Clinical Course

1
Clinical Course

• 10/09/2000 admission at FEMH
• 48y/o male, presented with
• General malaise, poor appetite and abd.
  discomfort for 2 wks
• Icteric sclera, tea-color urine, BWL (84?79Kgw in
  2 wks)
• Past history
• Operation, transfusion or systemic disease nil
• Alcoholism for 20 years (??, ½ BPD quitted 3
  months ago for fear of BWG)
• HBV infection, noted since 10 years ago
  deterioration of LFT in recent 4 years
• Herb drug 6 days ago for the C.C. and reducing
  body weight (?, 1?/?, 3 days)
• Family history
• Father (87y/o) HCC

2

• Lab.
• GOT 1040, GPT 1405, PT 43.7(11.9), Bil. (T/D)
  19.3/11.1, ammonia 111 ?M/L, AFP 207 ng/ml
• HBsAg(), HBeAg(-), Anti-HBe(), anti-HCV(-)
• Sonography CLPD, no ascites
• Supportive care, including Lamivudine 100mg/day
  (starting on 10/11)
• Clear consciousness but deteriorated lab.
• For impending hepatic failure, pt was
  transferred to NTUH on 10/13/2000

3

• 10/13/2000 admission at NTUH
• Lab.
• HBV DNA 1.47 pg/ml(??PCR, lt0.5 pg/ml),
  anti-Delta (-), anti-HAV IgM(-), CMV IgM(-),
  EBV-VCA IM(-), HSV (-)
• ANA(-), Ceruloplasmin 22.7 mg/dl (-)
• Clinical condition
• Deterioration with ongoing drowsy consciousness,
  hyperbilirubinemia, and prolonged PT
• Complicated with UGI bleeding

4

• 10/19/2000 transfer to SICU
• Dialysis with Biological DT system for 5 times
• Renal shut down, presented with progressive
  decreased urine amount, since 10/21
• B/C grew Candida albican S/C grew MRSA,
  Neisseria and Yeast-like organisms then,
  strongest antibiotics (Imepinem and Amphotericin
  B) were used on 10/25 but sepsis seemed
  intractable
• Continuous venous-venous hemodialysis was started
  on 10/27 for renal failure
• Bradycardia and hypotension developed on 11/1 and
  then recurred even using high dose of
  vasopressors and inotropes
• Expire was declared on the same day (11/1)

5
Serial lab. after transfer to SICU
6
48y/o male Alcoholism for 20 years HBV carrier
for 10 years
2wks
General malaise, poor appetite and abd.
discomfort
6 days
Herbs, 3 days use for weight reduction and above
symptoms
Icteric sclera, tea-color urine, BWL (5Kgw in 2
weeks)
At FEMH GOT/GPT, Bil(T), PT, NH3, AFP HBsAg(),
HBeAg(-), Anti-HBe(), Anti-HCV(-) Start
Lamivudine 100mg/day on 10/11 Deterioration of
clinical condition
10/9
10/13
At NTUH, GOT/GPT, Bil(T), PT, AFP HBV DNA 1.47
pg/ml HAV, HDV, CMV, EBV, HSV, ANA,
Wilsons(-) Deterioration with ongoing drowsy
consciousness, ?Bil.,?PT
10/19
At SICU Dialysis with Biological DT system,
5X ARF(CVVH), Sepsis (Fungemia Bacteremia)
Expire
11/1
7
Acute exacerbation
Supportive care Lamivudine
AHF
Herbs
Biological DT system
MOF
ARF Sepsis
Antibiotics CVVH
Death
8
Acute hepatic failureFulminant hepatitis,
fulminant hepatic failure

• Definition by IASL(1996)
• Interval between onset of jaundice and
  encephalopathy lt 4 wks
• 2 most important complications cerebral edema
  and sepsis
• Prognostic markers age gt 40 yrs, bilirubin gt 15
  mg/dl, PT prolongation gt 25s, cerebral edema (3
  or 4 factors, MR gt 90)

9
Liver transplantation

• Urgent LT is now the standard Tx for AHF
• One year survival rate 46-89
• Main problems lack of donor livers and few
  qualified centers

10
Alternatives to LT

• Bridge to LT
• Hepatocyte transplantation, liver-directed gene
  therapy, xenotransplantation, extracorporeal
  liver support, tissue-engineered organs
• Using biological DT system, 4/20 survived
  (including 2 FHB, 1 flare-up of HBV)
• WJ Ko (ISFA, 2001)

11
Acute exacerbation
Supportive care Lamivudine
AHF
Herbs
Biological DT system
MOF
ARF Sepsis
Antibiotics CVVH
Death
12
Alcoholic liver disease

• Fatty liver ? Alcoholic hepatitis ? Cirrhosis ?
  Hepatoma
• Dose and duration dependent (80g/day for 10 yrs
  ?)
• Risk factors female, viral hepatitis, gene,
  nutrition
• ??(45) 150 cc/day (YF Liaw TJ Chen, 1992)

(Small 55, 300cc)
13
Alcoholic hepatitis

• GOT/GPT gt 2
• GOT lt 300 IU/dl
• ? Alk-p and ?-GT(15X)

14
ALD and HBV

• Alcohol consumption intensifies the liver disease
  caused by HBV
• Nomura (AJE, 1988)
• Asymptomatic HBV carriers were at risk of hepatic
  abnormalities when drinking more than 80g/day
• Villa (Lancet, 1982)

