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Clin. Lab. 2014;60:63-68
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ORIGINAL ARTICLE
Hepatic Impairment Induced by Scrub Typhus is Associated with
New Onset of Renal Dysfunction
XU-JING LIANG 1, *, SI-MIN HUANG 1, *, JIAN-PING LI 2, XIAN-NV ZHU 3, YONG-PING LU 1,
BERTHOLD HOCHER 1, 4, YOU-PENG CHEN 1
1
#
both contributed equally and are listed in alphabetic order
Department of Infectious Diseases, the first Affiliated Hospital of Jinan University, Guangzhou 510630, China
2
Department of Infectious Diseases, the eighth People’s Hospital of Guangzhou, Guangzhou 510060, China
3
Department of Infectious Diseases, the second People’s Hospital of Yuebei, Shaoguan 512028, China
4
Institute of Nutritional Science, University of Potsdam, D-14558 Nuthetal-Potsdam, Germany
SUMMARY
Background: Scrub typhus is a potentially fatal infectious disease caused by Orientia tsutsugamushi. There is little
attention given to hepatic impairment in the adults with scrub typhus. This study investigated the incidence and
the prognostic implications of hepatic impairment in patients with scrub typhus.
Methods: We retrospectively reviewed a total of 143 adult patients with scrub typhus who were admitted between
January 1999 and December 2010 in Guangdong province, China. The patients were divided into three groups,
e.g., normal, mild, and moderate to severe groups based on the elevated serum ALT and/or total bilirubin levels.
Furthermore, clinical characteristics and prognosis of the patient groups were compared.
Results: 109 patients (76.2%) had abnormal liver function. Among the patients with hepatic impairment 45 cases
(31.4%), 54 cases (37.8%), and 10 cases (7.0%) had mild, moderate, and severe hepatic damage, respectively. The
moderate to severe hepatic impairment group had higher levels of serum creatinine compared with that of normal
hepatic function. The incidence of new onset of renal dysfunction - defined as peak serum creatinine ≥ 176 µmol/L
during hospital stay with no evidence of renal disease prior hospitalization - was 0% in the mild hepatic impairment group, 8.9% in the moderate hepatic impairment group, and 21.9% in the severe hepatic impairment group,
(p = 0.005 for trend). Additionally, the patients with hepatic impairment (n = 109) had higher incidences of episodes of thrombocytopenia (45.9% vs. 8.82%, p < 0.001), hypoalbuminemia (50.5% vs. 11.8%, p < 0.001), new
onset of renal dysfunction (16.5% vs. 0.0%, p = 0.011), and electrocardiogram abnormality (28.4% vs. 8.82%, p =
0.019) than the patients without hepatic impairment.
Conclusions: The degree of hepatic impairment induced by scrub typhus is associated with new onset of renal dysfunction.
(Clin. Lab. 2014;60:63-68. DOI: 10.7754/Clin.Lab.2013.121203)
Tbil - total bilirubin
WBC - white blood cell
ECG - electrocardiogram
KEY WORDS
hepatic impairment, renal dysfunction, complication,
outcome, scrub typhus
INTRODUCTION
LIST OF ABBREVATIONS
Scrub typhus is an acute febrile disease caused by the
organism Orientia tsutsugamushi. It is common in eastern and southern Asia, northern Australia, and the Pacific Islands [1]. Scrub typhus has been endemic in
southern China including Guangdong province for
ALT - alanine aminotransferase
AST - aspartate aminotransferase
_____________________________________________
Manuscript accepted Februar 7, 2013
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63
XU-JING LIANG et al.
hospital stay (176 µmol/L) [11,12]. Laboratory and clinical values were then compared among the three groups,
and the correlation between the hepatic impairment and
the clinical parameters representing severity of scrub typhus values was evaluated.
many decades [2]. Clinical manifestations include fever,
maculopapular rashes, eschar, and lymphadenopathy
[3]. It is characterized by focal or disseminated vasculitis and perivasculitis, which may involve the lung,
heart, liver, spleen, and central nervous system. Usually,
the symptoms of this disease are mild and its clinical
course is uneventful. However, scrub typhus may have
severe and fatal outcomes (in up to 30% of cases) under
certain circumstances [4]. Hepatic impairment is a common finding in critically ill patients and is a predictor of
mortality [5,6]. However, the relationship between hepatic impairment and other organic damages has been
given little attention in scrub typhus. Therefore, we investigated the incidence of abnormal liver function in
scrub typhus and the significance of hepatic impairment
on the outcome of patients with scrub typhus.
