Original Article

Yonago Acta Medica 2017;60:40–46

Serum Procalcitonin in Patients with Acute Liver Failure
Takaaki Sugihara, Masahiko Koda, Toshiaki Okamoto, Kenichi Miyoshi, Tomomitsu Matono, Kenji Oyama,
Keiko Hosho, Jun-ichi Okano and Hajime Isomoto

Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University
Faculty of Medicine, Yonago 683-8504, Japan

ABSTRACT

Conclusion Serum PCT level was significantly higher
in patients with ALF.

Background Procalcitonin (PCT) is a known diagnos-

tic marker of bacterial infection. There are no previous
reports of PCT concerning acute liver failure (ALF). We
evaluated the clinical value of serum PCT levels in patients with ALF.
Methods Forty-four patients with acute hepatitis (19men and 25 women; median age, 40 years; range, 20–79
years) were retrospectively enrolled from January 2001
and June 2015. PCT levels were measured by saved
serum samples obtained within 3 days after admission.
ALF was defined as prothrombin time (PT) < 40% regardless of hepatic encephalopathy.
Results Serum PCT levels were significantly higher inthe patients with ALF (n = 16) than in those with nonALF (n = 28) [0.25 (0.13–2.66) ng/mL vs. 0.165 (0.03–
1.08), P = 0.00967]. Creatinine, total bilirubin, anddirect bilirubin were positively correlated, and PT was
negatively correlated with PCT. Receiver operating characteristic curve analysis showed an area under the curveof 0.74 for detecting ALF. With a PCT cut-off value of
0.5 ng/mL, the presence of ALF could be demonstrated
with low sensitivity (37.5%) and high specificity (96.5%)
with high positive (85.7%) and negative (72.9%) predictive value. Multivariate analysis showed that PCT wasan independent factor associated with the presence of
ALF. The cumulative survival rate was also significantly
lower in patients with PCT ≥ 0.5 ng/mL (P = 0.0314), but
it was not an independent prognostic factor.

Key words

acute hepatitis; acute liver failure; fulminant hepatitis; procalcitonin
Acute liver failure (ALF), especially fulminant hepatitis
is a severe liver disorder with high mortality.1 Despiteadvances in intensive care, the mortality rate remains
high.2 Liver transplantation (LT) is regarded as the standard therapy for patients with ALF, and the cumulative
survival rates at 1, 5, and 10 years after LT in Japan were79%, 74%, and 73%, respectively.3 For early predictionof disease severity, it is critically important for patientsto receive LT. Scoring systems using multiple factors [age;duration from onset to hepatic encephalopathy; creatinine (Cre), bilirubin, and cholinesterase levels; platelet
counts; prothrombin time (PT); arterial blood pH; andliver atrophy] have been reported to be useful for predicting the severity and prognosis of ALF.4–9 Moreover,factor V levels, interleukin-10, tumor necrosis factor-α,
serum Gc-globulin, and M30 have also been identified
to predict the prognosis of ALF as single prognostic factors.10–13
Procalcitonin (PCT), the prototype of a hormokine
mediator, is released from all cell types throughout the
body by microbial infections and is regarded as a reliable
marker of sepsis.14, 15 Serum PCT levels have also beenshown to be higher in cirrhotic patients with bacterial
infection than in those without infection.16–20 However,no previous reports have evaluated PCT as a biomarker
of ALF. This study aimed to evaluate the clinical valueof serum PCT levels in patients with ALF.

Corresponding author: Takaaki Sugihara, MD, PhD
sugitaka@med.tottori-u.ac.jp
Received 2016 December 12
Accepted 2017 January 18
Abbreviations: AFP, alpha-fetoprotein; AIH, autoimmune hepatitis;
ALF, acute liver failure; ALP, alkaline phosphatase; ALT, alanine
aminotransferase; anti-HBc, antibody to hepatitis core antigen;
AST, aminotransferase; BT, bacterial translocation; Cre, creatinine;
CRP, C-reactive protein; CMV, cytomegalovirus; DILI, drug-induced liver injury; DLBCL, diffuse large B cell lymphoma; EBV,
Epstein-Barr virus; GGT, gamma-glutamyl transpeptidase; HAV,
hepatitis A virus; HBeAg, hepatitis B envelop antigen; HbsAg,
hepatitis B surface antigen; HBV, hepatitis B viral; HCV, hepatitis
C virus; HE, hepatic encephalopathy; HEV, hepatitis E virus; HGF,
hepatocyte growth factor; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M; LT, liver transplantation;
PCT, procalcitonin; PT, prothrombin time; ROC, receiver operating
characteristic; SBP, spontaneous bacterial peritonitis

