-limited course of SARS and did not suffer progression to respiratory failure. Twenty-one patients received intensive care and intubation during hospitalization. All patients who required intensive care also required intubation. There were no significant differences in age, sex, severity of SARS and hepatitis B virus carrier status between patients with normal ALT and abnormal ALT levels (Table 1). Only two patients received abdominal ultrasonography. One had only mild parenchyma liver disease and the other had liver cirrhosis. Sixteen patients died and the mortality was 30.7%. No autopsies were performed. Forty-six provided nasopharygeal swabs for a reverse transcriptase–polymerase chain reaction (RT-PCR) and 19 patients provided rectal swabs. The positive rates of the RT-PCR of pharyngeal and rectal swabs were 26% and 5%, respectively. Convalescent serum antibody to SARS coronavirus was not available because some patients died and some surviving patients refused further examination.
View larger version (17K):
[in this window]
[in a new window]
|
FIGURE 1. Percentage of serum transaminase levels in patients with severe acute respiratory syndrome. AST = aspartate aminotransferase; ALT = alanine aminotransferase.
|
|
View larger version (35K):
[in this window]
[in a new window]
|
FIGURE 2. Sequential changes of serum median aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in patients with severe acute respiratory syndrome. CPK = creatine kinase.
|
|
View this table:
[in this window]
[in a new window]
|
TABLE 1 Univariate analysis of clinical and laboratory variables associated with abnormal alanine aminotransferase (ALT) levels
|
|
|
DISCUSSION
|
Elevation of serum aminotransferase levels is believed to be the result of leakage from damaged cells and thus reflects hepatocyte injury. The levels of these enzymes are elevated in many forms of liver disease, especially those associated with significant hepatocyte necrosis, such as acute viral hepatitis and chemical or ischemic injury.14 The results of our study show that 53% of the patients with SARS had mildly elevated levels of serum aminotransferases. There was no alcoholism in these patients. Abnormal data for two patients with evidence of severe hypoxemia or shock were excluded from this study. A major side effect of ribavirin is reversible hemolytic anemia,15 but no evidence that hepatic damage could be induced by ribavirin or steroids has ever been reported. These medications (including ribavirin and steroids) were not likely to be related to the hepatic damage seen in our study. Thus, it is suggested that SARS might be involved in liver damage without a relationship to medicinal or ischemic injury.
In our study, during hospitalization some patients presented with mildly elevated aminotransferase levels at the second week after the onset of SARS. Peiris and others reported that the clinical progression of SARS was divided into a triphasic pattern.11 They also hypothesized that lung damage at the second week may be related to immunopathologic damage as a result of an overly exuberant host response, rather than uncontrolled viral replication.11 Although we did not perform liver biopsies on these patients, some investigators found that patholologic evaluation of the fatal SARS cases showed that hepatocytes underwent fatty degeneration, cloudy swelling, apoptosis, and dot necrosis, with Kupffer cell proliferation and portal lymphocyte infiltrations.16,17 Suckling mice inoculated with SARS-infected samples also demonstrated hepatocytic lesions, including vacuolar and hydropic degenerations, focal cellular condensation, and necrosis, and no coronavirus-like particles were found in the hepatocytes.18 According to our study and the earlier description, we suspect that the mechanism of liver injury by SARS coronavirus may be related to immunopathologic damage.
Chronic infection with hepatitis B virus was reported to be an important independent risk factor in the severity of SARS,11 but in our study we could not find any relationship between SARS and infection with hepatitis B virus. Because only eight patients had chronic infection hepatitis B virus in our study, the power to show effect of hepatitis B virus infection on the progression of SARS was small. Of the hepatitis B virus carriers in our study, only one, the patient with cirrhosis, progressed to respiratory failure. In our study, there was no significant correlation in age, sex, infection with hepatitis B virus, or poor progression between SARS patients with abnormal liver function, and no evidence of medication injury. Thus, the abnormal liver function may be due to a SARS-induced systemic inflammatory reaction. Duan and others19 reported elevated levels of ALT and (or) AST in 37.7% of 154 patients (43% were mildly elevated and 56.9% were moderately elevated); 75% of the ALT levels normalized within two weeks; levels of six types of interleukin and TNF-alpha were higher during the first week of hospitalization than those during the fourth week and in control groups; and the levels of some factors, such as interleukin-1ß (IL-1ß), IL-6, and IL-10, in patients with elevated levels of ALT were higher than those in patients with normal ALT levels. Duan and others also suggested that there may be a systemic inflammatory response in most SARS patients at an early stage, and liver damage is only a partial sign of this. In our study, elevated ALT levels in 53% of the patients (77% of the abnormal ALT levels were mildly elevated and only 3.8% were greater than five times the ULN) normalized in 63% of the patients within two weeks. Further study is needed to determine the hypothesis of the mechanism of liver injury.
