Liver injury in Adult Dengue

Liver injury in Adult Dengue
Sombat Treeprasertsuk, MD., Ph.D.
Chulalongkorn University
Aug 7, 2014
Prevalence of Liver function tests abnormality
in adults patients with dengue infection




N = 127 adult dengue patients at Hospital of
Tropical Medicine, Bangkok, Thailand
Mean age 26.4±11.5 years.
Classification of Dengue infection by WHO criteria
were DF 4.7%,
- DHF grade I 26%,
- DHF grade II 63%
- DHF grade III 6%.
Mean duration-fever clearance time 6±1.9 days
Treeprasertsuk S, Kittitrakul C, et al AJG 2003 abstract
Prevalence of Liver function tests abnormality
in adults patients with dengue infection







Abnormal AST and ALT were found in 88% and
69% of patients
High-level AST and ALT (>10x) occurred in 11%
and 7%
Abnormal AST during febrile stage was
associated with bleeding
Shock occurred in 6% after av. 5.6 days
All patients recovered within 1 day of shock,
without using vasopressor.
Pleural effusion occurred in 1.6%.
No patient died.
Treeprasertsuk S, Kittitrakul C, et al AJG 2003 abstract
Cohort : Liver injury in Adult Dengue
in Pakistan : Age>14 yr
DENGUE INFECTION 699 CASES
65% = MALE
AGE 31.9 Yr
IPD/ exclude cirrhosis
DF 86%, DHF12%, DSS 2%
• Mortality rate 2.7%
• Severe hepatitis 15%
• ARF 3.9%
• Encephalopathy 2.9%
• Bleeding 1.7%
Parkash O, et al. BMC Gastroenterology 2010; 10: 43.
Primary outcome measures according to
severity of hepatitis within 2 categories ;
DF-DHF in Pakistan
Diagnosis
Categories
Dengue
fever (DF)
(n=517)
DHF/ DSS
(n=82)
Death
(n)
Death rate
(Deaths/10
day)
H.R (95% Cl;)
P value
(Difference
in death
rate)!
LOS+SD
P
value
Mild to
Moderate
Hepatitis
(n=436)
3
0.019
2.97 (0.48,18.6)
0.283
3.50+1.54
<0.025
Severe hepatitis
(n=81; 16%)
3
0.093
Mild to
Moderate
Hepatitis (n=60)
3/60
(5%)
0.010
Severe hepatitis
(n=22; 27% )
9/22
(40%)
0.073
Severity of
hepatitis
3.96+2.27
5 (1.3, 16)
0.003
Parkash O, et al. BMC Gastroenterology 2010; 10: 43.
4.60+2.87
5.60+3.85
.212
Complications in 2 groups of patients with DF
infection by severity of hepatitis
Complications
Mild to moderate (n=496)
Severe hepatitis (n=103)
P value
Bleeding1 (n)
3
7
<0.0016
Renal failure2 (n)
8
8
0.002
Encephalopathy3
(n)
7
11
0.02
Shock4 (n)
6
2
0.406
Acalculus
cholecystitis5 (n)
14
7
0.04
1.
2.
3.
4.
5.
6.
Either mucosal bleeding (epistaxis or gum bleed) or Gastrointestinal (GI) bleed
Acute Renal Failure (ARF) was defined as rise of creatinine > 3 times
Encephalopathy = altered mental status for >8 hr (drowsiness, lethargy, agitation, coma)
Shock was defined as Hypotension (defined as systolic pressure < 90 mm Hg)
Acalculus cholecystitis was defined as inflammation of gallbladder without stone on US
Analyzed by fischer exact test
Parkash O, et al. BMC Gastroenterology 2010; 10: 43.
Mild/mod. hepatitis
Severe hepatitis
ALT < 5*UNL: Mild hepatitis
ALT >5-10 *UNL: mod hepatitis
ALT >10*UNL: severe hepatitis
Parkash O, et al. BMC Gastroenterology 2010; 10: 43.
Characteristic histological changes to the liver parenchyma.
Midzonal (zone 2) necrosis of the liver is the classic
pathological expression of dengue infection
Gasperino J. Liver Int. 2007;27(8):1148-51.
Factors associated with acute liver injury
or Liver failure in Dengue patients.
• Direct viral effect on liver cells or an adverse
consequence of dysregulated host immune responses
against the virus (Seneviratne et al., 2006)
• Liver involvement occur more frequently caused by
DEN-3/ DEN-4 serotypes
• Prolonged shock/ hemorrhage (ischemic hepatitis)
• Drugs induced liver injury: acetaminophen,
salicylates (Suvatte et al 1990)
• Preexisting liver damage (Chung et al 1992)
Nguyen TL, et al. Res. Virol. 1997; 148: 273-277
Gasperino J. Liver Int. 2007 Oct;27(8):1148-51.
Ling LM. J Clin Virol 2007 Mar;38(3):265-8.
Comparison of mean levels of transaminase in
HbsAg-positive and HbsAg-negative DHF patients.
AST (U/l)
DHF with HbsAg+ (n=5)
116+17.8
DHF with HbsAg- (n=40)
120+23.6
P value
ALT
(U/l)
P
value
37+2.5
NS
Nguyen TL, et al. Res. Virol. 1997; 148: 273-277
38+13.8
NS
FHF and Acetaminophen