SUBJECTS AND METHODS
Subjects

Between January 2001 and June 2015, a total of 85 consecutive hospitalized patients with acute hepatitis in the
Department of Gastroenterology, Tottori Univeristy Hospital in Yonago were retrospectively evaluated. In thisstudy, we defined acute hepatitis as ALT of more than 1.5
times the upper normal limit (using 19IU/L for female
and 30IU/L for male) without underlying chronic liverdisease.21, 22 Chronic liver disease including cirrhosis
40Serum procalcitonin in acute liver failure

was diagnosed according to clinical, biochemical, and/or imaging findings. Patients with underlying chronic
liver disease, a history of alcoholism (ethanol consumption more than 40 g/day and longer than 25 years), anddrug-induced liver injury (DILI) were excluded from thestudy. All patients whose serum samples within 3 days
after admission were unavailable were excluded fromthe study. A total of 44 patients (19 men and 25 women;
median age, 40 years; range, 20–79 years) were enrolled.

used in order to determine the sensitivity and specificityof the serum PCT values for the detecting ALF in the
study population. Univariate and multivariate analyses
were performed using the multiple logistic regression
analysis method. The cumulative survival rate was calculated by the Kaplan-Meier method and significant differences between the two groups were calculated using
the log-rank test. All statistical analyses were performed
using StatFlex (Windows ver. 6.0; Artech, Osaka, Japan). Statistical significance was set at P < 0.05.

Definitions and examined items

RESULTSIn Japan, ALF is defined as percent PT < 40% regardless of hepatic encephalopathy (HE), and it is divided
into “ALF without HE” and “ALF with HE”.23 In thisstudy, all the HE were diagnosed after admission. All
the patients underwent blood biochemical examinations
including Cre, total and direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT),
alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), alpha-fetoprotein (AFP), PT, and C-reactive protein (CRP) within 24 h after hospitalization.
All the patients were also tested for immunoglobulin M(IgM) and G (IgG) antibody against hepatitis A virus(HAV), hepatitis B surface antigen (HBsAg), hepatitis
B envelop antigen (HBeAg), IgM antibody to hepatitis
core antigen (IgM anti-HBc), hepatitis B viral (HBV)DNA, hepatitis C virus (HCV) antibody, HCV-RNA,and immunoglobulin A (IgA) antibodies to hepatitis E
virus (HEV) using routine commercially available enzyme immune assays. IgM and IgG antibodies against
Epstein-Barr virus (EBV), herpes simplex virus, cytomegalovirus (CMV) were assayed. In all the patients,
systemic and focal bacterial infection was checked by
2 sets of blood culture, urine test, ultrasonography andcomputed tomography. Serum PCT levels were measured with an Electro Chemi Luminescence Immuno
Assay (BRAHMS PCT; Roche Diagnostics, Tokyo,
Japan) in their saved sera obtained within 3 days after
admission.

Patient background

Baseline characteristics of the patients are presented
in Table 1. Twenty-nine patients (66%) underwent liverbiopsy. The etiology of acute hepatitis included HBV
infection (n = 9), HCV infection (n = 3), CMV infection
Table 1. Characteristics of 44 patients with acutehepatitis
Male/Female
19:25
Age (years)
40 (20–79)
Etiology
Viral infection
18 (40.9%)
HBV
9
HCV
3
CMV
3
EBV
3
Autoimmune hepatitis
7 (15.9%)
Others*
8 (18.2%)
Indeterminate
11 (25%)
Acute liver failure
16 (36.4%)
with HE
6 (13.6%)
without HE
10 (22.7%)
Laboratory values
AST
1025(47–20490)
IU/L
ALT
884
(51–14510)
IU/L
ALP
503
(122–2706)
IU/L
GGT
186
(27–994)
IU/L
Total bilirubin
3.85(0.6–40.5)
IU/L
D/T ratio
0.55(0.11–0.73)
PT
59.4(5–116)%IgG
1603(836–3690)
mg/dL
Creatinine
0.7(0.41–6.68)
mg/dL
CRP
0.35
(0.04–20.11) mg/dL
AFP
4.9(0.1–191.6)
ng/mL
PCT
0.2
(0.03–2.66)
ng/mL*Other etiologies include Syphilis, Chlamydia, Mycoplasma, anddiffuse large B cell lymphoma. Data are expressed as median(range).
AFP, alpha-fetoprotein; ALP, alkaline phosphatase; ALT, alanine
aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; CMV, cytomegalovirus; D/T ratio, direct and total
bilirubin ratio; EBV, Epstein-Barr virus; GGT, gamma-glutamyltranspeptidase; HBV, hepatitis B virus; HCV, hepatitis C virus;
HE, hepatic encephalopathy; Ig, immunoglobulin; PCT, procalcitonin; PT, percent prothrombin time.

