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Hepatology Research 2012
Original Article
Sepsis-associated liver injury: Incidence, classification and
the clinical significance hepr_1069
Haruhiko Kobashi,1 Junichi Toshimori1 and Kazuhide Yamamoto2
1
Department of Hepatology, Japanese Red Cross Okayama Hospital, and 2Department of Gastroenterology and
Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,
Okayama, Japan
Aim: Although it is a common complication of sepsis, sepsis-
associated liver injury has not been substantially recognized,
because its diagnostic criteria and clinical implications are
unclear. We aimed to elucidate the incidence, manifestation,
disease type classification and prognosis of sepsis-associated
liver injury.
Methods: The subjects were 588 patients admitted to
our hospital for sepsis between 2001 and 2010. They were
classified into “normal liver function”, “sepsis-associated
liver injury” and “sepsis-not-associated liver injury” groups.
Sepsis-associated liver injury was classified as either “chole-
static”, “hepatocellular” or “shock liver.” Each of these three
subgroups was further classified into “with jaundice” or
“without jaundice”. The primary end-point was the “poor
prognosis ratio”, defined as the proportion of patients whose
prognosis was “unchanged”, “worsened” or “died”.
Results: Among the 449 subjects except for sepsis-not-
associated liver injury (n = 139), the incidence of sepsis-
INTRODUCTION
S EPSIS IS A critical clinical condition, frequently
leading to multiple organ failure and death. Sepsis is
now defined as a systemic clinical manifestation, namely,
a systemic inflammatory response syndrome (SIRS),
induced by infection.1,2 Since as early as 1837, it has been
well known that liver dysfunction and jaundice occur
frequently in cases of sepsis,3 and it is important to
recognize these manifestations as complications of
sepsis. Nonetheless, sepsis-associated liver injury or
cholestasis has not been recognized enough, as shown by
Correspondence: Dr Haruhiko Kobashi, Department of Hepatology,
Japanese Red Cross Okayama Hospital, 2-1-1 Aoe, Kita-ku, Okayama
700-8607, Japan. Email: kobashi0584@gmail.com
Received 30 December 2011; revision 1 June 2012; accepted 20 June
2012.
© 2012 The Japan Society of Hepatology
doi: 10.1111/j.1872-034X.2012.01069.x
1..12
associated liver injury was 34.7% (156/449), including 75
cholestatic (48.1%), 34 hepatocellular (21.8%) and 47 shock
liver (30.1%) cases. Jaundice was a complication in 25 (33%),
six (17.6%) and four (8.5%) patients in each group, respec-
tively. The poor prognosis ratio was higher in males (37.5%)
and in the elderly (47.7%); it was 48.0%, 38.2% and 62.8%
in the cholestatic, hepatocellular and shock liver groups,
respectively, and higher than the normal liver function
(18.4%) group (P < 0.0001). It was also higher in patients with
jaundice (68.6%) than in those without (45.5%) (P < 0.0001).
Conclusion: Sepsis-associated liver injury, especially with
jaundice, is a significant predictive sign of poor prognosis in
patients with sepsis.
Key words: cholestasis, jaundice, sepsis, sepsis-associated
liver injury, shock liver, systemic inflammatory response
syndrome
the lack of coverage in standard medical textbooks, jour-
nals and conference presentations. Actually, physicians
rarely mention that sepsis-associated liver injury is one of
the most common causes of jaundice and that it may be
overlooked.4 This seems due in part to the lack of a
comprehensive understanding of sepsis-associated liver
injury, as well as to a lack of clinical evidence. In fact, no
definite criteria for the diagnosis or even standardized
terminology have been established for this condition.
We therefore performed this retrospective large-scale
cohort study on sepsis-associated liver injury using data
on sepsis in patients who were admitted to and treated
in our hospital in the past 10 years in order to elucidate
the incidence, clinical manifestations and relationship
of sepsis to prognosis, and thus to clarify the clinical
significance of this condition. In this study, we also
attempted to classify the disease types of sepsis-
associated liver injury according to the patterns of liver
1
2 H. Kobashi et al.
function tests, in order to further elucidate the patho-
physiological conditions of sepsis.
METHODS
Subjects
T HE SUBJECTS CONSISTED of a total of 1027
patients who were admitted to Japanese Red Cross
Okayama Hospital and treated for sepsis during the
10 years between January 2001 and December 2010. A
patient with a history of at least two admissions for
sepsis was counted as a single case whose first admission
was applied. Infants under 1 year of age at the time of
admission (180 cases) were excluded because of the
difficulty of distinguishing neonatal jaundice from
septic cholestasis. The sepsis cases not definitely diag-
nosed (259 cases) were also excluded. Finally, 588 cases
were selected as eligible for inclusion in this study.
Sepsis was diagnosed based on the definition estab-
lished in the 2001 SCCM/ESICM/ACCP/ATS/SIS Inter-
national Sepsis Definitions Conference;1 that is, by the
presence of both of the following conditions. First,
the clinical manifestations of infection, a pathological
process induced by microorganisms, were shown by
clinical symptoms, physical examination, laboratory
tests such as elevation of plasma C-reactive protein and
plasma procalcitonin more than 2 standard deviations
above the normal value, and/or blood culture. Second,
at least two of the following manifestations of SIRS were
present: (i) hyperthermia (>38.3°C) or hypothermia
(<36.0°C); (ii) tachycardia (heart rate >90/min); (iii)
tachypnea (>90/min or PaCO2 <32 torr); and (iv) leu-
kocytosis (white blood cell [WBC] count >12 000/mL),
leukopenia (WBC count <4000/mL) or normal WBC
count with more than 10% immature forms. This study
was designed and performed in accordance with the
provisions of the Declaration of Helsinki and Good
Clinical Practice guidelines. The study was approved by
the Institutional Committee for Human Rights.
Study design
This was a retrospective cohort study. The subjects’ data,
including history, present illness, physical examination,
clinical course, laboratory examination, image diagnosis
and condition on discharge, were investigated from the
medical records.
Classification of subjects and diagnosis of
sepsis-associated liver injury
The subjects were classified by the existence or non-
existence of complications of liver injury according to
© 2012 The Japan Society of Hepatology
Hepatology Research 2012
the maximum value of liver function test during the
admission period. “Liver injury” was defined as a state in
which the patient’s blood laboratory results met at least
one of four conditions: (i) serum total bilirubin (T.Bil)
of 3.0 mg/dL or greater; (ii) aspartate aminotransferase
(AST) of 41 IU/L or greater; (iii) alanine aminotrans-
ferase (ALT) of 41 IU/L or greater; and (iv) g-glutamyl
transpeptidase (GGT) of 51 IU/L or greater. The patients
