Book on hepatitis from page 532 to 544

Book on hepatitis from page 532 to 544

532  Hepatology 2012
Table 3. Grade of hepatic encephalopathy (West Haven criteria).
Grade  Clinical findings  Asterixes  EEG
I  Changes in behavior, euphoria,
depression, mild confusion
+/–  Triphasic waves
II  Inappropriate behavior, lethargy,
moderate confusion
+  Triphasic waves
III  Marked confusion, somnolence  +  Triphasic waves
IV  Coma  –  Delta waves
Prognosis
With persistently high, although variable, mortality rates from ten to ninety percent,
accurate prediction of the clinical course is crucial for accurate management and
decision-making. Most importantly, identification of the underlying etiology
improves prognosis and opens the door for specific treatment. The degree of hepatic
encephalopathy is traditionally considered an important indicator of prognosis
(O'Grady 1989). Cerebral edema and renal failure worsen the prognosis
dramatically. In some studies,  the INR was determined as a strongest single
parameter to predict the prognosis of ALF. Another interesting point is that the
presence of hepatic encephalopathy means a poor prognosis for acetaminophen
induced ALF, which in contrast has little meaning for mushroom poisoning. LTx is
the ultimate treatment option in patients with ALF, in which conservative treatment
options fail and a lethal outcome is imminent. Therefore, assessment of likelihood
of the individual patient to undergo a fatal course is important for timely listing of
the patient. Standardised prognosis scores, based on reproducible criteria are
important in times of donor organ shortage and to avoid LTx in patients that might
fully recover without LTx (Canbay 2011).
King’s college criteria (KCC) was established in the 1990s based on findings
from a cohort of 588 patients with ALF  (O'Grady 1989). The authors also
introduced a classification based on the onset of encephalopathy after an initial rise
in bilirubin levels into hyperacute (<7 days), acute (8-28 days) and sub-acute (5-12
weeks) liver failure (O'Grady 1993). KCC includes assessment of encephalopathy,
coagulopathy (INR), acid homeostasis (pH), bilirubin and age. For patients with
acetaminophen-induced ALF, another KCC formula was implied from that in
patients with non-acetaminophen-induced liver injury. Clichy criteria were
introduced for patients with fulminant HBV infection and include the degree of
encephalopathy and factor V fraction as a measure for hepatic synthesis (Bernuau
1986). The model for end stage liver disease (MELD) was designed to predict the
likelihood of survival after transjugular portacaval shunt (TIPS) in cirrhotic patients.
However, it has recently been established as an allocation tool for LTx in patients
with cirrhosis in the US and Europe. It has been tested as a model for prediction of
ALF and was found to be superior to KCC and Clichy criteria in independent
studies (Schmidt 2007, Yantorno 2007). Novel approaches that include mechanistic
characteristics of ALF like the CK-18 modified MELD, which includes novel
markers for hepatocellular death or lactate are promising, but need validation in
prospective cohorts (Bechmann 2010, Hadem 2008).
Acute Liver Failure  533
Table 4. Scoring systems in patients with ALF for emergent LTx.
Scoring System    Prognostic factors
King’s College
Criteria
Paracetamol
intoxication
Arterial pH <7.3 or
INR >6.5 and creatinine >300 μmol/L and
hepatic encephalapathy grade 3-4
Non-paracetamol  INR >6.5 and hepatic encephalapathy or
any of these three: INR >3.5 and bilirubin >300
μmol/L and age >40 years and unfavorable
etiology (undetermined or drug-induced)
Clichy Criteria   HBV  Hepatic encephalopathy grade 3-4 and factor V
<20% (for <30 years old); <30% (for >30 years
old)
MELD     10x(0.957xInserum creatinine +0.378x Intotal
bilirubin +1.12xInINR+0.643)
CK-18 modified
MELD
10x(0.957xInserum creatinine +0.378x
InCK18/M65 +1.12xInINR+0.643)
Bilirubin-Lactate-Etiology Score (BILE
score)
Bilirubin (μmol/)/ 100+ Lactate (mmol/L)
+4 (for cryptogenic ALF, Budd-Chiari or
Phenprocoumon induced)
-2 (for acetaminophen-induced)
+0 (for other causes)
Adapted from Canbay 2011; INR, International Normalized Ratio; MELD, model of end stage
liver disease.