15
More severe Chronic liver injury
Limited illness
Rapid downhill course
Acute Flare-up
HBeAg Clearance
Mutant HBV
Hepatoma
Chronic hepatitis B
Spontaneous reactivation
Hepatitis A
Hepatitis E ?
Drug reaction
Hepatitis C
Corticosteroid Immuosuppressant C/T
Hepatitis D
16
Viral superinfection in chronic HBV carrier
17
Superinfection of hepatitis C
18
Rapid downhill course
Acute Flare-up
HBeAg Clearance
Mutant HBV
Chronic hepatitis B
Drug reaction
19
Natural course of chronic hepatitis B
20
Natural course of chronic hepatitis B

• Indicators of HBV replication
• HBeAg HBV DNA in serum

21
SeroconversionHBeAg(-), Anti-HBe()

• 17 per year male gt female
• Liaw (1983,1984)
• Cessation of HBV replication and clinical
  biochemical resolution
• Realdi (1980), Hoofnagle(1981), Sanchez(1984)

22
Decompensation in seroconversionIS Sheen
(Gastroenterology, 1985)

• 376 HBeAg(), 7 years
• 165 HBeAg clearance (seroconversion)
• 4 hepatic decompensation (2.42) and one died

23
Window period of seroconversionYF Liaw
(Hepatology, 1984)

• Anti-HBe appeared in days to years after
  disappearance of HBeAg
• 79 in one year
• 41 in one month
• Shortest is 9 days
• Longest is 3 years
• Shorter in patient with AE

Patient Profile HBeAg(-) Anti-HBe()
24
AFP in hepatitis B with AEYF Liaw (Liver, 1984)
Patient Profile AFP 207
25
Rapid downhill course
Acute Flare-up
HBeAg Clearance
Mutant HBV
Chronic hepatitis B
Drug reaction
26
AE in Anti-HBe() HBV DNA()

• AE in Anti-HBe() vs. HBeAg()
• Incidence/year 10.3 vs. 26.8 (plt0.001)
• Bilirubin and AFP slightly higher in Anti-HBe()
• No significance in S/S, GPT and histology
• 62.5 with HBV DNA () reactivation of HBV
  infection
• YF Liaw (Hepatology, 1987)
• 16 non-cirrhotic Anti-HBe() with AE
• 88 (14/16) with HBV-DNA() reactivation of HBV
  infection
• MY Lai (Hepato-gastroenterology, 1988)

27
Detection of HBV DNA

• Real-time Quantitative PCR
• HBV DNA 1.47 pg/ml ( lt 0.5 0.05 pg/ml)
• 30 X of the minimal detectable titer

?????
28
HBV DNA in relation to GPTYF Liaw (Liver, 1988)
29
Role of HBV DNA

• An absence or low levels of circulating HBV DNA
  (PCR) in the serum on HBV replication
• Hepatocellular injury is a likely sequela of the
  host immune response to HBV Ag and is not due to
  a direct cytopathic effect of the virus

HBV-DNA pg/ml
0
9
0-250
78
67
251-500
CAHCLH
501-1000
20
8
CM CHU (Hepatology,1985)
gt1000
30
Pre-Core mutants of HBV

• Carman (Lancet, 1989)
• 7 of 8 anti-HBe() HBV DNA() (mostly CAH)
• TGG?TAG (stop codon) (G-to-A substitution at
  nucleotide 1896) resulting in failure to produce
  HBeAg
• Low prevalence in fulminant hepatitis B in France
  and North America(lt10) but high in Israel and
  Japan (80-100)

31
Pre-Core mutant in TaiwanCM Chu (J Clin
Microbiol, 1996)
Immune tolerance phase Wild type HBV
predominant Immnue clearance phase Precore
mutant emerging Immune integrated phase Precore
mutant prevailing
32
Pre-Core mutants after seroconversionRN Chien
(Spring convention, 2000)

• After spontaneous seroconversion
• 67 remain stable
• 33 have AE
• 70 precore mutant (23 of all)
• 21 re-appearance of HBeAg (5 of all)

33
AFP in hepatitis B with AEYF Liaw (Liver, 1986)
Patient Profile AFP 207
34
Benefit of Lamivudine in AERN Chien (Spring
convention, 2000)

• Hepatitis B with AE (? Bil. PT)
• Lamivudine 150mg/d for 8 weeks

35
Rapid downhill course
Acute Flare-up
HBeAg Clearance
Mutant HBV
Chronic hepatitis B
Drug reaction
36
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37
?? Scutellariae Radix

• ????
• Liver injuries induced by herbal medicine,
  syo-saiko-to (xiao-chai-hu-tang).
• Itoh S. (DDS, 1995)

38
??? Moutan Radicis Cortex

• ?????
• Hepatitis induced by traditional Chinese herbs
  Possible toxic components.
• Kane JA. (Gut, 1995)

39
?? Gentianae Radix

• ?????
• Hepatitis induced by traditional Chinese herbs
  Possible toxic components.
• Kane JA. (Gut, 1995)

40
Herbal drugs related hepatotoxicity
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43
Acute exacerbation
Supportive care Lamivudine
AHF
Herbs
Biological DT system
MOF
ARF Sepsis
Antibiotics CVVH
Death
44
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