who met none of these criteria were classified as the
“normal liver function” group.
The etiology of liver injury was investigated using
medical records, namely, present illness, history, physi-
cal examination, clinical course, blood chemistry, viral
markers, autoantibodies, and images such as ultra-
sonography (US), computed tomography (CT) and
magnetic resonance imaging (MRI). The “sepsis-not-
associated liver injury” group consisted of patients
whose liver injuries were derived from primary hepato-
biliary diseases and not from sepsis, according to the
following criteria. Patients with habitual daily alcohol
intake of more than 20 g ethanol were defined as having
“alcoholic liver disease”. Patients with positive hepatitis
B surface antigen were defined as having “hepatitis B
virus (HBV)-related liver disease”. Patients with positive
anti-hepatitis C virus (HCV) antibody were defined as
having “HCV-related liver disease”. Patients with “drug-
induced liver injury” were diagnosed according to the
Japanese Society of Hepatology (JSH)-2004 criteria.5
Patients with “extrahepatic bile duct and gallbladder
disease” were diagnosed based on symptoms, physical
examinations and imaging diagnoses such as those of
US, CT and MRI. “Non-alcoholic fatty liver disease” was
diagnosed based on the finding of fat deposition in the
liver by US or CT. “Rhabdomyolysis” was diagnosed
based on the symptom of muscle pain and the
co-elevation of creatine kinase (CK). Other diseases
such as liver abscess, primary or secondary liver neo-
plasms, metabolic liver diseases, autoimmune liver dis-
eases diagnosed from specific markers of blood test such
as antinuclear antibody, or specific findings of imaging
(US, CT, MRI), were designated as “others”.
Classification of disease type in
sepsis-associated liver injury
The “sepsis-associated liver injury” group consisted of
patients belonging to the liver injury group except for
the sepsis-not-associated liver injury group. Sepsis-
associated liver injury was classified into three catego-
ries: “cholestatic”, “hepatocellular” and “shock liver”.
Shock liver was defined as a liver function test with
both AST and ALT over 200 IU/L after an episode of
Hepatology Research 2012
hypotension or shock, with the predominance of AST
over ALT, along with GGT under 100 IU/L, and AST and
ALT values decreasing rapidly in a few days. Liver injury
outside of the criteria of shock liver was classified as
either cholestatic or hepatocellular according to the fol-
lowing definitions. First, activities of ALT and GGT were
expressed as multiples of their upper limits of normal
(ULN). The ratio of ALT activity to GGT activity, namely,
(ALT/ULN) : (GGT/ULN), was defined as the R ratio.
When either the ALT value or the GGT value was under
the ULN, the ULN was substituted as the value. The ULN
of ALT and GGT were 40 IU/L and 50 IU/L, respectively,
in our hospital. Liver injury was designated cholestatic
when there was an increase in GGT above 50 and the R
ratio was 2 or lower. It was designated hepatocellular
when there was an increase in ALT above 40 IU/L and
the R ratio was above 2. Sepsis-associated liver injury
was further divided into “with jaundice” when T.Bil was
3.0 mg/dL or greater, and “without jaundice” when T.Bil
was under 3.0 mg/dL.
Estimation of prognosis
In order to estimate prognosis, the condition on dis-
charge was classified into five categories: “recovered”,
“improved”, “unchanged”, “worsened” and “died”.
Recovered and improved were defined as “good prog-
nosis”, and unchanged, worsened and died were defined
as “poor prognosis”. The primary end-point was “the
poor prognosis ratio”, defined as the proportion of
patients with a poor prognosis.
Statistical analysis
Parameters represented by continuous variables were
expressed as the median and the range (minimum–
maximum). Parameters were compared using the
Mann–Whitney U-test for continuous variables and
using the c2-test for categorical data. A P-value of less
than 0.05 was considered statistically significant. Statis-
tical analysis was performed with JMP software ver.
5.01J (SAS Institute, Cary, NC, USA).
RESULTS
Study population and demographics
T HE DEMOGRAPHICS OF the 588 subjects eligible
for this study are shown in Table 1. All patients were
Japanese, comprising 342 men and 246 women. Their
age range was 1–101 years, with a median of 68 years
and a bimodal distribution of infants and the elderly
of 65–90 years (Fig. 1). The median (minimum–
Sepsis-associated liver injury 3
maximum) serum T.Bil, AST, ALT and GGT were
0.8 mg/dL (0.1–45.9), 37 IU/L (2–11270), 24.5 IU/L
(2–3208) and 30 IU/L (1–1857), respectively. The main
etiology of sepsis, namely, the original focus of infec-
tion, included various diseases, of which the major ones
were pneumonia (including mediastinitis) (26.0%),
urinary tract infection (acute pyelonephritis in main)
(10.7%), acute upper air tract infection mainly in
infants (pharyngitis, tonsillitis, laryngitis, and sinusitis)
(9.0%), bacterial colitis (9.0%), bacterial skin infection
(such as cellulitis and decubitus in bedridden patients)
(7.7%) and acute obstructive suppurative cholangitis
(6.8%). As for background physical conditions, sepsis
complicated malignant neoplasms, diabetes mellitus,
diseases of the nervous system such as cerebral vascular
diseases, diseases of the circulatory system, chronic renal
failure and diseases of the respiratory system in 11.9%,
10.2%, 9.0%, 8.5%, 4.8% and 2.7% of the patients,
respectively.
Incidence and classification of liver injury
All subjects (Fig. 2)
Among the total of 588 patients, 139 belonged to the
sepsis-not-associated liver injury group, comprising 19
patients with alcoholic liver disease, three with HBV-
related liver disease, 18 with HCV-related liver disease,
21 with drug-induced liver injury, 43 with extrahepatic
bile duct and gallbladder disease, 14 with non-alcoholic
fatty liver disease, six with rhabdomyolysis, and 15 with
others including liver abscess (n = 6), metastatic liver
cancer (n = 4), autoimmune hepatitis (n = 2), chronic
graft-versus-host disease after blood stem cell transplan-
tation for leukemia (n = 1), type 1 glycogen storage
disease (n = 1) and a case of unknown etiology (n = 1).
Among 449 patients outside of the sepsis-not-associated
liver injury group, 293 patients (65.3%) belonged to
the normal liver function group, and the remaining
156 patients (34.7%) were complicated with sepsis-
associated liver injury. The disease types of liver injury
among the 156 patients in the sepsis-associated liver
injury group included cholestatic in 75 patients
(48.1%), hepatocellular in 34 patients (21.8%) and
shock liver in 47 patients (30.1%).
Subjects aged 39 years or younger, and
those aged 40 years or older (Fig. 3)
Considering the bimodal age distribution, the subjects
aged 39 years or younger (n = 178) were analyzed sepa-
rately from those aged 40 years or older (n = 410).
Among the 167 patients aged 39 years or younger
© 2012 The Japan Society of Hepatology
4 H. Kobashi et al. Hepatology Research 2012