In conclusion, SARS may be associated with a mild elevation of aminotransferase levels, and the SARS coronavirus may induce liver damage. In our study, we found that serum aminotransferase levels were only mildly elevated and developed at approximately the second week after the onset of fever in most patients with SARS. This suggests that these results might be due to the immune response induced by the SARS coronavirus rather than the cytotoxic effect of the virus. Based on our study, there was no correlation between hepatitis B virus infection and the progression of SARS. Further large-scale, longitudinal studies are needed to clarify these findings.
Received November 24, 2003.
Accepted for publication February 5, 2004.
Authors’ addresses: Keng-Liang Wu, Sheng-Nan Lu, Chi-Sin Changchien, King-Wah Chiu, Chung-Huang Kuo, Seng-Kee Chuah, and Chuan-Mo Lee, Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China. Jien-Wei Liu, Division of Infectious Disease, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China. Meng-Chih Lin, Division of Pulmonary and Critical Care, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China. Hock-Liew Eng, Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China. Shun-Sheng Chen, Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China. Chao-Long Chen, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China.
Reprint requests: Chuan-Mo Lee, Division of Hepato-Gastro-enterology, Department of Internal Medicine, Kaohsiug Chang Gung Memorial Hospital, 123 Ta-Pei Road, Niao Sung Hsiang 833, Kaohsiung Hsien, Taiwan, Republic of China, Telephone: 886-7-7317123 extension 8301, Fax: 886-7-7322402, E-mail: chmolee{at}ms15.hinet.net.
|
REFERENCES
|
- World Health Organization, Cumulative number of reported probable cases of severe acute respiration syndrome. (http://www.who.int/csr/sars/country/en).
- Peiris JS, Lai ST, Poon LL, Guan Y, Yam LY, Lim W, Nicholls J, Yee WK, Yan WW, Cheung MT, Cheng VC, Chan KH, Tsang DN, Yung RW, Ng TK, Yuen KY; SARS study group, 2003. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet 361: 1319–1325.[ISI][Medline]
- Ksiazek TG, Erdman D, Goldsmith CS, Zaki SR, Peret T, Emery S, Tong S, Urbani C, Comer JA, Lim W, Rollin PE, Dowell SF, Ling AE, Humphrey CD, Shieh WJ, Guarner J, Paddock CD, Rota P, Fields B, DeRisi J, Yang JY, Cox N, Hughes JM, LeDuc JW, Bellini WJ, Anderson LJ; SARS study group, 2003. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med 348: 1953–1966.[Abstract/Free Full Text]
- Drosten C, Gunther S, Preiser W, van der Werf S, Brodt HR, Becker S, Rabenau H, Panning M, Kolesnikova L, Fouchier RA, Berger A, Burguiere AM, Cinatl J, Eickmann M, Escriou N, Grywna K, Kramme S, Manuguerra JC, Muller S, Rickerts V, Sturmer M, Vieth S, Klenk HD, Osterhaus AD, Schmitz H, Doerr HW, 2003. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med 348: 1967–1976.[Abstract/Free Full Text]
- Rota PA, Oberste MS, Monroe SS, Nix WA, Campagnoli R, Icenogle JP, Penaranda S, Bankamp B, Maher K, Chen MH, Tong S, Tamin A, Lowe L, Frace M, DeRisi JL, Chen Q, Wang D, Erdman DD, Peret TC, Burns C, Ksiazek TG, Rollin PE, Sanchez A, Liffick S, Holloway B, Limor J, McCaustland K, Olsen-Rasmussen M, Fouchier R, Gunther S, Osterhaus AD, Drosten C, Pallansch MA, Anderson LJ, Bellini WJ, 2003. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science 300: 1394–1399.[Abstract/Free Full Text]
