MM of HBV related cirrhosis

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Saraya Herbal medicines Glycyrrhizin
Extract of licorice root (Glycyrrhiza Glabra).A
sulphated polysaccharide of plant lectin.Two
molecules of glycerrhetinic acid one molecule
glucoronic acid.
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Saraya Herbal medicines Glycyrrhizin

• Glycyrrhizin
• Extract of licorice root (Glycyrrhiza Glabra). A
  sulphated polysaccharide of plant lectin, with
  two molecules of glycerrhetinic acid one
  molecule glucoronic acid.
• Mechanism of Action
• Induction of endogenous interferon Abe et al.
  Microbiol Immunol 1982 26535-39).
• Cytoprotection Shiki et al J Gastroenterol
  hepatol 1992 7 12-16
• Lysis of liver cell by antiliver cell antibody.
  Nagai et al Jap J Pharmacol 1992 58 209 - 218
  (Rat ischemia re-perfusion model)
• Prevent free radical injury, by stimulating
  protein kinase C (Mori 1989).
• Prevent cell to cell infection by nonspecific
  blocking of cell receptors

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Saraya Herbal medicines Glycyrrhizin

• Commercial preparation of Glycyrrhizin
• Stronger Neominophagan C Glycyrrhizin 0.2
• Glycine 2
• Cysteine 0.1
• Glycine protects hepatocytes from injury caused
  by anoxia, cold ischemia and mitochondrial
  inhibitors
• (Marsh 1993)

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Saraya Herbal medicines Glycyrrhizin

• Existing therapy
• SHF - No specific treatment available
• Major cause viral (97)
• INF??, LAM only for HBV.
• CH - Mostly viral HCV, HBV or mixed
• Option Interferon and Nucleoside analogue
• Cirrhosis Usually resistant to antiviral therapy
  
• Interferon may lead to flare up.
• If transplanted high rate of reinfection.
• Rationale for use of glycyrrhizin
• Cytoprotective and anti viral properties
• Safe, minimal side effects
• Therapeutic options limited in SHF,CH and
  cirrhosis
• Liver transplant still in infancy
• Cheaper as compared to other modalities

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Saraya Herbal medicines Glycyrrhizin

• Parenteral glycyrrhizin in SHF
• Study period Jan 1993-Dec 2001Consecutive
  patients with SHF
• Diagnosis Histology AHBN
• No portal hypertension
• No ingestion of hepatotoxins
• ALT gt 2.5x normal
• SHF patients treated with supportive therapy for
  Jan 83-1992 satisfying same criteria acted as
  control (98/200)
• Exclusion criteria Encephalopathy, renal
  failure, sepsis, active gastrointestinal
  hemorrhage
• Mortality with complication 95. So drug may not
  have adequate time to act.

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Sub-acute hepatic failure (SHF) Contd.
Saraya Herbal medicines Glycyrrhizin

• Drug dosage schedule -
• 100 ml I/V daily x 1 month
• 100 ml I/V Alternate day x 2 months
• Follow up till 9 months (Based an experience in
  Japan)
• Out come measures
• 1. Survival
• 2.chronic liver disease in survivors

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Saraya Herbal medicines Glycyrrhizin

• Investigations
• Haematological, LFT, RFT At admission, once
  weekly.
• Hepatotropic viral markers At inclusion, 3M,
  9M.Liver histology (PM or AM)/CT- all at /close
  to inclusion, after 6 month of Rx in survivors.
• Hepatotropic Viral Markers HBsAg, HBeAg, IgM anti
  HBc, IgM anti HAV,
• IgM anti HEV Anti HCV (Elisa)
• HCV RNA (RT PCR). HEV RNA (RT PCR),
• HBV DNA (PCR) in sera -ve for all above
  serological markers.
• At base line, at end of therapy (3M), at end of
  FU(9M)

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Saraya Herbal medicines Glycyrrhizin