Table 1 Demographics of study population

Total number 588
Male/female‡ (proportion, %, of male) 342/246 (58.2)
Age (years)† 68 (1–101)
Liver function test† T.Bil, mg/dL (range) 0.8 (0.1–45.9)
AST, IU/L (range) 37 (2–11 270)
ALT, IU/L (range) 24.5 (2–3208)
GGT, IU/L (range) 30 (1–1857)
Main etiology of sepsis‡ Pneumonia 153 (26.0)
Urinary tract infection 63 (10.7)
Pharyngitis, tonsillitis, laryngitis and sinusitis 53 (9.0)
Bacterial colitis 53 (9.0)
Cellulitis and decubitus 45 (7.7)
Acute obstructive suppurative cholangitis 40 (6.8)
Infectious arthritis and spondylitis 33 (5.6)
Infectious endocarditis 32 (5.4)
Panperitonitis 29 (4.9)
Intestinal wall necrosis 23 (3.9)
Meningitis 10 (1.7)
Liver abscess 10 (1.7)
Burn 7 (1.2)
Pelvic inflammatory disease 5 (0.9)
Immunodeficiency due to leukemia 5 (0.9)
Retroperitoneal abscess 3 (0.5)
Pelvic and femoral bone fracture 2 (0.3)
Others 2 (0.3)
Unknown 20 (3.4)
Background‡ Malignant neoplasms 70 (11.9)
Diabetes mellitus 60 (10.2)
Diseases of the nervous system 53 (9.0)
Diseases of the circulatory system 50 (8.5)
Chronic renal failure 28 (4.8)
Diseases of the respiratory system 16 (2.7)

†Values are median (range).