Ethical Considerations

The study protocol was approved by the Institutional
Review Board of our institute (No.1512A098) under theguidelines of the 1975 Declaration of Helsinki.
Statistical analysis

Data are expressed as median (range). Statistical analyses for significant differences among the groups were
performed using Mann-Whitney’s U test or the Kruskal-Wallis test. Correlations were calculated using Pearson’s product-moment correlation coefficient. Receiver
operating characteristic (ROC) curve analysis was also
41

T. Sugihara et al.

BA(ng/mL)**

3

Procalcitonin

Procalcitonin(ng/mL)3

2

P = 0.084

2

1

1

0

0
Non acute
Acuteliver failure liver failure

The others Acute liver failure
with HE(n = 28) (n = 16)(n = 38)(n = 6)

Fig. 1. Differences in serum PCT levels in acute hepatitis. A: The serum PCT levels were significantly higher in patients with ALF (n =16) than in those with non-ALF (n = 28) [0.25 (0.132.66) vs. 0.165 (0.03–1.08) ng/mL, P = 0.009]. **P < 0.01. B: relatively higher in ALF
with HE (n = 6) than the others (n = 38) [0.52 (0.13–2.66) vs. 0.19 (0.03–1.73) ng/mL, P = 0.084]. ALF, acute liver failure; HE, hepatic encephalopathy; PCT, procalcitonine.

1.0

1.0

PCT < 0.5ng/mL

Cumulative survival rate

Sensitivity

*

0.5

0

0.5

1.0

PCT > 0.5ng/mL

0.5

01-specificity

30

60

90

Days

Fig. 2. The ROC curve of serum PCT levels for detecting ALF.
The AUROC for serum PCT was 0.74 for detecting ALF in thecases of acute hepatitis on admission. ALF, acute liver failure;
AUROC, area under the receiver operator characteristic; PCT,
procalcitonine; ROC, receiver operating characteristic.

Fig. 3. Cumulative survival rate with a PCT cut-off level of 0.5 ng/
mL. The cumulative survival rate was significantly lower in thepatients with PCT ≥ 0.5 ng/mL (P = 0.031). *P < 0.05. PCT, procalcitonine.

42Serum procalcitonin in acute liver failure(n = 3), EBV infection (n = 3), autoimmune hepatitis (n =7), other etiology (n = 8) and indeterminate (n = 11). Tenpatients had ALF without HE and six patients had ALF
with HE. Four patients of “ALF with HE” died (one bysuicide) during the study period. One patient with HE
was not ALF since the HE was considered to be induced
by a disorder in the urea cycle. The main etiology of
ALF was HBV (43.8%). None of the patients were diagnosed with a systemic or focal bacterial infection. There
were no cases of spontaneous bacterial peritonitis (SBP).
Six patients received artificial liver support using hemodialysis, and 10 patients underwent plasma exchange
in addition to conventional supportive treatment. Sub-sequently, three patients died of hepatic failure and one
patient unfortunately committed suicide after recovery.
No patient received liver transplantation because of noavailable donor organs. There were no missing data oroutliers in obtained serum PCT.
Analysis of serum procalcitonin levels