Treatment
General management
Given the high risk of deterioration and development of hepatic coma, immediate
transfer of the patient presenting with ALF to the ICU is mandatory. Early referral
or at least consultation of an experienced transplant center is indicated in any ALF
patient, since LTx is the ultimate treatment for ALF in case conservative therapy
fails. The cause of ALF should be determined as soon as possible. Besides specific
detailed history taking, laboratory and radiologic tests need to be done in order to
establish the diagnosis of ALF and identify the underlying cause. Diagnostic studies
include, but are not limited to, arterial blood gas analysis, glucose, electrolytes,
bilirubin, ammoniac, lactate, protein, albumin, C-reactive protein (CRP),
procalcitonin (PCT), urine electrolytes, urinalysis, and chest X-ray, cranial
computed tomography (CT) in patients with advanced hepatic encephalopathy as
well as assessment of intracranial pressure (ICP) in some cases. Additional to
specific diagnostic studies (HBV serology, ceruloplasmin, urine copper
concentration, etc.) transjugular or laparoscopic liver biopsy might be indicated to
identify the underlying disease (Canbay 2011).
Hepatic encephalopathy
In general in patients with hepatic encephalopathy, sedative agents should be
avoided and if necessary restricted to short-acting benzodiazepines or propofol, as it
might decrease intracranial pressure (Wijdicks 2002). Some studies favor utilization
of ICP monitoring, especially in patients with hepatic encephalopathy grade III/IV,
534  Hepatology 2012
and clinical signs of brain edema. Mannitol therapy (0.5-1 g/kg) might be beneficial
in some patients. Head elevation, induction of hypothermia and hyperventilation are
recommended by some experts in patients with increased ICP. With worsening of
brain edema, the patients present with systemic hypertension and bradycardia
(Cushing reflex), dilated and fixed pupils, and in the end respiratory arrest. The
target ICP should remain below 20 mmHg, with cerebral perfusion pressure above
70 mmHg and jugular venous saturation of 55-80%. Phenytoin is the drug of choice
for treatment of seizures and hypertonic sodium chloride might be beneficial on ICP
(Larsen 2011). Symptomatic treatment of encephalopathy includes bowel
decontamination with neomycin or rifaximin, induction of diarrhea and reduction of
colonic pH and thus reduction of ammonia absorption by lactulose as well as
treatment with branched-chain aminoacids to improve peripheral ammonia
metabolism, although large, randomized clinical trials have failed to show clinical
improvement (Larson 2010, Nguyen 2011).
Coagulopathy
In general, without clinical signs of bleeding, fresh frozen plasma (FFP) or
individual coagulation factor treatment is not indicated. To exclude vitamin K
deficiency, vitamin K challenge should be performed. Platelets and recombinant
activated factor VII are indicated in case of bleeding or before invasive procedures.
Liver Transplantation
LTx, is the therapy of choice for ALF in those individuals with insufficient
regeneration capacity and an otherwise fatal prognosis. In patients without
contraindications to LTx, the one-year survival rate is as high as 80-90% with a
five-year survival of 55%. As mentioned above, with LTx available as the most
favorable therapy, the accurate assessment of the patient’s prognosis is crucial to
initiate evaluation of the patient for LTx and decision making in this clinical setting.
The underlying disease, the clinical condition and the status of the graft influence
the patient’s prognosis after the transplant. In times of general organ shortage, the
graft pool might be extended by utilisation of living-donor transplants, split liver
surgery or transplantation of livers in reduced conditions (Canbay 2011).