Statistical analysis
The results were analyzed using SPSS v15.0 (SPSS,
Inc., Chicago, IL, USA). Categorical variables were
compared by Fisher’s exact test or chi-square test and
continuous variables were compared by the ANOVA. A
difference was considered statistically significant if the
p value was less than 0.05.
RESULTS
In this study, the 143 patients revealed that the proportions of patients with the disease did not differ between
the genders; 71 (49.7%) patients were male. Patient
ages ranged from 18 to 77 years, with a median age of
48 years. 109 (76.2%) patients had abnormal liver function in which 45 cases (31.4%), 54 cases (37.8%), and
10 cases (7.0%), had mild, moderate, and severe hepatic
impairment, respectively. There were no differences in
age and gender among the three groups. There were no
differences in clinical signs and symptoms such as
fever, chill, headache, fatigue, anorexia, abdominal
discomfort, skin rash, eschar, lymphadenopathy, and
splenomegaly among groups except for nausea/vomiting (χ2 = 6.415, p = 0.040) and hepatomegaly (χ2 =
7.188, p = 0.027). The incidence of nausea/vomiting
and hepatomegaly in group I and group II (χ2 = 0.024, p
= 0.878 and χ2 = 0.011, p = 0.917, respectively) was no
different and data were merged, while the incidence of
nausea/vomiting and hepatomegaly in group III was
higher than that of group I and group II (χ2 = 6.251, p =
0.012; and χ2 = 7.181, p = 0.007) as shown in Table 1.
A summary of initial laboratory findings at admission
for groups I, II, and III is shown in Table 2. The serum
ALT and total bilirubin levels in group I, II, and III
were 24.00 ± 9.33 IU/L and 0.75 ± 0.32 mg/dL, 68.96 ±
13.52 IU/L and 0.78 ± 0.31 mg/dL, and 168.53 ± 129.98
IU/L and 2.73 ± 4.30 mg/dL, respectively. The serum
AST levels in groups I, II and III (41.94 ± 34.50 IU/L,
82.44 ± 40.52 IU/L, and 194.61 ± 138.41 IU/L, respectively) were different among the groups (F = 33.22, p <
0.001, one-way ANOVA). The serum albumin levels
were different among the groups (p < 0.001, one-way
ANOVA) and were lower with less severe damage to
the liver function. The serum creatinine levels were
higher in group III compared with group I (p = 0.019),
while there were no difference in group II compared
with group I or group III (p > 0.05). Platelet count was
significantly higher in group I compared with group II
(p = 0.002) or group III (p < 0.001). The incidence of
thrombocytopenia and hypoalbuminemia was lower in
group I compared with group II (χ2 = 8.587, p = 0.003;
and χ2 = 7.684, p = 0.006) or group III (χ2 = 17.452, p <
MATERIALS AND METHODS
Study population and design
We retrospectively reviewed a total of 143 cases (aged
≥ 18 years old) with scrub typhus who were admitted
between January 1999 and December 2010 to three
hospitals: the first Affiliated Hospital of Jinan University, the second People’s Hospital of Yuebei, and eighth
People’s Hospital of Guangzhou, Guangdong province,
southern China. The diagnosis of scrub typhus was confirmed with three and/or more of the following conditions [7,8]. Firstly, history of outdoor activities in vegetated areas. Secondly, acute-onset fever and eschar or
ulcer. Thirdly, enlarged lymphnode, maculopapular skin
rashes. Fourthly, a positive Weil-Felix test (an OXK titer
≥ 1:160, a four-fold or a greater rise in titer). The patients with chronic liver disease, chronic renal failure
and/or dysfunction, chronic heart disease, hematologic
disease, and inflammatory bowel disease were excluded.
Hepatic impairment was defined by serum total bilirubin and alanine aminotransferase (ALT) levels [9,10].