Serum PCT levels were significantly higher in the patients with ALF (n = 16) than in those with non-ALF (n= 28) [0.25 (0.13–2.66) vs. 0.165 (0.03–1.08) ng/mL, P =0.00967] (Fig. 1A), and relatively higher in ALF with HE
than the others [0.52 (0.13–2.66) vs. 0.19 (0.03–1.73) ng/
mL, P = 0.084] (Fig. 1B). Creatinine, total bilirubin, anddirect bilirubin were positively and PT was negatively
correlated with PCT. (Table 2). The area under the ROC(AUROC) was 0.74 for detecting ALF on admission(Fig. 2). The cutoff value of 0.5 ng/mL for PCT showeda low sensitivity (37.5%) and a higher specificity (96.5%)
for detecting ALF on admission. The positive predictive
value (PPV) and negative predictive value (NPV) were
85.7% and 72.9%, respectively. We compared the clinical parameters between patients with low PCT (< 0.5 ng/mL) and those with high PCT (≥ 0.5 ng/mL). The prevalence of HE was significantly higher in the high PCTgroup than in the low PCT group. On the other hand,the serum GGT and PT levels were significantly lower
in the high PCT group than in the low PCT group (Table3). It is not surprising that the number of patients complicated with HE was greater in ALF group. The levelsof serum AST [589 (47–3016) vs. 1925 (154–24090), P =0.0011], ALT [639.5 (51–3612) vs. 2782 (141–14510), P =0.0004], total bilirubin [1.8 (4.3–5.8) vs. 10 (1.4–40.5), P= 0.0002], D/T ratio [0.39 (0.11–0.69) vs. 0.65 (0.3–0.73),

Table 2. Correlations between serum PCT levels andclinical/biochemical parameters
Patients (n = 44)r(95% CI)P valueAge (year)
0.1711(–0.133–0.445)
0.267
AST
0.171
(–0.133–0.445)
0.268
ALT
0.157
(–0.146–0.434)
0.307
ALP
–0.130(–0.411–0.173)
0.399
GGT
–0.161(–0.437–0.143)
0.297
Total bilirubin
0.454( 0.182–0.663)
0.002
Direct bilirubin
0.541( 0.288–0.724) < 0.001
D/T ratio
0.225(–0.081–0.492)
0.146
PT–0.3930(–0.618–0.109)
0.008
IgG
–0.1164(–0.406–0.194)
0.463
Creatinine
0.8078( 0.672–0.891) < 0.001
CRP
0.2528(–0.051–0.514)
0.102
AFP
0.1936(–0.160–0.503)
0.280
AFP, alpha-fetoprotein; ALP, alkaline phosphatase; ALT, alanine
aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; CRP, C-reactive protein; D/T ratio, direct and total
bilirubin ratio; GGT, gamma-glutamyl transpeptidase; Ig, immunoglobulin; PCT, procalcitonin; PT, percent prothrombin activity.

Table 3. Comparison of background between patients with low PCT and high PCT levels
PCT (ng/mL)< 0.5 (n = 36)≥ 0.5 (n = 8)

P value

Gender (male:female)
16:20
3:5
0.720
Age (year)
38 (20–79)
48 (22–71)
0.692
Etiology (viral:non-viral)
16:20
2:6
0.312
Hepatic encephalopathy (yes:no)
33:3
4:4
0.004
AST
(IU/L)
1030 (47–24090)
929 (254–15604)
0.503
ALT
(IU/L)
985 (51–9598)
676 (217–14510)
0.715
ALP
(IU/L)
521 (122–2706)
466 (275–617)
0.196
GGT
(IU/L)
189 (38–994)
94 (27–266)
0.037
Total bilirubin(mg/dL)3.05 (0.6–29.7)
7.15 (0.9–40.5)
0.385
D/T ratio
0.57 (0.11–0.73)
0.58 (0.27–0.71)
0.673
PT
(%)
69 (12–116)
28 (5–24)
0.011
Creatinine(mg/dL)0.69 (0.41–2.23)
0.74 (0.51–6.68)
0.308
CRP
(mg/dL)0.88 (0.04–20.11)
2.6 (0.23–14.66)
0.139
AFP
(ng/dL)
4.9 (0.1–83.4)
6.15 (0.7–191.6)
0.585
Data are expressed as median (range). AFP, alpha-fetoprotein; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate
aminotransferase; CRP, C-reactive protein; D/T ratio, direct and total bilirubin ratio; GGT, gamma-glutamyl transpeptidase; PCT, procalcitonin; PT, percent prothrombin activity.