Extracorporal liver support systems
Extracorporal systems include support devices or bioreactors, which provide
individual or a combination of functions that are insufficiently performed by the
diseased liver. The scientific and clinical aim of the introduction of these novel
techniques is to stabilize the patient until a donor organ is available or ideally until
the liver completely recovers. However, adequately powered, randomized studies to
establish these techniques in the treatment of ALF are either lacking or have failed
to show any benefit over conventional therapy. Thus, treatment with these devices
most likely remains a part of a bridging to transplantation strategy within an
academic setting. The same accounts for novel stem cell and adult hepatocyte
transplant approaches (Canbay 2011).
Acute Liver Failure  535
Specific treatment options
Table 5. Specific treatments for the causes of ALF.
Causes  Medication  Doses
Acetaminophen  Activated oral charcoal  1 g/kg
N-acetyl cysteine (oral/IV)  150 mg/kg loading dose,
50 mg/kg for 4h,
100 mg/kg for 20h
Mushroom  Silibin  20-50 mg/kg/day
Acute HBV  Lamivudine 100-300 mg/day
Entecavir 0.5-1 mg/day
Tenofovir  245 mg/day
Pregnancy   Delivery
Autoimmune  Prednisolone  1-2 mg/kg/day
Budd-Chiari syndrome  TIPS/surgical shunt
HSV  Acyclovir  3x10 mg/kg/day
Acetaminophen Poisoning
Activated oral charcoal (1 g/kg) might be indicated if administered up to four hours
after acetaminophen ingestion. N-acetyl cysteine infusion to restore glutathione
should be administered until as late as 24-36 hours after ingestion, and continued for
20 hours or longer. Monitoring of blood acetaminophen levels might help in
decision-making regarding the duration or initiation of treatment. N-acetyl cysteine
should be started as soon as possible, even in patients with a low probability of
acetaminophen overdose or even in patients with non-paracetamol drug-induced
ALF (Lee 2009). Moreover, steroid and ursodeoxycholic acid combination seems to
be effective in drug-induced severe liver injury (Wree 2011).
Mushroom poisoning
Silibin, with its cytoprotective affects against amatoxin is used despite a lack of the
controlled trials (Broussard 2001).
Acute HBV infection
Antiviral therapy with lamivudine or entecavir has proven as efficient and safe in
fulminant HBV infection (Tillmann 2006). Moreover, with initiation of entecavir
within the first days of admission, HBsAg concentrations and cell death were
significantly reduced (Jochum 2009).
Pregnancy related
Immediate delivery and abortion are the available causal treatments. With early
delivery, the rates of fetal death remain high, however the mortality rate of the
mother decreases significantly (Westbrook 2010).
Autoimmune hepatitis
Steroid treatment should be initiated and if started in time might help to avoid the
need for LTx. With improvement of liver function, prednisone might be tapered and
azathioprine treatment added to the regimens. Recent studies identified the topical
536  Hepatology 2012
steroid budesonide as a potential substitute for systemic prednisone therapy
(Schramm 2010).
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538  Hepatology 2012
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Acute Liver Failure  539
540  Hepatology 2012
541
Index
A
Abacavir  308
Abbott RealTime 192
Abstinence  495
ABT‐072  240
ABT‐333  240
ABT‐450  240
Acetaminophen 535
Acetaminophen intoxication  527