Patients were classified as having mild liver impairment
if serum ALT levels were between the upper level of
normal (ULN) and two and a half times ULN (40 - 100
IU/L) and total bilirubin was less than 2 mg/dL. Moderate liver impairment was defined as ALT levels between 2.5 and 10 times ULN (101 - 400 IU/L) and/or a
total bilirubin level of 2.1 - 5.0 mg/dL. Severe liver impairment was defined as ALT levels of more than 10
times ULN (400 IU/L) and/or a total bilirubin level of
more than 5 mg/dL. For the purpose of this study, patients with scrub typhus with normal liver function were
defined as ‘group I’, while those with mild liver impairment were defined as ‘group II’, and those with
moderate to severe liver impairment were defined as
‘group III’. The serum ALT and total bilirubin levels
were checked on the first blood samples taken upon
their visit to the hospital. Initially - before infection - no
patients had any renal impairment. New onset renal dysfunction was defined as serum creatinine ≥ 2.0 mg/dL at
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HEPATIC IMPAIRMENT AND RENAL DYSFUNCTION IN SCRUB TYPHUS
Table 1. Demographic and clinical characteristics of 143 patients.
Group II
(n = 45)
47.1 ± 13.6
Group III
(n = 64)
45.5 ± 14.0
t - or x2 - value
p-value
Age, mean ± SD, years
Group I
(n = 34)
44.3 ± 18.2
0.349
0.706
Gender, male, n (%)
13 (38.2%)
24 (53.3%)
34 (53.1%)
2.325
0.313
Fever, n (%)
33 (97.1%)
44 (97.8%)
63 (98.4%)
0.734
1.000
Chill, n (%)
21 (61.8%)
25 (55.6%)
39 (60.9%)
0.417
0.812
Headache, n (%)
23 (67.6%)
30 (66.7%)
52 (81.3%)
3.644
0.162
Fatigue, n (%)
28 (82.4%)
37 (82.2%)
60 (93.8%)
4.229
0.121
Anorexia, n (%)
20 (58.8%)
30 (66.7%)
49 (76.6%)
3.483
0.175
Characteristics
Nausea/Vomiting, n (%)
4 (11.8%)
7 (15.6%)
20 (31.3%)*
6.415
0.040
Abdominal discomfort, n (%)
2 (5.9%)
7 (15.6%)
11 (17.2%)
2.493
0.287
Skin rash, n (%)
11 (32.4%)
14 (31.1%)
17 (26.6%)
0.455
0.797
Eschar, n (%)
18 (52.9%)
33 (73.3%)
47 (73.4％)
5.027
0.081
Lymphadenopathy, n (%)
17 (50%)
27 (60%)
35 (54.7%)
0.798
0.671
Hepatomegaly, n (%)
5 (14.7%)
7 (15.6%)
22 (34.4%)*
7.188
0.027
Splenomegaly, n (%)
5 (14.7%)
7 (15.6%)
16 (25%)
2.170
0.338
*
The incidence of nausea/vomiting and hepatomegaly in group III was higher than that of group I and group II (p = 0.012 and p = 0.007, respectively).
Table 2. Laboratory tests of 143 patients with scrub typhus at admission.
WBC (103/μL)
Group I
(n = 34)
7.81 ± 4.84
Group II
(n = 45)
8.84 ± 5.41
Group III
(n = 64)
8.35 ± 4.38
t - or
x2 - value
0.439
Hematocrit (%)
34.24 ± 5.38
35.61 ± 5.85
33.36 ± 5.42
2.172
0.118
Characteristics
p-value
0.645
Hemoglobin (g/dL)
11.26 ± 1.65
12.09 ± 2.06
11.52 ± 2.40
1.605
0.205
Platelet (x 103/mm3)
188.71 ± 108.27*,§
129.55 ± 81.39
112.07 ± 69.69
9.454
0.000
,§
17 (37.77%)
33 (51.56%)
17.402
0.000
ALT (IU/L)
24.00 ± 9.33
68.96 ± 13.52
168.53 ± 129.98
35.10
0.000
AST (IU/L)
41.94 ± 34.50
82.44 ± 40.52
194.61 ± 138.41
33.22
0.000
Thrombocytopenia, n (%)
3 (8.82%)*
Tbili (mg/dL)
0.75 ± 0.32
0.78 ± 0.31
2.73 ± 4.30
8.158
0.000
Albumin (g/dL)
3.50 ± 0.59*,§
3.14 ± 0. 80
2.83 ± 0.64
10.709
0.000
18 (40%)
37 (57.81%)
19.469
0.000
88.88 ± 35.47
120.29 ± 95.64
4.272
0.016
,§
Hypoalbuminemia, n (%)
4 (11.76%)*
Serum creatinine (µmol/L)
83.78 ± 30.66§
Values are mean ± SD. WBC = white blood cell; ALT = alanine aminotransferase; AST = aspartate aminotransferase; Tbil = total bilirubin.