43

T. Sugihara et al.
Table 4. Differences between non-ALF and ALF
Non-ALF (n = 28)

ALF (n = 16)

P value

Gender (male:female)
12:16
7:9
0.956
Age (year)
39 (20–79)
40 (22–71)
0.877
Etiology (viral:non-viral)
11:17
7:9
1.000
Hepatic encephalopathy (yes:no)
1:27
5:11
0.010
AST
(IU/L)
589 (47–3016)
1925 (154–24090)
0.001
ALT
(IU/L)
639.5 (51–3612)
2782 (141–14510)< 0.001
ALP(IU/L)
546 (122–2706)
465.5 (275–617)
0.089
GGT
(IU/L)
189 (38–994)
162.5 (27–613)
0.193
Total bilirubin(mg/dL)
1.8 (4.3–5.8)
10 (1.4–40.5)< 0.001
D/T ratio
0.39 (0.11–0.69)
0.65 (0.3–0.73)
0.013
Creatinine(mg/dL)
0.66 (0.41–1.17)
0.82 (0.41–6.68)
0.022
CRP
(mg/dL)0.89 (0.06–20.11)
1.3 (0.04–5.93)
0.450
AFP
(ng/dL)28.5 ( 0.1–56.7)
6.15 (0.7–191.6)
0.290
PCT
(ng/dL)0.165 (0.03–1.08)
0.22 (0.13–2.66)
0.008
Data are expressed as median (range). ALF, acute liver failure; ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase; D/T ratio, direct and total bilirubin ratio; CRP, C-reactive protein; AFP,
alpha-fetoprotein; PCT, procalcitonin.

Table 5. Multivariate analysis for detecting ALF on admission
Odds ratio

95% CI

P value

PCT(ng/dL)
52.15(1.08–2525.65)
0.046
AST >1000(IU/L)
1.50(0.09–24.21)
0.775
ALT >1000(IU/L)
5.97(0.35–101.39)
0.217
Total bilirubin(mg/dL)
1.08(0.92–1.27)
0.363
D/T ratio
6.37(0.01–4256.02)
0.577
Creatinine(mg/dL)
27.43(0.41–1855.89)
0.124
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; D/T ratio, direct and total bilirubin ratio; PCT,
procalcitonin.

P = 0.0132], Cre [0.66 (0.41–1.17) vs. 0.82 (0.41–6.68),
P = 0.022], and serum PCT [0.165 (0.03–1.08) vs. 0.22
(0.13–2.66), P = 0.0082], showed significant differences
between non-ALF and ALF patients (Table 4). Multiple
logistic regression analysis revealed PCT to be an independent factor for detecting ALF on admission (Table5). In this multiple regression analysis, HE was excluded
because it was not the factor on admission. The cumulative survival rate was significantly lower in patients with
PCT ≥ 0.5 ng/mL than in those with PCT < 0.5 ng/mL (P= 0.0314) (Fig. 3). However, multivariate analysis did notdemonstrate PCT as an independent prognostic factor.

evaluated serum PCT in acute hepatitis. Elefsiniotis etal.24 evaluated serum PCT levels in a small sample (n =13) of patients with acute icteric viral hepatitis (including
4 patients with acute exacerbation of chronic viral hepatitis), and indicated no remarkable elevation (0.37 ± 0.22
ng/mL) as compared with a group of decompensatedcirrhosis with culture-proven bacterial infection (9.8 ±16.8 ng/mL). Another report was a case presentation of
acute Q-fever granulomatous hepatitis.25 The hepatitis
was induced by bacterial (Coxiella brunetii) infection
and treated by antibiotics; the authors concluded that theserum PCT level was useful for monitoring the treatmentof bacterial hepatitis. In both these reports, serum PCTlevels were not evaluated in ALF cases. On the other
hand, some reports have evaluated serum PCT levels in
cirrhotic patients with chronic liver failure.16–20 In thesereports, the serum PCT levels were mainly evaluated for
detecting bacterial infection in cirrhosis, such as SBP induced by bacterial translocation (BT). No study has thus
far evaluated the clinical significance of serum PCT in

DISCUSSION
This study provided two novel findings. First, serum
PCT levels in patients with ALF were significantly higher than those in non-ALF patients. Second, this is thefirst report to demonstrate that the serum PCT level was
independently associated with ALF.
To our knowledge, only two reports have thus far
44