• Comparison of clinical parameters among survivors
  of Glycyrrhizin treated and control patients with
  SHF (3 months)
• Parameters Glycyrrhizin Controls
• Number 77 98
• Survivors 56 (73) 31 (33) (plt0.001)
• Jaundice
• Absent 50 (90) 16 (54) (plt0.01)
• Present 6 (10) 15 (46)
• Ascites
• US non detectable 46 11
• Minimal (US) 6 9
• Clinically detectable 4 (7) 11 (35.5)

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Saraya Herbal medicines Glycyrrhizin

• Liver function profile before and after therapy
  among survivors (3 month)
• Parameters Glycyrrhizin (n56) Controls (n31)
• Before After Before After
• S.bilirubin (mg/dl) 20.3 10.9 1.05
  0.89 16.9 3.2 3.2 2.1
• ALT (IU/L) 122.5 119.5 29.2 16.4 142
  71 78 38
• Prothom time (Sec) 10.3 11.8 1.9 0.8 16.6
  9.2 9.6 89
• S. Albumin (g/dl) 2.7 0.64 3.4 0.62 2.6
  1.3 2.3 1.0
• P lt 0.001 P lt 0.01

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Saraya Herbal medicines Glycyrrhizin

• Survivors among SHF developing CLD
• Etiology No. of Pts. Death FUgt6M Chronicity
• HAV 2 (2.6) 0 (0) 2 0/2 (0)
• HBV
• Isolated 36 10 26 15
• Mixed (HBVHEV) 9 1 8 3
• HCV 3 (4) 1 (33) 2 1/2 (0)
• HEV
• Isolated 8 2 6 0
• Mixed (HEVHAV) 2 0 2 0
• NANE 16 (21) 7 (44) 9 3/9 (33)
• ATT 1 (1.3) 0 (0) 1 0/1 (0)
• Total 77 21(27) 56 22/56(39)
• HBV/HCV/NANE - 33- 50 Survivors develop
  chronicity
• HAV/HEV/ATT - Survivors had complete recovery

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Saraya Herbal medicines Glycyrrhizin

• Summary
• Amongst Glycyrrhizin treated patients with SHF,
  survival (73) was significantly better than
  controls (33).
• The complication rate due to liver failure was
  also lower amongst the Glycyrrhizin treated
  patients (37.5) than in controls (82).
• The clinical and biochemical improvement was
  faster and better amongst Glycyrrhizin treated
  patients than in controls.
• Unlike in AVH/AHF in whom HEV was the major cause
  at our centre, HBV was the most important cause
  of SHF. 9/45 (20) HBV SHF were due to HEV
  super infection over HBsAg carrier state.
• Chronic sequalae amongst SHF survivors were
  documented in 40 of the patient. HBV and or HCV
  related SHF only developed chronic sequalae.
  HEV/HAV/ATT induced SHF when survived were
  completely cured without any chronic sequalae.

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Saraya Herbal medicines Glycyrrhizin

• Glycyrrhizin in chronic hepatitis
• Pilot study - 46 pts screened and 24 included
• Inclusion criteria - Bx proven cases of CH of
  viral aetiology with gt2 Times ?ALT on 2 occasion
  2 weeks apart at start of therapy
• Exclusion criteria GI bleed, encephalopathy,
  renal failure sepsis and evidence of PHT,
  Wilsons disease, autoimmune hepatitis, drug
  toxicity,refused.
• Dosage schedule - 60 ml daily I/V - 1month, 60
  ml alternate day- 5 mths
• Investigations and follow-up - same as in SHF
• End point
• Completion of therapy
• Loss to follow up
• Death

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Saraya Herbal medicines Glycyrrhizin

• Glycyrrhizin in chronic hepatitis
• Assessment of remission
• Complete remission Normal ALT at end of 6 month
  remain so for 8 weeks
• Partial - 50 ? in ALT with elevate after
  stoping of Rx
• No response lt 50 ? in ALT
• Relapse - rise in ALT after 8 weeks of
  normalization

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Saraya Herbal medicines Glycyrrhizin

