Case Report:

Metformin-Induced
Liver Disease

You-Meei Lin, M.S., R.Ph.1, Hsiang-Yin Chen, M.S.,

Pharm.D.1,2, Ming-Shun Wu, M.D.1, Chun-Jen Chang, M.D.1
Taipei Municipal Wan-Fang Hospital1
Taipei Medical University2,
Taipei, Taiwan.
March 27, 2003
1
 Outline
Introduction
Description of the case
Assessment
Literature review
Conclusion

2
 Introduction
Metformin has antihyperglycaemic
efficacy and benefits of countering
insulin resistance
It is an acceptable first-line therapy for
overweight patients with type II
diabetes mellitus who are not
adequately controlled with diet and
exercise
3
 Introduction
Most serious adverse reaction
associated with metformin is lactic
acidosis
Gastrointestinal adverse effects occur in
less than 20 % of patients
Metformin-induced liver disease is rare

4
 General Data
Patient Name: XXX
Age : 67 Sex : F
Allergies: NKDA
PMH: Type II DM, HTN,
Chronic non-B, non-C Hepatitis
Date ADR Noted: 10/17/2000

5
 Suspected Drug

Glucophage 1g tid P0 (7/11/2000)

6
 Description of the ADR
Patient was prescribed with glucophage 500
mg bid on 5/16/2000
She tolerated well and there was only mild
elevation of hepatic enzyme
(AST=42 and ALT=52 on 7/11/2000)
To improve glycemic control, glucophage was
slowly titrated and increased to 1g tid on
7/11/2000
About 3 months after increasing the dose of
glucophage, the patient developed
hepatotoxicity
7
 Description of the ADR
When abdominal pain, diarrhea and malaise
occurred, she went to OPD for evaluation
Abnormal laboratory values included
AST=351 and ALT=680 on 10/17/2000
Echogram showed fatty liver and
splenomegaly on 11/2/2000
A liver biopsy revealed: piecemeal necrosis
with inflammation consistent with
drug-induced hepatitis on 11/7/2000

8
 Description of the ADR
The patient was hospitalized and treated
with durasilymarin on 10/31/2000
Glucophage was discontinued at the same
time
One month later, symptoms and liver
condition was improved

9
 Drug Profile
Date 5/16 6/20 7/11 8/8 9/12 10/3 10/31
Drug
Gliclazide (80 mg/tab) 1# bid 1# qd 0.5# qd 1# qd 1# qd 1# qd DC
Glucophage(500 mg/tab) 1# bid 2# bid 2# tid 2# tid 2# tid 2# tid DC
Felodipine 5 mg bid ● ● ● ● ● ● ●
Perindopril 4 mg bid ● ● ● ● ● ● ●
Silymarin 70 mg tid ● ● ● ● ● ● ●
Oxazolam 10 mg tid ● ● ● ●
Alverine 60 mg tid ● ●
Mixtard 30HM ●
22U BBF 18U BD
10
Relevant Laboratory Data
5/15 7/11 10/17 11/1 11/10 11/24 11/25
T Bil (mg/dL) 1.97
D Bil (mg/dL) 0.83
AST (U/L) 39 42 351 386 106 68 37
ALT (U/L) 60 52 680 533 130 70 36
LDH (U/L) 325
ALP (U/L) 307
GGT (U/L) 443
PT (Sec) 20.4
Albumin (g/dL) 3.6
BUN (mg/dL) 11 7
Cr (mg/dL) 0.6 0.7

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Other Relevant History
Hepatitis B or C (-)
Alcohol consumption (-)
Patient denied other drug exposure

12
 Assessment
Severity
Causality
Naranjo Causality Assessment Method
Roussel Uclaf Causality Assessment Method
(RUCAM)

Preventability

13
 Severity of ADR
Minor No antidote, therapy or prolongation
of hospitalization is required
Moderate Requires a change in drug therapy,
specific treatment, or an increase in
hospitalization
Severe Potentially life-threatening causes
permanent damage or requires
intensive medical care
Fatal Directly or indirectly contributes to the
death of the patient.
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 Naranjo ADR Causality Assessment
Item Yes No Do Not
Know
1. Are there previous conclusive reports on this reaction? +1 0 0
2. Did the adverse event appear after the suspected drug was +2 -1 0
administered?
3. Did the adverse reaction improve when the drug was +1 0 0
discontinued or a specific antagonist was administered?
4. Did the adverse reaction reappear when the drug was +2 -1 0
readministered?
5. Are there alternative causes (other than the drug) that could -1 +2 0
on their own have caused the reaction?
6. Did the reaction reappear when a placebo was given? -1 +1 0
7. Was the drug detected in the blood (or other fluids) in +1 0 0
concentrations known to be toxic?
8. Was the reaction more severe when the dose was increased +1 0 0
or less severe when the dose was decreased?
9. Did the patient have a similar reaction to the same or +1 0 0
similar drugs in any previous exposure?
10. Was the adverse effect confirmed by any objective +1 0 0
evidence?
Total Score: 5
Definite ADR  9
Probable ADR 5-8
Possible ADR 1-4
Doubtful ADR 0