Serum procalcitonin in acute liver failure

ALF. The present study showed that serum PCT levels
in ALF patients were significantly higher than those in
non-ALF patients.
There were some patients with elevated CRP, however, none of the patients was diagnosed with focal andsystemic bacterial infection. There are only small number of reports mentioned about the relationship between
hepatitis and CRP. Wigmore SJ et al.26 indicated that theserum CRP concentration in patients with fulminant hepatic failure on the day of admission was high [6 (2.2–8.6)
mg/dL], and they thought it may have been stimulated
by pro-inflammatory cytokines. Atono Y et al.27 also
reported that CRP was markedly increased in the acutephase of acute hepatitis type A (1.34 ± 2.18mg/dL) and B(0.88 ± 0.78mg/dL). According to these reports, to someextent, serum CRP levels might be affected by acutehepatitis. Considering our four patients with higher CRP(≥ 5), their final diagnoses were autoimmune hepatitis(AIH) (CRP 5.93mg/dL), diffuse large B cell lymphoma(DLBCL) (CRP 7.06mg/dL) and two unknowns (CRP
14.7 and 20.1mg/dL). In the AIH case, the CRP gradually decreased from 5.93 to 1.83 mg/dL at two weeks ofadmission, and in DLBCL case, it also decreased gradually from 7.06 to 0.4 mg/dL at three weeks of admission.
Probably, these CRP levels might be affected by thesebackgrounds. On the other hand, one of the two patients with unknown cause was administered antibiotics
empirically, and the CRP level decreased from 14.7 to
2.4mg/dL at fourth day of admission. The other patientwith unknown cause was not administered any antibiotics, and the CRP decreased from 20.1 to 2.8 mg/dL atfourth day of admission. These two cases demonstrated
a similar clinical course in CRP levels regardless of antibiotics. There were no remarkable inflammatory backgrounds such as autoimmune diseases in these cases.
The dynamics of CRP in acute hepatitis with unknown
causes has still been remained unclear.
In the absence of bacterial infection, serum PCT levels were also reported to be elevated in cases of surgery,trauma, cardiogenic shock, severe pancreatitis, severe
renal and liver dysfunction (Child-Pugh C), and multiple
organ failure.28
In this study, we found the strong positive correlation between PCT and Cre. PCT has been reported to
predict the acute kidney injury complicated with infection or acute pancreatitis.29, 30 The reason may be due tothe plasma disappearance rate prolongation of PCT inrenal dysfunction.31 Renal dysfunction is also reported
frequently complicated with ALF.32 However, no previous reports demonstrated the relation between PCT andrenal dysfunction in ALF.
Although the mechanism for the PCT elevation in

ALF remains unknown, subsequent endotoxemia andsystemic inflammation may also play important roles in
PCT elevation. BT may be involved in high serum PCTlevels in ALF.33 Further study with a larger number ofpatients is needed to clarify these observations.
We selected serum PCT level of 0.5 ng/mL as an
optimal cut-off level for detecting ALF. This cut-off value showed high specificity but low sensitivity. Although
the cut-off value of 0.5 ng/mL is used for diagnosing
sepsis,28 an optimal cut-off value for ALF needs to bevalidated by further studies.
This is the first report to evaluate PCT in ALF.
However, this study is a retrospective study with a relatively small number of cases. Therefore, we could notdemonstrate PCT as a distinct predictive and prognostic biomarker for ALF with HE. To evaluate PCT as apredictive and prognostic marker for ALF with HE, ourfindings should be validated in a larger sample size witha prospective cohort.
In conclusion, serum PCT level was significantly
higher in patients with ALF following acute hepatitis.
PCT is expected to be an early predictive biomarker inacute hepatitis.
Acknowledgments: The authors would like to thank Yuki Yasunaka for supporting data collection.
The authors declare no conflict of interest.