Thrombocytopenia: platelet count < 100 x 103/mm3; Hypoalbuminemia: serum albumin < 3.0 g/dL. * Group I vs. group II, p < 0.05; § group I
vs. group III, p < 0.05; group II vs. group III, p < 0.05.
0.001; and χ2 = 19.348, p < 0.001). On the other hand,
there were no statistical differences in WBC, hematocrit, or hemoglobin between the three groups. Three
cases had electrocardiogram abnormalities in group I,
including one case of sinus tachycardia, one case of
sinus tachycardia with occasional premature ventricular
contractions, and one case of sinus bradycardia. Eleven
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cases had electrocardiogram abnormalities in group II,
including four cases of sinus tachycardia, one case of
premature ventricular contractions, one case of firstdegree atrioventricular block and five cases of ST segment/T wave changes. Twenty cases had electrocardiogram abnormalities in group III, including five cases of
sinus tachycardia, seven cases of ST segment/T wave
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XU-JING LIANG et al.
Table 3. Complications and outcomes of scrub typhus in 143 patients.
Group II
(n = 45)
1 (2.2)
Group III
(n = 64)
4 (6.3)
t - or x2 - value
p-value
Deaths, n (%)
Group I
(n = 34)
0 (0)
2.148
0.313
Hospitalization, days
9.50 ± 4.60
9.46 ± 4.60
11.56 ± 6.92
2.307
0.103
Pneumonitis, n (%)
7 (20.6)
13 (28.9)
26 (40.6)
4.409
0.110
New onset renal dysfunction, n (%)
0 (0)§
4 (8.9)
14 (21.9)
10.473
0.005
Characteristics
§
ECG abnormalities, n (%)
3 (8.8)
11 (24.4)
20 (31.3)
6.178
0.046
Myocarditis, n (%)
0 (0)
1 (2.2)
6 (9.4)
4.182
0.102
Meningitis/meningoencephalitis, n (%)
2 (5.9)
1 (2.2)
4 (6.3)
1.014
0.602
Values are mean ± SD. § group I vs. group II and group III, p < 0.05.
ECG = electrocardiogram; Renal dysfunction: serum creatinine ≥ 176 µmol/L.
Figure 1. Renal dysfunction in groups. * p < 0.005, group I vs. group II and group III.
also compared these clinical factors between patients
with and without hepatic impairment. The patients with
hepatic impairment (n = 109) had higher incidences of
episodes of thrombocytopenia (45.9% vs. 8.82%, χ2 =
17.25, p < 0.001), hypoalbuminemia (50.5% vs. 11.8%,
χ2 = 10.01, p = 0.000), renal dysfunction (16.5% vs.
0.0%, χ2 = 6.42, p = 0.011), and electrocardiogram abnormality (28.4% vs. 8.82%, χ2 = 5.50, p = 0.019) than
the patients without hepatic impairment (n = 34).
changes, four cases of premature ventricular contractions, two cases of sinus bradycardia and sinus arrhythmia, one case of sinus arrhythmia, and one case of complete right bundle branch block. The incidence of renal
dysfunction and electrocardiogram abnormality was no
different in group II and group III (χ2 = 3.232, p =
0.072; and χ2 = 0.601, p = 0.438) and the data were
merged. The merged data was higher than that of group
I (χ2 = 6.423, p = 0.011; and χ2 = 5.503, p = 0.019, respectively) as shown in Figure 1 and 2.