Case control study: Paracetamol ingestion for the
current febrile illness compared between 25
cases of FHF vs 33 age matched controls
Results: Supra-therapeutic doses of paracetamol
(mean 145 mg/kg/day) were consumed by all 25
cases vs none in the control group
Mean duration of paracetamol intake prior to
admission in cases was 3.5 days vs 1.8 days in
the control group
Ranganathan SS, et al. Indian J Pediatr 2006;73(10):871-5
Antibiotics associated hepatotoxicity
in King Chulalongkorn Memorial Hospital
(2002-2006) : N = 244
Acetaminophen
21%
7%
ARV
ATB
6%
6%
7%
5%
40%
Anti -TB
unknown
AntiTB
Antiretroviral
Allopurinol
Antithyroid
Herbs
Acetaminophen
Antibiotics
Immunosuppressive
NSAIDs
Antiepileptic
Treeprasertsuk S, et al. Aliment Pharmacol Ther 2010; 31:1200
DF and Acetaminophen; case report




8-month-old female infant with severe DF
Given therapeutic paracetamol for
severe dengue, developed FHF with
encephalopathy, GI hemorrhage and severe
coagulopathy (INR>8)
Day11; AST 1,539 IU/L, ALT 5,497 IU/L
Responded to supportive measures and
N-acetylcysteine infusion, day 25-improved
Gan CS, et al. Singapore Med J 2013 ;54(2):e35-7.
Treatment of patients with
Fulminant hepatic failure-Dengue
Recent interest has focused on
1. Supportive medical manangement;
N-acetylcystein (NAC)
2. Providing temporary support as a
bridge to Liver transplantation:
Artificial Liver Support
- Limitation: no RCT, small sample size

1. N-acetylcystein (NAC) and
Dengue severe hepatitis

Repletion of hepatocellular glutathione
stores

Scavenges free radicals, improves
antioxidant defense

Vasodilator to improve oxygen delivery and
consumption

NAC-benefit is seen if used early stage of
liver failure rather than late stage
Dose applied
non-acetaminophen
FHF
Lee WM,from
et al. Gastroenterology.
2009;137:856–64.

N-acetylcystein (NAC) and
Dengue severe hepatitis
- Dose/Duration
 iv NAC 100 mg/kg/day infusion x 5 days
(Habaragamuwa, et al.- adult)
iv. 150 mg/kg bolus over 15 min followed by
12.5 mg/kg/h for 4 h and then 6.25 mg/kg/h
x 72 h (Kumarasena, et al.- Ped)
- or 100 mg/kg/day x 6 days (Lim, et al.- Ped)

Lee WM, et al. Gastroenterology. 2009;137:856–64.
Sklar GE, et al. Ann Pharmacother. 2004;38:498–500.
N-acetylcystein (NAC) and Dengue
severe hepatitis - Outcomes
Studies
Case report LFT - presentations
Habaragamu
wa BW et al,
2014
54-yearFemale
FHF-AST 16,261 U/L, GCS = 11
ALT 4,545 U/L,
INR 1.7, TB 6 mg/dl
Survive
with
normal
LFT 2 wk
Lim G, et al
2012
6-year-old
boy
FHF
No details
Survive
Kumarasena
RS, et al,
N =7;
Age 6 mo 12 yr
FHF
Low GCS,
prolonged
shock
Survive
2010
Complications
Outcome
2.Liver Support Therapy


Artificial Liver Support
A. MARS - Molecular Adsorbent Recirculating System
(MARS, Gambro, Sweden); by Stange/Mitzner in 1993
B. Prometheus (Fresenius, Germany);
by Falkenhagen, et al in 1999
C. SPAD (Single pass albumin dialysis)
Bioartificial Liver Support : NO any clinical beneficial effect,
due to safety concern with xenotransplantation of porcine cells or
use of liver-tumor derived human cell lines
Carpentier, et al. Gut 2009;58:1690–1702.
Benefit of Artificial Liver Support
Improvement of jaundice.
 Improvement of hemodynamic instability
(Mean arterial pressure, Stroke volume,
Systemic vascular resistance).
 Reduction of portal pressure.
 Reduction of intracranial pressure; ALF cases
 Improvement of hepatic encephalopathy.