REFERENCES
1 Bernal W, Wendon J. Acute liver failure. N Engl J Med.
2013;369:2525-34. DOI: 10.1056/NEJMra1208937. PMID:
24369077.
2 Bernal W, Lee WM, Wendon J, Larsen FS, Williams R.
Acute liver failure: A curable disease by 2024? J Hepatol.
2015;62:S112-20. DOI: 10.1016/j.jhep.2014.12.016. PMID:
25920080.
3 Yamashiki N, Sugawara Y, Tamura S, Nakayama N, Oketani
M, Umeshita K, et al. Outcomes after living donor liver transplantation for acute liver failure in Japan: results of a nationwide survey. Liver Transpl. 2012;18:1069-77. DOI: 10.1002/
lt.23469. PMID: 22577093.
4 O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early
indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97:439-45. PMID: 2490426.
5 Rossaro L, Chambers CC, Polson J, Bowlus CL, Hynan LS,
Fontana RJ, et al. Performance of MELD in Predicting Outcome in Acute Liver Failure. Gastroenterology 2005;128:A705.
DOI: http://dx.doi.org/10.1053/j.gastro.2005.04.003.
6 Takahashi Y, Kumada H, Shimizu M, Tanikawa K, Kumashiro
R, Omata M, et al. A multicenter study on the prognosis offulminant viral hepatitis: early prediction for liver transplantation. Hepatology. 1994;19:1065-71. PMID: 8175127
7 Yoshiba M, Sekiyama K, Inoue K, Yamada M, Kako M,
Nagai K, Takatori M, et al. Accurate prediction of fulminant
hepatic failure in severe acute viral hepatitis: multicenter45

T. Sugihara et al.
study. J Gastroenterol. 2002;37:916-21. PMID: 12501858.
8 Takikawa Y, Endo R, Suzuki K, Fujiwara K, Omata M. Fulminant Hepatitis Study Group of Japan. Prediction of hepatic
encephalopathy development in patients with severe acutehepatitis. Dig Dis Sci. 2006;51:359-64. PMID: 16534681.
9 Naiki T, Nakayama N, Mochida S, Oketani M, Takikawa Y,
Suzuki K, et al. Intractable Hepato-Biliary Disease Study
Group supported by the Ministry of Health, Labor and Welfare of Japan. Novel scoring system as a useful model topredict the outcome of patients with acute liver failure: Application to indication criteria for liver transplantation. Hepatol
Res. 2012;42:68-75. DOI: 10.1111/j.1872-034X.2011.00902.x.
PMID: 22044730.
10 Bernuau J, Goudeau A, Poynard T, Dubois F, Lesage G,
Yvonnet B, et al. Multivariate analysis of prognostic factors
in fulminant hepatitis B. Hepatology. 1986;6:648-51. PMID:
3732998
11 Nagaki M, Iwai H, Naiki T, Ohnishi H, Muto Y, Moriwaki H.
High levels of serum interleukin-10 and tumor necrosis factor-alpha are associated with fatality in fulminant hepatitis. J
Infect Dis. 2000;182:1103-8. PMID: 10979906.
12 Schiødt FV, Rossaro L, Stravitz RT, Shakil AO, Chung RT,
Lee WM. Acute Liver Failure Study Group. Gc-globulin andprognosis in acute liver failure. Liver Transpl. 2005;11:1223-7.
PMID: 16184570.
13 Rutherford A, King LY, Hynan LS, Vedvyas C, Lin W, Lee
WM, et al. ALF Study Group. Development of an accurate
index for predicting outcomes of patients with acute liver
failure. Gastroenterology. 2012;143:1237-43. DOI: 10.1053/
j.gastro.2012.07.113. PMID: 22885329.
14 Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud
J, Bohuon C. High serum procalcitonin concentrations inpatients with sepsis and infection. Lancet. 1993;341:515-8.
PMID: 8094770.
15 Simon L, Gauvin F, Amre DK, Saint-Louis P, Lacroix J. Serum procalcitonin and C-reactive protein levels as markers
of bacterial infection: a systematic review and meta-analysis.
Clin Infect Dis. 2004;39:206-17. PMID: 15307030.
16 Li CH, Yang RB, Pang JH, Chang SS, Lin CC, Chen CH,
et al. Procalcitonin as a biomarker for bacterial infections
in patients with liver cirrhosis in the emergency department. Acad Emerg Med. 2011;18:121-6. DOI: 10.1111/j.15532712.2010.00991.x. PMID: 21276124.
17 Rahimkhani M, Einollahi N, Khavari Daneshvar H, Dashti N.
Survey of serum procalcitonin in cirrhotic patients. Acta Med
Iran. 2013;51:153-6. PMID: 23605598.
18 Cekin Y, Cekin AH, Duman A, Yilmaz U, Yesil B, Yolcular
BO. The role of serum procalcitonin levels in predicting ascitic fluid infection in hospitalized cirrhotic and non-cirrhotic patients. Int J Med Sci. 2013;10:1367-74. DOI: 10.7150/ijms.6014.
PMID: 23983598.
19 Lin KH, Wang FL, Wu MS, Jiang BY, Kao WL, Chao HY,
et al. Serum procalcitonin and C-reactive protein levels as
markers of bacterial infection in patients with liver cirrhosis: asystematic review and meta-analysis. Diagn Microbiol InfectDis. 2014;80:72-8. DOI: 10.1016/j.diagmicrobio.2014.03.029.
PMID: 24974271.