‡Values are number (proportion, %) of patients.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, g-glutamyl transpeptidase; T.Bil, total bilirubin.

outside of the sepsis-not-associated liver injury group,
18 patients (10.8%) were complicated with sepsis-
associated liver injury. Meanwhile, among the 282
patients aged 40 years or older outside of the sepsis-not-
associated liver injury group, 138 patients (48.9%) were
complicated with sepsis-associated liver injury. The pro-
portion of disease types was cholestatic, hepatocellular
and shock liver in 22.2%, 66.6% and 11.1%, respec-
tively, in the subjects aged 39 years or younger. Mean-
while, the types were 51.5%, 15.9% and 32.6%,
respectively, in the subjects aged 40 years or older.
Clinical aspect of sepsis-associated
liver injury
The onset of sepsis-associated liver injury was at day 0 of
admission in 91 out of 156 patients (58.3%), days 1–6
after admission in 39 (25.0%), days 7–30 in 19 (12.2%)
and days 31 or afterwards in eight (5.1%) (Fig. 4). The
median ages were 27, 68, 52 and 70 years in the normal
liver function, cholestatic, hepatocellular and shock
liver groups, respectively, with significant differences
among the four groups (P < 0.0001) (Fig. 5a). The inci-
dence of sepsis-associated liver injury by age segment
was 9.9% at ages 1–15 years, 37.4% at ages 16–60,
60.2% at ages 61–75 and 42.2% at ages 76 and older,
indicating significantly higher incidences in older age
segments (P < 0.0001) (Fig. 5b). It was significantly
(P < 0.001) higher in those aged 61 years or older
(49.8%) than in those aged 60 years or younger
(17.0%).
The incidence of sepsis-associated liver injury was sig-
nificantly (P < 0.0001) higher in males (42.0%) than in

© 2012 The Japan Society of Hepatology

Hepatology Research 2012 Sepsis-associated liver injury 5

(number) females (26.2%). The proportions of males were 70.7%,

61.8% and 59.6% in the cholestatic, hepatocellular and
100 shock liver groups, respectively; these percentages were
significantly higher than those in the normal liver func-
tion group (48.1%; P = 0.0026) (Fig. 6a). The propor-
75
tions were 75.0%, 75.0% and 100% in the cholestatic,
hepatocellular and shock liver groups, respectively, in
50 the subjects aged 39 years or younger. Meanwhile, they
were 70.4%, 54.6% and 57.8% in the cholestatic, hepa-
tocellular and shock liver groups, respectively, in the
25 subjects aged 40 years or older (Fig. 6b,c).
The proportions of patients with jaundice, namely,
T.Bil of 3.0 mg/dL or greater, were 35 out of 156 patients
0 10 20 30 40 50 60 70 80 90 100 (22.4%), 25 out of 75 (33.3%), six out of 34 (17.6%),
(years) and four out of 47 (8.5%) patients in the sepsis-
associated liver injury, cholestatic, hepatocellular and
Figure 1 Age distribution of the all subjects with sepsis
(n = 588). Age was 68 years in median, ranging 1–101 years,
shock liver groups, respectively, with significant differ-
with a bimodal distribution of infants and the elderly of ences (P < 0.0001) (Fig. 7).
65–90 years.

Sepsis (N = 588)

Sepsis–Not–associated liver injury ( N = 139)

Alcoholic liver disease (N = 19)

HBV–related liver disease (N = 3)
N = 449 HCV–related liver disease (N = 18)
Drug–induced liver injury (N = 21)
Extrahepatic bile duct and gallbladder disease (N = 43)
Non–alcoholic fatty liver disease (N = 14)
Rhabdomyolysis (N = 6)
Others (N = 15)

65.3% 34.7%

Normal liver function Sepsis–associated liver injury

(N = 293) (N = 156)

48.1% 21.8% 30.1%

Cholestatic (N = 75) Hepatocellular (N = 34) Shock liver (N = 47)

Figure 2 Overview of classification of all subjects (n = 588). At first, 139 patients complicated with “sepsis-not-associated liver
injury”, namely, liver injury due to primary hepatobiliary diseases, were excluded. Among the remaining 449 subjects, 293 (65.3%)
were of the “normal liver function” group and 156 (34.7%) were of the “sepsis-associated liver injury” group, comprising 75
(48.1%) in the “cholestatic” group, 34 (21.8%) in the “hepatocellular” and 47 (30.1%) in the “shock liver”. HBV, hepatitis B virus;
HCV, hepatitis C virus.