However, there was no difference in hospital stay,
mortality, and complications such as pneumonitis, myocarditis, meningitis/meningoencephalitis between the
three groups (p > 0.05) as shown in Table 2 and 3. We
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HEPATIC IMPAIRMENT AND RENAL DYSFUNCTION IN SCRUB TYPHUS
Figure 2. ECG abnormalities in group. * p < 0.005, group I vs. group II and group III.
phus, about 34.1% - 69.2% of patients presented hypoalbuminemia [23,24]. Hypoalbuminemia in scrub typhus is related to the frequency of various complications. Lee et al. [23] reported hypoalbuminemia, as a
criterion, was an important marker of clinical outcome
in this patient population. Although the mechanism of
hypoalbuminemia in patients with scrub typhus is still
not well known, it is considered to be associated with
plasma protein leakage from the blood vessels due to increased vascular permeability [25]. Moreover, the patients with hepatic impairment (group II and group III)
tended to have a greater incidence of renal dysfunction
and electrocardiogram abnormalities than the patients
without hepatic impairment (group I). Renal complications may prolong its morbidity and even lead to death,
and an elevated creatinine level was found to be an independent predictor of mortality [26].
The finding that we did not observe any differences
with regard to hospital stay or even mortality among
groups is due to the fact that our study is underpowered
for these hard clinical endpoints.
In conclusion, our study indicated that the degree of hepatic impairment in patients with scrub typhus is related
to signs of cardiac damage as indicated by ECG abnormalities and in particular the likelihood for acute kidney
failure.
DISCUSSION
Scrub typhus is an acute febrile disease caused by infection with Orientia tsutsugamushi and characterized
by fever, an eschar at the chigger bite site, regional
lymphadenopathy, and a maculopapular rash. Hepatic
impairment is frequently observed but overlooked in the
acute stage of scrub typhus [13,14]. In this study, 76.2%
scrub typhus patients had abnormal liver function tests
(31.4%, 37.8%, and 7.0% for mild, moderate, and severe hepatic impairment, respectively), and the degree
of hepatic impairment was mainly mild or moderate,
similar to the results of previous studies [15,16]. Regarding hepatitis-like manifestations, nausea/vomiting
and hepatomegaly occurred more frequently in the patients with moderate to severe hepatic impairment.
Therefore, if patients are found with fever of unknown
origin, varying degrees of hepatic impairment, even severe hepatic impairment, and skin lesions (including eschar and maculopapular rash) in endemic areas, we
should take scrub typhus into consideration. The mechanism of hepatic impairment is unknown so far. It might
be a result of direct invasion of Orientia tsutsugamushi
[17,18], and cellular immunity may be attributed to the
pathogenesis of the hepatic injury [19].
In the current study, thrombocytopenia and hypoalbuminemia were more severe in the group with hepatic
impairment (group II and group III). Thrombocytopenia
is one of the most common laboratory abnormalities in
critically ill patients and likely a marker of disease
severity [20,21]. Generally, hypoalbuminemia is known
to be associated with complications and mortality in patients with acute infectious disease [22]. In scrub ty-
Clin. Lab. 1/2014
Acknowledgement:
The authors gratefully acknowledge the contributions of
the general practitioners and the patients taking part in
the study.
67
XU-JING LIANG et al.
Declaration of Interest:
There is no conflict of interest for any of the authors.
16. Wu KM, Wu ZW, Peng GQ, et al. Radiology pulmonary findings,
clinical manifestations and serious complications in scrub typhus:
experiences from a teaching hospital in eastern Taiwan. International Journal of Gerontology 2009;3:223-32.
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Correspondence:
Prof. Berthold Hocher, MD, PhD
Lehrstuhl für Exp. Ernährungsmedizin
Institut für Ernährungswissenschaft
Arthur-Scheunert-Allee 114-116
14558 Nuthetal, Germany
Tel.:
+49 33200 88-508
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http://www.uni-potsdam.de/eem
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Associate Prof. You-Peng Chen, MD
Department of Infectious Diseases
the First Affiliated Hospital of Jinan University
Guangzhou 510630, China
Tel.:
+86 20 38688205
Fax:
+86 20 38688205
Email: [email protected]
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