20 Cai ZH, Fan CL, Zheng JF, Zhang X, Zhao WM, Li B, etal. Measurement of serum procalcitonin levels for the early
diagnosis of spontaneous bacterial peritonitis in patients withdecompensated liver cirrhosis. BMC Infect Dis. 2015;15:55.
DOI: 10.1186/s12879-015-0776-4. PMID: 25887691.
21 Limdi JK, Hyde GM. Evaluation of abnormal liver function
tests.Postgrad Med J. 2003;79:307-12. PMID: 12840117
22 Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, Del
Vecchio E, et al. Updated definitions of healthy ranges forserum alanine aminotransferase levels.Ann Intern Med.
2002;137:1-10. PMID: 12093239
23 Sugawara K, Nakayama N, Mochida S. Acute liver failure in
Japan: definition, classification, and prediction of the outcome.
J Gastroenterol. 2012;47:849-61. DOI: 10.1007/s00535-0120624-x. PMID: 22825549.
24 Elefsiniotis IS, Skounakis M, Vezali E, Pantazis KD,
Petrocheilou A, Pirounaki M, et al. Clinical significance of serum procalcitonin levels in patients with acute or chronic liverdisease. Eur J Gastroenterol Hepatol. 2006;18:525-30. PMID:
16607149.
25 Lai CH, Lin JN, Chang LL, Chen YH, Lin HH. Circulatingcytokines and procalcitonin in acute Q fever granulomatous
hepatitis with poor response to antibiotic and short-course
steroid therapy: a case report. BMC Infect Dis. 2010;10:193.
DOI: 10.1186/1471-2334-10-193. PMID: 20594295.
26 Wigmore SJ, Walsh TS, Lee A, Ross JA. Pro-inflammatory
cytokine release and mediation of the acute phase protein
response in fulminant hepatic failure. Intensive Care Med.
1998;24:224-9. PMID: 9565803.
27 Atono Y, Sata M, Tanikawa K. Kinetics of C-reactive protein
in acute viral hepatitis. Gastroenterol Jpn. 1989;24:655-62.
PMID: 2514117.
28 Meisner M. Update on procalcitonin measurements. Ann
Lab Med. 2014;34:263-73. DOI: 10.3343/alm.2014.34.4.263.
PMID: 24982830.
29 Nie X, Wu B, He Y, Huang X, Dai Z, Miao Q, et al. Serumprocalcitonin predicts development of acute kidney injury
in patients with suspected infection. Clin Chem Lab Med.
2013;51:1655-61. DOI: 10.1515/cclm-2012-0822. PMID:
23509222.
30 Huang HL, Nie X, Cai B, Tang JT, He Y, Miao Q, et al.
Procalcitonin levels predict acute kidney injury and prognosis in acute pancreatitis: a prospective study. PLoS One.
2013;8:e82250. DOI: 10.1371/journal.pone.0082250. eCollection 2013. PMID: 24349237.
31 Meisner M, Lohs T, Huettemann E, Schmidt J, Hueller M,
Reinhart K. The plasma elimination rate and urinary secretionof procalcitonin in patients with normal and impaired renal
function. Eur J Anaesthesiol. 2001;18:79-87. PMID: 11270029.
32 Moore JK, Love E, Craig DG, Hayes PC, Simpson KJ.
Acute kidney injury in acute liver failure: a review. Expert Rev Gastroenterol Hepatol. 2013;7:701-12. DOI:
10.1586/17474124.2013.837264. PMID: 24134153.
33 Adawi D, Kasravi FB, Molin G, Jeppsson B. Effect of Lactobacillus supplementation with and without arginine on liver
damage and bacterial translocation in an acute liver injury
model in the rat. Hepatology. 1997;25:642-7. PMID: 9049212.

46