© 2012 The Japan Society of Hepatology

6 H. Kobashi et al. Hepatology Research 2012

Sepsis (N = 588)

Aged ≤ 39 (N = 178) Aged ≥ 40 (N = 410)

Sepsis–Not–associated Sepsis–Not–associated liver injury (N = 128)

liver injury (N = 11)
Alcoholic liver disease (N = 1)
Drug–induced liver injury (N = 5)
Extrahepatic bile duct
and gallbladder disease (N = 1)
Non–alcoholic fatty liver disease (N = 1)
Others (N =3)
Alcoholic liver disease (N = 18)
HBV–related liver disease (N= 3)
HCV–related liver disease (N = 18)
Drug–induced liver injury (N = 16)
N = 167 N = 282 Extrahepatic bile duct
and gallbladder disease (N = 42)
Non–alcoholic fatty liver disease (N = 13)
Rhabdomyolysis (N = 6)
Others (N = 12)

89.2% 10.8% 51.1% 48.9%

Normal liver Sepsis–associated Normal liver Sepsis–associated liver

function (N = 149) liver injury (N = 18) function (N = 144) injury (N = 138)

22.2% 66.6% 11.1% 51.5% 15.9% 32.6%

Cholestatic Hepatocellular Shock liver Cholestatic Hepatocellular Shock liver
(N = 4) (N = 12) (N = 2) (N = 71) (N = 22) (N = 45)

Figure 3 Overview of subjects aged 39 years or younger and those aged 40 years or older. Among the 167 patients aged 39 years
or younger outside of the “sepsis-not-associated liver injury” group, 18 patients (10.8%) were complicated with “sepsis-associated
liver injury”. Meanwhile, among the 282 patients aged 40 years or older outside of the sepsis-not-associated liver injury group, 138
patients (48.9%) were complicated with “sepsis-associated liver injury”. The proportion of disease types was “cholestatic”,
“hepatocellular” and “shock liver” in 22.2%, 66.6% and 11.1%, respectively, in the subjects aged 39 years or younger. Meanwhile,
the types were 51.5%, 15.9% and 32.6%, respectively, in the subjects aged 40 years or older. HBV, hepatitis B virus; HCV, hepatitis
C virus.

In the subjects aged 40 years or older, the proportions Prognosis

of patients who developed jaundice were 35.2% (25/
71), 27.3% (6/22) and 8.9% (4/45) in the cholestatic,
hepatocellular and shock liver groups, respectively. Of
the subjects aged 39 years or younger, however, none
developed jaundice in the cholestatic (n = 4), “hepato-
cellular” (n = 12) and shock liver (n = 2) groups.
The incidence of sepsis-associated liver injury was
almost equivalent among the etiologies of sepsis, yet it
was slightly higher in the patients with opportunistic
infection in patients with immunodeficiency due to
conditions including leukemia, retroperitoneal abscess,
extensive burn, pelvic and femoral bone fracture, and
panperitonitis (Fig. 8).
The poor prognosis ratio, namely, the proportion of the
patients who died or whose condition had worsened or
was unchanged, was 29.6% (133/449) in total. The poor
prognosis ratios were 2.0%, 25.5%, 44.7% and 50.0% in
the patients aged 1–15, 16–60, 61–75 and 76 years or
older, respectively (P < 0.0001) (Fig. 9a). It was 47.7%
(116/243) in the elderly aged 61 years or older. Regard-
ing sex, the poor prognosis ratios were 37.5% in males
and 20.4% in females, with a significant difference
between sexes (P < 0.0001) (Fig. 9b).
The poor prognosis ratio was 50.6% in the patients
with sepsis-associated liver injury. As for the disease

© 2012 The Japan Society of Hepatology

Hepatology Research 2012 Sepsis-associated liver injury 7

100 (5/149), 0% (0/4), 0% (0/12) and 50% (1/2) in the

91
normal liver function, cholestatic, hepatocellular and
80 shock liver groups, respectively. In the subjects aged
40 years or older, however, they were 45.4% (127/282 in
60 total) and 34.0% (49/144), 50.7% (36/71), 59.1% (13/
Number

22) and 64.4% (29 out of 45) in the normal liver func-
40 39
tion, cholestatic, hepatocellular and shock liver groups,
respectively.
20 19
The poor prognosis ratios were 68.6% in the patients
8
with jaundice and 45.5% in those without jaundice,
0 with a significant difference (P < 0.0001) (Fig. 10b). In
0 1~6 7~30 31~
Days detail, the poor prognosis ratio was higher in the shock
liver patients without jaundice, the cholestatic patients
Figure 4 Onset of sepsis-associated liver injury. Onset of
with jaundice and the hepatocellular patients with jaun-
sepsis-associated liver injury was at day 0 of admission in 91
dice (P < 0.0001) (Fig. 11).
out of 156 patients (58.3%), days 1–6 after admission in 39
(25.0%), days 7–30 in 19 (12.2%) and day 31 or afterwards in
eight (5.1%).
DISCUSSION

type, the poor prognosis ratios were 48.0%, 38.2% and

62.8% in the cholestatic, hepatocellular and shock liver
groups, respectively, which were significantly higher
than the 18.4% of the normal liver function group
(P < 0.0001) (Fig. 10a).
In the subjects aged 39 years or younger, the poor
prognosis ratios were 3.6% (6/167) in total, and 3.4%
T HE MECHANISMS OF sepsis-associated liver injury
can be divided into primary and secondary hepatic
dysfunctions.6 Primary dysfunctions include hypoxic
liver damage due to shock and resuscitation.7,8 Second-
ary include hepatocyte damage caused by tissue necrosis
factor-a; interleukin (IL)-1, IL-6 and IL-12; and reactive
oxygen products6–10 released by Kupffer cells activated
by endotoxin derived from Gram-negative bacteria, as
well as lipoprotein and teichoic acid derived from