ACH‐1625 240
Acute hepatitis
hepatitis B 36
hepatitis C 47
hepatitis C treatment 226
hepatitis E 59
Acute Liver Failure 526
Adefovir 137, 138, 142, 164, 295, 297,
323
Adherence 220, 269
ADV 138
Adverse drug reactions see Side effects
Albinterferon 256
Alcoholic Hepatitis  488
Alisporivir 240
Amanita intoxication  528
Aminotransferase levels 227
Amplicor 192
ANA598  240
Antidepressants 266
Anti‐TNF α antibodies 465
Anti‐TNF‐α therapy  497
Antiviral resistance 206
ARFP  92
Arterial chemoembolisation 343
Arthralgia 262
Arthropathy 417
Asthenia 263
Asunaprevir  239
Autoimmune hemolytic anemia  273, 281
Autoimmune hepatitis  453, 529
Autoimmune thyroidopathies  273
Azathioprin 471
Azathioprine 458
B
Baraclude 137
BI201335  239
BI207127  240
BILB 1941 240
Biochemical response 136
Blood transfusion 45
hepatitis B virus 34
BMS‐650032 239
BMS‐790052 240, 251
BMS‐824393 240, 251
Boceprevir  205, 208, 239, 244, 253, 308
adverse effects 268
Breakthrough 204
Budd‐Chiari syndrome 522
Budesonide 462
C
Cardiac arrhythmias 416
Cardiomyopathy  273, 416
Celgosivir  240
Ceruloplasmin 440
cEVR  204
Cholestyramine 470
Chronic hepatitis
hepatitis B 37
hepatitis C 48
Hepatitis D 174
Ciluprevir  239, 243
Cirrhosis
HBV/HCV coinfection 322
hepatitis C 49
Cirrhosis complications
end‐stage liver disease 389
Clevudine 181
Cobas AmplicorHCV  193
Cobas Ampliprep 192
Cognitive disturbances 262
Coinfection
HBV/HCV 318
Coinfections 230
Colchicine 471
Competitive PCR 193
Complete Early Virological Response 204
Consensus Interferon 205
542
Copegus 205
Copper 441
Corticosteroids 495
Cryoglobulinemic vasculitis  273
Cyclophilin B inhibitors 252
Cyclophosphamide 462, 464
Cyclosporin 462, 471
Cyclosporine 464
D
Daclatasvir 240
Danoprevir 239
Debio‐025 240
Deferasirox 418
Deflazacort 463
Delirium 262
Delta hepatitis see Hepatitis D
Depressive episodes 262
Diabetes mellitus  273, 416
Dimercaprol 443
Direct sequence analysis 197
Disease progression
hepatitis C 50
Disorders of the hepatic artery 514
Disorders of the hepatic veins 522
Disorders of the portal vein 518
D‐penicillamine  471
Drug abuse 230
Drug interactions 225
Drug‐induced liver injury  527
Dyspnea 264
E
Early Virological Response  204
Efavirenz 308
Emtricitabine 164, 296, 308
End‐stage liver disease
HIV infection 386
Entecavir 137, 138, 143, 161, 297, 323
Epidemiology
hepatitis A 27
hepatitis C 44
hepatitis D 176
eRVR  204
ESLD see End‐stage liver disease
ETV  138
EVR  204
Extended Rapid Virological Response
204
Extracorporal liver support systems 534
Extrahepatic manifestations
hepatitis A 29
hepatitis B 41
hepatitis C 49, 230
hepatitis E 61
F
Famcyclovir  181
Fatigue 262
Ferroportin Disease 420
Filibuvir 240
Flu‐like symptoms 262
G
Gastrointestinal disorders 263
Genotypes
hepatitis C virus 86
GH‐insufficiency 273
Glomerulonephritis 41, 282
Graft versus host disease 529
GS‐5885 240, 251
GS‐9190 240
GS‐9451 240
H
HAART
liver transplantation 391
Haemochromatosis 405
juvenile hereditary 419
secondary 421
TFR2‐related 419
Hair loss 267
Hashimoto thyroiditis  273
HBcAg  120
HBeAg  121
HBeAg loss 149
HBeAg seroconversion 133
HBsAg  120
treatment response 150
HBsAg loss 134
HBV 65
animal models 75
serological tests 119
HBV DNA
treatment response 147
HBV genotypes  122
543
treatment response 147
HBV Virology 65
HBV/HCV Coinfection 318
HBV/HIV coinfection  291
HCC see Hepatocellular carcinoma
HCV See also Hepatitis C virus
HCV genotype 1 207
HCV genotypes 2 and 3 215