• LFT and serological profile
• Parameters Basal (n21) 6 months
  (n21)
• S.bilibubin (mg/dl) 4.1 6.1 1.21.2 plt0.01
• ALT (IU/dl) 76.546.9 51.959.1 plt0.05
• S. Albumin (g/dl) 3.60.6 3.50.9
• PT Prolongation 3.25.0 1.63.6 plt0.05
• Icterus present 4 4
• HBsAg 11 9
• HbeAg/HBVDNA 7 5
• HCVRNA 4 4
• HbsAgHCVRNA 3 3
• No marker 3 3
• Complete response in 7, partial 5, relapse 6

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Saraya Herbal medicines Glycyrrhizin

• Summary
• Synthetic function of liver showed improvement
• ALT decrease in 57 but relapse a seen in 50
• 25 showed histologoical improvement
• serological clearance poor.
• Drug is cytoprotective rather then antiviral.
• Based on these observations we planned a RCT

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Saraya Herbal medicines Glycyrrhizin

• Glycyrrhizin in Chronic hepatitis- RCT
• Number of patients screened 61
• Number of patients included 27
• Number of patients completing 6 months of
• therapy and included for analysis 27
• Number of patients excluded 34
• Reasons for exclusion
• Interferon therapy- 26
• Cirrhosis- 4
• Primary sclerosing cholangitis- 2
• Refusal to be included in the study 2

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Saraya Herbal medicines Glycyrrhizin

• LFT and virological clearance
• Glycyrrhizin (n14)
  controls (n13)
• Before After p Before After p
• S. bil 6.269.03 0.8 67 lt0.001 2.546.02 0.91
  lt0.001
• ALT 7771 38.6 46.6 lt0.001 67.645.3 58.8
  47.5 NS
• S. Alb 2.61.64 3.11.8 lt0.05 3.51.2 2.81.65 lt0.
  05
• PT 3.4 4.2 2.9 2.6 NS 3.5 4.8 4.23.7 NS
• HBsAg 7 5 NS 7 7 NS
• HBeA/DNA 5 4 NS 5 5 NS
• HCVRNA 3 3 NS 2 2 NS
• HBHCV 1 1 NS 1 1 NS
• No markers 3 3 NS 3 3 NS
• The values after end of therapy amongst
  Glycyrrhizin treated and control patients however
  were similar (pgt0.1)

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Saraya Herbal medicines Glycyrrhizin

• Biochemical response and relapse
• Glyr Controls p
• n 14 (n 13)
• Overall response 13(93) 4 (31)
• Complete response 8 3 lt0.05
• Partial response 5 1
• No response 1 9 lt 0.05
• Relapse 2 2 NS
• Pre Rx histo 13 13 NS
• Post Rx histo 7 7 NS
• Histologic improve 4 4 NS

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Saraya Herbal medicines Glycyrrhizin
LFT and virological clearance Glycyrrhizin
(n14) controls (n13) Before After E.
FU Before After E.FU S. Bil 3.45.6 2.22.8, 1
.37 1, 3.83.1 4.44.9 3.6
4.2 ALT 90.6119 41 23.8, 47.429 7212
1.6 74.5 118 79142 S. Alb 3.30.8 3.20.9 3.
40.8 3.00.7, 2.70.7, 2.70.6 PT 7.29.
8 5.4 6.4 4.53.4 5.38.0 8.05.5 6.65.7
p lt 0.05 Plt 0.01 AND P lt 0.05
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Saraya Herbal medicines Glycyrrhizin

• Summary
• At the end of treatment improvement in synthetic
  function of liver was noticed ALT showed a fall
  from base line value but in 50 relapse is seen
  after discontinuation of therapy
• Poor viral clearance seen
• 25 documented histological improvement
• None had any side effects.
• Thus drug is cytoprotective and not antiviral

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Saraya Herbal medicines Glycyrrhizin
Glycyrrhizine in cirrhosis (RCT) Rationale -
no specific therapy for cirrhosis with activity
- INF therapy may hasten liver failure - Re
infection high in transplanted patients . Aim -
prolong life - delay progression of liver
failure
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Saraya Herbal medicines Glycyrrhizin