(a) (b)

Age p < 0.0001 p < 0.0001

110
100%
100
90
80% 41
80
81
70 35
60 60%
136
50
40 40%
30 62
20 (60.2%) 59
20% 20
10 15 (37.4%) (42.2%)
0 (9.9%)
0%
Normal Cholestatic Hepatocellular Shock
liver function liver 1–15 16–60 61–75 76– (Age)

Figure 5 (a) Median ages of the patients were 27, 68, 52 and 70 years in the “normal liver function”, “cholestatic”, “hepatocellular”
and “shock liver” groups (P < 0.0001), respectively. (b) Incidence of sepsis-associated liver injury by age segment was 9.9% at age
1–15, 37.4% at age 16–60, 60.2% at age 61–75 and 42.2% at age 76 years and older, respectively, indicating significantly higher
incidence in older age segment (P < 0.0001). It was significantly (P < 0.001) higher in those aged 61 years or older (49.8%) than
in those aged 60 years or younger (17.0%).

© 2012 The Japan Society of Hepatology

8 H. Kobashi et al. Hepatology Research 2012

(a) (b)

p = 0.0026 p = 0.123
100% 100% 0

22 1 3
80% 13 19 80%
152 72

60% 60%
2
(100%)
40% 3 9
40% 53
21 (75.0%) (75.0%)
(70.7%) 28 77
141 (61.8%) (59.6%) (51.7%)
20%
20% (48.1%)

0%
0%
Normal Cholestatic Hepatocellular Shock
Normal Cholestatic Hepatocellular Shock
liver function liver
liver function liver

(c)

p = 0.0036
100%

21
80% 10 19
80

60%

40% 50
(70.4%) 12 26
64 (54.6%) (57.8%)
20% (44.4%)

0%
Normal Cholestatic Hepatocellular Shock
liver function liver

Figure 6 (a) Proportion of male sex was 70.7%, 61.8% and 59.6% in the “cholestatic”, “hepatocellular” and “shock liver” groups,
respectively, and significantly higher than that (48.1%) in the “normal liver function” group (P = 0.0026). (b) Proportion of male
sex was 75.0%, 75.0% and 100% in the cholestatic, hepatocellular and shock liver groups, respectively, in the subjects aged 39 years
or younger. (c) Proportion of male sex was 70.4%, 54.6% and 57.8% in the cholestatic, hepatocellular and shock liver groups,
respectively, in the subjects aged 40 years or older. , Female; , male.

Gram-positive bacteria. Hepatocyte damage is also
induced by protease and reactive oxygen radicals
released by neutrophils, which are recruited into the
sinus by leukotriene B4 (LTB4) released by Kupffer
cells.11 Endotoxin also causes a dysfunction of bilirubin
or bile acid transporters, such as organic anion tran-
sport proteins (OATP), multidrug-resistance-associated
protein (MRP2), the bile salt export pump (BSEP),
multiple drug resistance 1 transporter (MDR-1),
Na-K-ATPase and sodium-dependent taurocholate co-
transporter (NTCP). Sepsis-associated hyperbilirubine-
mia or cholestasis occurs by the dysfunction of these
transporters.12,13 Thus, liver damage can be induced by a
variety of mechanisms under the condition of sepsis.
The time of onset of sepsis-associated liver injury is an
important issue. In this study, liver function was tested

© 2012 The Japan Society of Hepatology

Hepatology Research 2012 Sepsis-associated liver injury 9

(n) precisely, because the span from the onset of sepsis to

300 293
admission could differ individually. This is considered a
limitation of a retrospective study. However, it seems
250
definite that sepsis-associated liver injury is more likely
200 to develop at a very early phase of the disease course of
156 sepsis. In some cases, the diagnosis of sepsis was con-
150
35 p < 0.0001 firmed after the development of liver injury. At least, it is
an important result of this study that detecting abnor-
100 75
121 malities in the liver function test may contribute to an
25 34 47
50 4 early diagnosis of sepsis.
50 6 43 The reason why it is difficult to diagnose sepsis-
28
0 associated liver injury is that there is a lack of specific
Normal liver Sepsis– Cholestatic Hepatocellular Shock
function associated liver diagnostic markers. In other words, it can be confirmed
liver injury only by ruling out all other possible hepatobiliary dis-
Figure 7 Incidence of jaundice between disease type of sepsis- eases. In the present study, the diagnosis of sepsis-
associated liver injury (n = 449). Incidence of jaundice with associated liver injury was confirmed by carefully
total bilirubin of 3.0 mg/dL or greater was 35 out of 156 excluding all other possible etiologies in each case. Espe-
patients (22.4%) in the “sepsis-associated liver injury” group, cially, drug-induced liver injury was the most carefully
including 25 out of 75 (33.3%) in the “cholestatic”, six out of ruled out, as follows. First, each patient’s drug history was
34 (17.6%) in the “hepatocellular” and four out of 47 (8.5%) researched carefully. Second, drug-induced liver injury
in the “shock liver” groups, respectively, with significant dif- was ruled out based on the documented diagnostic crite-
ference (P < 0.0001). , With jaundice; , without jaundice.
ria.5 Third, in most cases, sepsis-associated liver injury
was already present at admission when specific medica-
tion had not yet been started, or it developed within
at admission and at least three times per week after- 1 week, an insufficient span of drug sensitization for the
wards, in most cases. In the majority of subjects, sepsis- development of drug-induced liver injury. Fourth, sepsis-
associated liver injury developed at an early phase of associated liver injury resolved in parallel with the
sepsis. It was already present at admission in 58.3%, and remission of sepsis in all cases with a good prognosis,
it developed between day 1 and day 6 in 25.0% of the specifically a prognosis of recovered or improved.
patients with sepsis-associated liver injury. In some The incidence of sepsis-related liver injury was 34.7%
cases, it was difficult to determine the time of onset in total, except for sepsis-not-associated liver injury. As