- Lee N, Hui D, Wu A, Chan P, Cameron P, Joynt GM, Ahuja A, Yung MY, Leung CB, To KF, Lui SF, Szeto CC, Chung S, Sung JJ, 2003. A major outbreak of severe acute respiratory syndrome in Hong Kong. N Engl J Med 348: 1986–1994.[Abstract/Free Full Text]
- Booth CM, Matukas LM, Tomlinson GA, Rachlis AR, Rose DB, Dwosh HA, Walmsley SL, Mazzulli T, Avendano M, Derkach P, Ephtimios IE, Kitai I, Mederski BD, Shadowitz SB, Gold WL, Hawryluck LA, Rea E, Chenkin JS, Cescon DW, Poutanen SM, Detsky AS, 2003. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA 289: 2801–2809.[Abstract/Free Full Text]
- Poutanen SM, Low DE, Henry B, Finkelstein S, Rose D, Green K, Tellier R, Draker R, Adachi D, Ayers M, Chan AK, Skowronski DM, Salit I, Simor AE, Slutsky AS, Doyle PW, Krajden M, Petric M, Brunham RC, McGeer AJ; National Microbiology Laboratory, Canada; Canadian Severe Acute Respiratory Syndrome Study Team, 2003. Identification of severe acute respiratory syndrome in Canada. N Engl J Med 348: 1995–2005.[Abstract/Free Full Text]
- Vu TH, Cabau JF, Nguyen NT, Lenoir M, 2003. SARS in northern Vietnam (letter). N Engl J Med 348: 2035.[Free Full Text]
- Hon KL, Leung CW, Cheng WT, Chan PK, Chu WC, Kwan YW, Li AM, Fong NC, Ng PC, Chiu MC, Li CK, Tam JS, Fok TF, 2003. Clinical presentations and outcome of severe acute respiratory syndrome in children. Lancet 361: 1701–1703.[ISI][Medline]
- Peiris JS, Chu CM, Cheng VC, Chan KS, Hung IF, Poon LL, Law KI, Tang BS, Hon TY, Chan CS, Chan KH, Ng JS, Zheng BJ, Ng WL, Lai RW, Guan Y, Yuen KY; HKU/UCH SARS Study Group, 2003. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet 361: 1767–1772.[ISI][Medline]
- Centers for Disease Control and Prevention, Severe acute respiratory syndrome (SARS) updated interim case definition (Accessed April 22, 2003.at http://www.cdc.gov/ncidod/sars/casedefinition.htm.).
- So LK, Lau AC, Yam LY, Cheung TM, Poon E, Yung RW, Yuen KY, 2003. Development of a standard treatment protocol for severe acute respiratory syndrome. Lancet 361: 1615–1617.[ISI][Medline]
- Davern TJ, Scharschmidt BF, 2002. Biochemical liver tests. Feldman M, ed. Gastrointestinal and Liver Disease. Volume 2. Seventh edition. Philadelphia: W. B. Saunders, 1227–1239.
- Roberts RB, Laskin OL, Laurence J, Scavuzzo D, Murray HW, Kim YT, Connor JD, 1987. Ribavirin pharmacodynamics in high-risk patients for acquired immunodeficiency syndrome. Clin Pharmacol Ther 42: 365–373.[ISI][Medline]
- Zhang JZ, 2003. Severe acute respiratory syndrome and its lesions in digestive system. World J Gastroenterol 9: 1135–1138.[ISI][Medline]
- Hui AY, Chan HL, Liew CT, Chan PK, To KF, Chan CP, Sung JJ, 2003. Fatal outcome of SARS in a patient with reactivation of chronic hepatitis B. Am J Med 115: 334–336.
- Wang CE, Qin ED, Gan YH, Li YC, Wu XH, Cao JT, Yu M, Si BY, Yan G, Li JF, Zhu QY, 2003. Pathological observation on suckling mice and Vero E6 cells inoculated with SARS samples. Jifangjun Yixue Zuzhi 28: 383–384.
- Duan ZP, Chen Y, Zhang J, Zhao J, Lang ZW, Meng FK, Bao XL, 2003. Clinical characteristics and mechanism of liver injury in patients with severe acute respiratory syndrome. Zhonghua Gan Zang Bing Za Zhi 11: 493–495.[Medline]
This article has been cited by other articles:
|
|
|
|
 
T. C. Greenough, A. Carville, J. Coderre, M. Somasundaran, J. L. Sullivan, K. Luzuriaga, and K. Mansfield
Pneumonitis and Multi-Organ System Disease in Common Marmosets (Callithrix jacchus) Infected with the Severe Acute Respiratory Syndrome-Associated Coronavirus
Am. J. Pathol.,
August 1, 2005;
167(2):
455 - 463.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
ABSTRACT
INTRODUCTION