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 Liver Injury
Hepatocellular
ALT > 2N
ALT / ALP ≧ 5
A multiple of N
Measured together
Cholestatic
ALP > 2N
ALT / ALP ≦ 2
Mixed
ALT > 2N
2 < ALT / ALP < 5
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 RUCAM Score
Item Description Score
1. Time to *Before starting drug or more than 15 days after
onset stopping drug—incompatible unrelated
*From the beginning of drug—
+2
5~90 days Suggestive +2
<5 or >90 days Compatible +1
*From cessation of drug 15 days +1
2. Course *After cessation of drug, ALT decrease:
 50% within 8 days– Highly suggestive +3
 50% within 30 days– suggestive +2 +2
 50% after 30 days– Inconclusive 0
< 50% after 30 days– Against –2
3. Risk *Ethanol: Presence +1
factors Absence 0
+1
*Age: 55 years +1
55 years 0
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 RUCAM Score
Item Description Score
4. Time to onset incompatible 0
Concomitan Time to onset compatible but unknown reaction –1
t drugs 0
Time to onset compatible with known reaction –2
Role proved in this case –3
5. Non- Gr I (6causes):HAV, HBV, HCV, biliary obs,
drug alcoholism, acute hypotension
causes Gr II CMV, EBV, HSV, other underlying disease
Rule out Gr I & Gr II +2
0
Rule out Gr I +1
Rule out 5 or 4 of GrI 0
Rule out <4 of Gr I -2
Probable -3
6. Previous * Reaction unknown 0
information *Reaction published but unlabelled +1 +2
of drug *Reaction labeled in the product’s characteristics +2
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 RUCAM Score
Item Description Score
7. *Doubling of ALT with single drug: Positive +3
Rechalleng *Doubling of ALT with drugs: Compatible +1
e *Increase of ALT but < normal: Negative -2
0
or plasma concentration as toxic +3
or validated lab. Test: Possible +3
Negative -3
Total Score : 7 • 0: excluded
• 1~2: unlikely
• 3~5: possible
• 6~8: probable
• >8: highly probable

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 Preventability of ADR (I)
Hospital Pharmacy 1992; 27:538
(More than one “Yes” Implies Preventable ADR)

(1) Was the drug involved in the ADR considered

inappropriate for the patient’s clinical
condition?
(2) Was the dose, route or frequency of
administration of the drug inappropriate for
the patient’s age, weight and/or disease state/s?

20
 Preventability of ADR (II)
(3) Were required therapeutic drug monitoring
or other laboratory tests pertaining to this
drug not performed ?
(4) Was there a history of allergy or previous
reactions to the drug?
(5) Was a drug interaction involved in the
reaction?
(6) Was a toxic serum drug concentration (or
other laboratory test) determined ?
(7) Was non-adhere involved in the reaction?

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 Assessment
Severity Assessment:
Minor Moderate Severe Death
Naranjo Causality Assessment Method:
Doubtful Possible Probable Definite
Roussel Uclaf Causality Assessment Method
(RUCAM):
Excluded Unlikely Possible Probable Highly probable
Was the ADR preventable?
Yes No

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 Literature Review
Metformin Liver Toxicity
1. Babich MM, Pike I & Shiffman ML:
Metformin-induced acute hepatitis.
Am J Med 1998; 104:490-492
2. Arthur L M Swislocki:
Case report: Pseudohepatotoxicity of metformin.
Diabetes Care, Alexandria; Apr 1998; Vol. 21, Iss. 4;
677

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 Literature Review
Metformin Liver Toxicity
3. Cubuken A, Yilmaz MT, Satman I, Buyukdevrim AS:
Metformin-induced hepatitis.
Istanb-tip-fak-mecm 54:447452, 1991
4. Crespo Valades E:
Hepatotoxic reaction associated with metformin and
chlorpropamide treatment. [letter]
Rev Clin Esp - 1999 Feb; 199(2): 118-9
5. Krentz AJ:
Non-alcoholic steatohepatitis. [letter; comment]
Lancet - 1999 Oct 9; 354(9186): 1300

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 Conclusion
Adverse effect appeared when the dose of
metformin was increased, and its
improvement with discontinuation of the
agent implicates metformin cause this
adverse reaction
The patient was not rechallenged, and direct
causation could not be confirmed
Possibility of gliclazide, felodipine and
perindopril contributed to the development of
drug-induced hepatitis cannot be completely
excluded
25
 Conclusion
Metformin rarely has caused liver disease
All the cases, hepatotoxicity resolved within
several weeks following discontinuation of
metformin
It is still indicated in type 2 diabetes mellitus
patients with mild to moderate liver disease if
liver function test is performed periodically

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