Immunodeficiency due to leukemia (N =2)

Retroperitoneal abscess (N = 3)
Burn (N = 5)
Pelvic and femoral bone fracture (N = 2)
Panperitonitis (N = 24)
Pneumonia (N = 119)
Meningitis (N = 7)
Intestinal wall necrosis (N = 20)
Infectious arthritis and spondylitis (N = 26)
Urinary tract infection (N = 49)
Infectious endocarditis (N = 28)
Cellulitis and decubitus (N = 40)
Pelvic inflammatory disease (N = 5)
Bacterial colitis (N = 48)
Pharyngitis, tonsilitis, laryngitis, and sinusitis (N = 50)
0% 20% 40% 60% 80% 100%
Figure 8 Etiology of sepsis and incidence of sepsis-associated liver injury. The incidence of complication of sepsis-associated liver
injury was not significantly different equally among the focus lesions of sepsis, yet it was slightly higher in the patients with
opportunistic infection in patients with immunodeficiency due to conditions including leukemia, retroperitoneal abscess, burn,
pelvic and femoral bone fracture, and panperitonitis. , Normal liver function; , cholestasis; , hepato cellular; , shock liver.

© 2012 The Japan Society of Hepatology

10 H. Kobashi et al. Hepatology Research 2012

(a) (b)
p < 0.0001 p < 0.0001

100% 100%

80% 80%

60% 60%

40% 40%

50.0%
44.7% 20% 37.5%
20%
25.5% 20.4%
2.0%
0%
0%
Age 1 – 15 Age 16 – 60 Age 61 – 75 Age 76 – Male Female
(N = 151) (N = 55) (N = 103) (N = 140)

Figure 9 Age, sex and prognosis (total n = 449). (a) “Poor prognosis ratio” was 2.0%, 25.5%, 44.7% and 50.0%, in the patients
aged 1–15, 16–60, 61–75 and 76 years and older, respectively, and was significantly (P < 0.0001) higher in the elderly aged over
60 years. (b) Poor prognosis ratio was 37.5% in males and 20.4% in females, with a significant difference between sexes
(P < 0.0001). , Good prognosis; , poor prognosis.

(a) (b)
p < 0.0001 p < 0.0001
100% 100%

80% 80%

60% 60%

40% 40%
68.6%
63.8%
48.0% 45.3%
20% 20%
33.2%
18.4%
18.4%
0%
0% Normal liver function Sepsis–associated Sepsis–associated
Normal liver Cholestatic Hepatocellular Shock liver (N = 283) liver injury without liver injury with
function (N = 293) (N = 75) (N = 34) (N = 47) jaundice (N = 121) jaundice (N = 35)
Figure 10 Types of sepsis-associated liver injury and prognosis. (a) “Poor prognosis ratio” was 48.0%, 38.2% and 62.8% in the
“cholestatic”, “hepatocellular” and “shock liver” groups, respectively, and it was significantly higher in the patients with sepsis-
associated liver injury than in the “normal liver function” group (18.4%; P < 0.0001). (b) “Poor prognosis ratio” was 68.6% in the
patients with jaundice and 45.5% in those without jaundice, with a significant difference (P < 0.0001). , Good prognosis; , poor
prognosis.

© 2012 The Japan Society of Hepatology

Hepatology Research 2012 Sepsis-associated liver injury 11

100% p < 0.0001

80%

60%

83.3%
40% 72.0%
67.4%

20% 36.0%
28.6% 25.0%
18.4%
0%

)
)

)
6)
)

4)
3)