Nevens F, Laleman W. Best Practice & Research Clin Gastroenterol 2012; 26: 17–26.
A. MARS
(Molecular adsorbents recirculating system)



Based on the dialysis of blood with a membrane
separation system coated albumin
Enables the exchange of water-soluble and protein
bound toxins by an albumin-coated membrane and
recycled protein containing dialyzate
System consists of 3 compartments
- blood circuit
- albumin circuit
- renal circuit
Sambit,et al. Am J Gastroenterol ;2005:100 :468 – 475.
Steffen ,et al. Curr Opin Nephrol Hypertens 2007, 16:589–595.
Molecular adsorbent absorbent recirculating system (MARS) uses albumin as
dialyzer to remove albumin-bound and water-soluble toxins
BFR: 120 – 150 mL/min
MARS membrane
Blood from
patient
dialysis membrane
600 ML 20% Albumin
dialysate
ADSORBERS
Anion
exchange
resin
Hemofiltration
circuit
LOW FLOW
Activated
charcoal
To patient
1.blood
circuit
A. MARS
2.albumin
circuit
3.renal
circuit
MARS in patient with DHF-Acute liver failure
- Reveres hepatic encephalopathy and improved LFT
Penafiel A, et al. J Intensive Care Med 2006 Nov-Dec;21(6):369-71
Human serum albumin
(HSA)


Albumin binds bilirubin, copper and
nitric oxide, other liver-derived
hydrophobic toxins, +/- remove proinflammatory substances such as
chemokines
healthy adults,
albumin synthesis
occurs predominantly
in polysomes of
hepatocytes
(10-15 g/D)
half-life of between
12.7 and 18.2 days
(mean, 14.8 days)
Quinlan GJ, et al.
Hepatology 2005;41(6):1211-9.
C. Single pass albumin dialysis : SPAD





Dialyzes blood/plasma against a 4.4% solution
of albumin
A standard renal replacement therapy machine
is used without any additional perfusion pump
system (simpler)
Use of considerably more diluted albumin as the
dialysate (4.4%, vs. 20% in case of MARS)
Offsets the cost of not recirculating the dialysate.
Alb. dialysate flow rate: 1-2 L/h in CVVH circuit
Sen S, et al. Am J Gastroenterol 2005;100(2):468-75.
No. of cycles of SPAD = 2.8 +/- 1.2 in FHF
4.4%
solution of albumin
High flux dialysis filter
Flow 1-2 L/h in CVVH circuit
Mitzner S, et al. Ther Apher Dial 2006 Apr;10(2):108-17.
Sen S, et al. Am J Gastroenterol 2005 Feb;100(2):468-75.
Boonsrirat U, et al. Artif Organs. 2009;33(8):648-53.
MARS VS SPAD: No differences in the need for blood
transfusion, health scoring, or mortality between the two
treatment modalities were detected.
Changes of serum
bilirubin level
Kortgen A, et al. Ther Apher Dial 2009:13(5):419–425.
Effective bilirubin reduction by SPAD
in Liver failure - KCMH




Using 2% human S. albumin dialysate for 6 h.
SPAD significantly improved the levels of TB,
DB, urea, and creatinine (P < 0.001 for all
parameters).
Reduction ratios of TB 23+/- 4%,
- DB 21+/- 5%,
- BUN 19+/- 4%
- Cr 28+/- 3%
No significant changes in MAP were noted,
representing cardiovascular tolerability.
Boonsrirat U, et al. Artif Organs. 2009;33(8):648-53.
SPAD: Safety and outcome


SPAD : hemodynamically well tolerated
 Pre-and post-treatment mean arterial
pressures were 73.4±1.6 and 71.2±1.4 (NS)
 All patients could complete the 6-hr session
 No mortality and no dialysis-related
complications.
Cost of SPAD in the present study : one-fifth of
MARS (75,000 Bt = 2,420 US$ / 3 days)
Boonsrirat U, et al. Artif Organs. 2009;33(8):648-53.
Summary: Liver injury in Adult Dengue







Abn. LFT : common 88%: by AST /ALT elevated
AST >10X U/L = 11-14%, ALT >10X U/L = 7%
Mortality rate in DHF/DSS 0-2.7% (mild/ mod
3/60; 5% vs severe hepatitis 9/22; 40%);
with Hazard ratio of 5 (95% CI1.3-1.6)
Severe hepatitis (ALT >10x UNL) : may be a
significant contributing factor to mortality
AST, ALT are mandatory to monitor in Dengue
Severe hepatitis DHF: had higher spontaneous
bleeding episodes, renal failure, encephalopathy
Treatment: aim supportive; NAC?, SPAD?

Download Report