HCV genotypes 4, 5, and 6 218
HCV genotyping 196
HCV life cycle  240
HCV replicon systems 97
HCV SuperQuant  192
HCV/HBV Coinfection 318
HCV/HBV management
liver transplantation 390
HCV/HIV Coinfection 302
HCV‐796 240
HCV‐associated thrombocytopenia 281
HCVcc 98
HCVpp 98
HDV see Hepatitis D
Hemodialysis 230
transmission of HCV 47
Hemophilia 230
Hepadnaviridae 65
Hepatic fibrosis 326
Hepatitis A 27
prophylaxis 108
vaccination 110
Hepatitis B 32
chronic infection 124
coinfection with HCV 318
diagnostic tests 119
drug resistance 160
hepatitis C coinfection 40
hepatitis D coinfection 40
immunosuppression 154
liver biopsy  125
occult infection 125, 320
past infection 123
post‐exposure prophylaxis 113
pregnancy 153
prognostic factors 147
prophylaxis 109
serum transaminases 124
superinfection 320
treatment 128
treatment guidelines 130
vaccination 111
Hepatitis C 44
coinfection with HBV 318
diagnostic Tests 189
endocrine manifestations 283
extrahepatic manifestations 272
lifecycle 93
prophylaxis 109
serologic assays 190
superinfection 319
treatment 202
vaccination 114
virology 85
Hepatitis D
iagnostic procedures 174
prophylaxis 109
treatment 174
virology 175
Hepatitis E 55
virology 55
Hepatocellular carcinoma 338, 398
curative therapy 341
HBV/HCV coinfection 322
palliative therapy 343
Hepatoportal sclerosis 521
Hepsera 137
Hereditary hemorrhagic teleangiectasia
516
HEV See Hepatitis E virus
Histologic response  136
HIV
hepatitis E 60
HIV/HCV Coinfection 302
HIV/HVB coinfection
end‐stage liver disease 397
Horizontal transmission
hepatitis B virus 34
I
Idiopathic pulmonal fibrosis 273
IDX184  240
IDX320  240
IDX375  240
IL28B  160
Immune thrombocytopenic purpura 273
Incivek 244
Incivo 244
Infergen 205
Injection drug use 45
Insulin resistance 273
Interferon lambda 1 256
Interferon α 182
544
Interferon α‐2a 137, 205
Interferon α‐2b 137, 205
Interferons  139
Intron 137, 205
Iron overload 405
Irritability 262
L
LAM 138
Lamivudine 137, 138, 142, 161, 296, 308
LdT  138
Lead‐In  204
Lichen planus 273
Liver biopsy 327
Liver cancer
prophylaxis 345
Liver cirrhosis
compensated 228
Liver fibrosis
surrogate markers  329
Liver retransplantation
HIV infection 398
Liver transplantation 349
AIH 466
hepatitis delta 183
HIV infection 386
NASH 433
PSC  478
M
Malignant lymphoproliferative disorders
276
Membrano‐proliferative
glomerulonephritis 273
Mericitabine 240, 248, 250
Methotrexate 471
Miravirsen 240
Mixed cryoglobulinemia 272
treatment 277
MK‐3281 240
MK‐5172 239
MK‐7009 239
Molecular‐targeted therapeutic
strategies 344
Monoclonal gammopathies 273
Mushroom poisoning 535
Myalgia 262
Mycophenolate mofetil 462
Mycophenolic acid 464
Myopathy  273
N
N‐acetyl cysteine 497
NAFLD 427
Narlaprevir  239
NASH 427
Natural history
hepatitis B 36
hepatitis C 49
Needlestick injury
transmission of HCV 47
Nephropathy 41
Nexavar 344
NIM811  240
Nitazoxanide  240, 253
NM283 240
Nodular regenerative hyperplasia 521
Non‐Hodgkin lymphomas 273
Nonresponse  204
Nosocomial infection
hepatitis B 35
NS2 91
NS3 91
NS3‐4A protease inhibitors  241
NS4A 91
NS4B  91
NS5A 92
NS5A inhibitors  251
NS5B  92
NS5B polymerase inhibitors  248
Nucleic acid testing for HCV  191
Nucleos(t)ide analogs 138, 141
Nucleoside analogs
delta hepatitis 181
Null response 204
O
Opioid antagonists 470
Organ transplantation
HCV transmission 46
hepatitis B virus 36
hepatitis E virus 60
Orthotopic liver transplant  392
outcome 394
Osler‐Weber‐Rendu syndrome 516