28
50

43
25
29

=
=
=

=
=

N
=

(N
(N

(N
N

)(

)(
(N

)(

ce

ce
e)
e)

e)
ce
ry

di

di
ic
ic

ic
di
ju

nd
nd

nd
un

un
Figure 11 Sepsis-associated liver injury,

un
in

au
au

au
ja

ja
ja
er

ith

ith
tj
tj

tj
with or without jaundice, and progno-
liv

ith

ou
ou

ou
w

(w
(w
o

r(
ith
ith

ith
sis. “Poor prognosis ratio” was higher in
N

er
la
tic

w
(w

(w

liv
lu
r(
shock liver, cholestatic with jaundice ta

el
ic

er

k
la
s

oc
at

oc

liv
le

lu
st

and hepatocellular with jaundice

Sh
ho

at
el

k
le

oc
ep
oc
C
ho

(P < 0.0001). , Good prognosis; ,

Sh
at

H
C

ep

poor prognosis.
H

for patient background, patients aged 61 years or older
were prone to sepsis-associated liver injury for all
disease types, whereas it was rare in patients aged
15–60 years. This tendency was presumably due to
age-related host immunological potency. In addition,
underlying conditions such as malignant neoplasms,
diabetes mellitus and cerebrovascular diseases might be
potent risk factors in the elderly. As for sex, the inci-
dence of sepsis-associated liver injury was significantly
higher in male patients than in females, although
no report has described the difference between sexes.
There was no definite relationship between the etiology
of sepsis and a tendency toward liver injury or to
jaundice.
In this study, we thoroughly researched the patterns
and courses of liver function test abnormality, which
may be related to pathophysiological mechanisms in
sepsis-associated liver injury. From the results, we
attempted to propose a prototype of a comprehensive
disease type classification for sepsis-associated liver
injury, consisting of cholestatic liver injury, hepatocel-
lular injury and shock liver (hypoxic liver injury), with
or without jaundice (hyperbilirubinemia), respectively.
The first two categories, cholestasis and hepatocellular,
were defined based on the documented criteria for drug-
induced liver injury.5,14 We adopted GGT instead of ALP
as a marker of cholestasis, because of the high values of
ALP due to physiological alteration in children and
osteoporosis in the elderly. For the sake of simplicity, a
mixed-type category was not created in this study. As a
result, the disease type of sepsis-associated liver injury
was cholestatic in 48.1%, hepatocellular in 21.8% and
shock liver in 30.1% of the patients. The incidence of
jaundice was 22.4% in the sepsis-associated liver injury
group, including 33.3% in the cholestatic, 17.6% in the
hepatocellular and 8.5% in the shock liver groups. In
sepsis-associated “cholestasis with jaundice” patients,
the elevation of conjugated bilirubin with dispropor-
tionately low elevations of AST, ALT and biliary
enzymes was characteristic, as previously reported.12,13
In shock liver, AST and ALT were rapidly and markedly
elevated, with early superiority of AST over ALT,
minimal elevation of GGT, and a rapid decrease in a few
days once the underlying course was corrected; these
patterns were also reported previously.15
In some cases in the cholestatic group, jaundice was
experienced at an early stage of sepsis even in the
absence of fever or leukocytosis. It has been recom-
mended that such jaundice should be considered an
early warning sign of sepsis.16,17 In previous papers, the
incidences of jaundice were reported to be 40% in
patients in an intensive care unit18 and 34% in sepsis
patients.17 In another report, bacterial infection was
responsible for up to 20% of cases of jaundice.19
However, the number of subjects in all of those previous
studies was small, no more than 100 patients. The
present study is, although retrospective, a rather large-
scale investigation of sepsis-associated liver injury. In

© 2012 The Japan Society of Hepatology

12 H. Kobashi et al.
the present study, 35 out of 449 patients (7.8%) had
hyperbilirubinemia of 3.0 mg or greater.
As for the prognosis of patients with sepsis-associated
liver injury, it was reported previously that the develop-
ment of jaundice in an intensive care unit led to a poor
prognosis.20 In another report, the overall mortality rate
of the septic patients complicated with jaundice was
61%.17 Elsewhere, it was reported that there were no
significant differences in bilirubin and liver enzyme
levels between survivors and non-survivors.21 In the
present study, on the other hand, the poor prognosis
ratio was significantly (P < 0.0001) higher in patients
with sepsis-associated liver injury than those in the
normal liver function group. In this study, prognosis
varied according to age, sex and disease type. The poor
prognosis ratio, namely, the proportion of patients
whose condition at discharge was unchanged, worsened
or died, was significantly higher in those over 60 years
of age than in patients aged 1–55 or 16–60. In addition,
the ratio was greater in males than in females. The
reason for the higher incidence and mortality of sepsis-
associated liver injury in males is unknown. It might be
due to a difference in the manners of immunological
reaction, such as the magnitude of release of cytokines
or chemical mediators from Kupffer cells, in response to
endotoxemia. The poor prognosis ratios were higher in
the patients with sepsis-associated liver injury than
normal liver function group. In addition, it was signifi-
cantly higher in patients with jaundice than in those
without. However, hepatic failure is rare if the underly-
ing process is detected and adequately treated.12 The
elevated bilirubin and liver enzyme levels decrease
rapidly if background sepsis is adequately treated.
In conclusion, sepsis-associated liver injury, especially
septic jaundice, is an important factor in the clinical
course of sepsis, particularly for diagnosis and progno-
sis. Detection of liver injury may become a clue to an
early diagnosis of developing sepsis, as well as a sign of
poor prognosis in patients with sepsis.
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