• Glycyrrhizine in cirrhosis
• Inclusion Criteria
• Patients of cirrhosis of non alcoholic etiology
  having raised ALT levels as in CH
• - Histological evidence of cirrhosis on biopsy
• - Biochemical evidence of activity ? ALT
• - viral markers positive
• Exclusion Criteria
• GI bleed, encephalopathy, renal failure sepsis
  and Wilsons disease, autoimmune hepatitis, drug
  toxicity, associated CAD and pulmonary disease
• Doses schedule
• Same as in CH

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Saraya Herbal medicines Glycyrrhizin

• Glycyrrhizine in cirrhosis (RCT)
• Response to therapy
• Complete response - ? ALT, during initial 6
  months and remains so for atleast 8 weeks after
  stopping treatment and absence of necro
  inflammatory activity on liver biopsy
• Partial response - 50 of above or normal ALT at
  6 moth with ? with in 8 weeks of stopping
  treatment
• Failure lt 50 improve or ? ALT drug therapy
• Follow up - for one year to evaluate biological
  relapse, complication
• End point Death completion of study ( 1½ yr
  after inclusion)development of complication on
  treatment

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Saraya Herbal medicines Glycyrrhizin

• Glycyrrhizin in cirrhosis (RCT)
• Number of patient screened 125
• Number of patients included 50
• Reasons for exclusion
• G.I. bleed 26
• Encephalopathy 15
• Alcoholic cirrhosis 20
• Renal failure 6
• Dibetes mellitus 1
• Unable to follow protocol/refusal 6
• Lost to follow up within 3 weeks of inclusion 7
• Adequate data for analysis 43
• No. of patients completing 6 months
• of therapy with Glycyrrhizin 43

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Saraya Herbal medicines Glycyrrhizin

• Glycyrrhizin in cirrhosis (RCT)
• Glycyrrhizin Controls
• Etiology
• HBV 10 15
• HCV 5 3
• HBV HCV 2 0
• Cryptogenic 4 4
• Childs score
• A 8 4
• B 10 14
• C 3 4
• All parameters between both groups were similar.

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Saraya Herbal medicines Glycyrrhizin

• Glycyrrhizin in cirrhosis (RCT)
• Parameters Glycyrrhizin Controls p
• 21 22 --
• Complete Response 10 4 lt0.01
• 16(76) 6(27)
• Partial response 6 2
• Failure 5 (24) 16 (73) lt0.01
• Biochemical relapse 6/16(36) 1/6(17) gt0.1
• Death 5 (24) 7(32) gt0.1
• Complications 5 (24) 11(50) gt 0.1
• (SBP/encephalopathy)

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Saraya Herbal medicines Glycyrrhizin

• Summary (RCT)
• 1. No significant difference seen in child score
  at the beginning but at the end of therapy more
  patients in treatment group had better childs
  score.
• 2. Biochemical remission better in treatment
  group as compare to controls (76 Vs 27 (ALT ? )
• 3. Synthetic function like serum albumin
  Prothombin time showed improvement is treatment
  group.
• 4. No difference in virological clearence seen
• 5. No histological improvement noticed .
• 6. Complication are seen in 25 pt in treatment
  arm are as compared to 50 in controls mortaltiy
  remained unchanged

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Saraya Herbal medicines Glycyrrhizin

• Conclusions
• Glycyrrhizin improve survival in patient with SHF
  although no effect seen on hepatotropic viruses
• HEV induced SHF have better prognosis and do not
  have chronic sequelae. Drug may be of great help
  as hepatoprotective almost curative.
• In HBV HCV related SHF survival improved but
  high chronocity seen. So once synthetic functin
  improve there patietns can be treated with
  antiviral
• In chronic hepatitis drug can help in improving
  synthetic liver function and decreases
  inflammatory activity so that antiviral can be
  used subsequently
• Not effective in clearing both HBV HCV

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Saraya Herbal medicines Glycyrrhizin

• Conclusions
• In cirrhosis with activity although no effective
  therapy is available Glycyrrhizin helps by
  improving synthetic function, decreases ALT and
  bilirubin in substantial proportion of patient.
  Discontinuation of therapy leads to relapse of
  necro inflammatory activity,
• No histolgical remission, viral clearance or
  survival benefit noted. Hence these patient may
  need long term therapy
• Further studies are needed to assess utility of
  this drug.