INDICES> Drug-induced jaundice (2)

["Kirsten Myhr" <kirsten.myhr@relis.ulleval.no>]

INDICES> Drug-induced jaundice (2)
-----------------------------------------------

>Is there anyone who have encountered perindopril induced jaundice?
>Will metronidazole cause a acute increase in ALT/AST and T. Bilirubin and
>jaundice.

Dear Lau Chee Lan

This is from Micromedex Drug consult.

ACE INHIBITOR-INDUCED HEPATOTOXICITY RESPONSE:

1 INCIDENCE
1.A Rare (incidence less than 0.1%).
1.A.1 Rare cases of cholestatic jaundice and of hepatocellular injury with
secondary cholestasis have been reported in patients receiving captopril.
No
cause-effect relationship has been established (Prod Info Capoten(R),
2000).
Through 1996, 21 cases had been reported either in the literature or
directly to the manufacturer (Nissan et al, 1996). Enalapril, fosinopril,
and lisinopril have been linked to overt hepatotoxicity (Gonzales de la
Puenta et al, 2001; Romero-Gomez et al, 2001; Jeserich et al, 2000; Larrey,
1990).
2 OUTCOME
2.A Severe (mortality reported).
2.A.1 Most hepatic toxicity is mild and transient, although elevations in
transaminases, lactic dehydrogenase, alkaline phosphatase, and serum
bilirubin have led to drug withdrawal in up to 0.7%. The elevations are
generally mild and transient which resolve after discontinuation of therapy
(Prod Info Monopril(R), 2000). Deaths secondary to liver failure from
hepatic necrosis, secondary to perforated duodenal ulcer during recovery,
or
following orthotopic liver transplantation secondary to enalapril-induced
liver failure have been reported (Gonzales de la Puenta et al, 2001;
Jeserich et al, 2000; Prod Info Capoten(R), 2000; Hagley et al, 1993;
Larrey, 1990).
3 ASSOCIATED SYMPTOMS
3.A Abdominal pain or tenderness; clay colored stools; dark urine;
decreased
appetite; fever; headache; itching; loss of appetite; nausea and vomiting;
skin rash; swelling of feet or lower legs; unusual tiredness or weakness;
yellow eyes or skin.
4 ONSET/DURATION
4.A EARLIEST ONSET: 5 days (Hagley et al, 1993).
4.B LATEST ONSET: 3 years (Jeserich et al, 2000).
4.B.1 A 46-year-old man treated exclusively with enalapril 10 mg daily for
3
years presented with acute hepatic failure, leading to orthotopic liver
transplantation 7 weeks later, followed by multiorgan failure and death 2
weeks after transplantation (Jeserich et al, 2000).
4.B.2 One case noted with onset of symptoms 6 weeks after increasing the
dose of captopril from 25 mg to 50 mg daily, which had been used for the
previous 2 years (Hagley et al, 1993).
4.C DURATION OF SYMPTOMS (with treatment): 2 weeks to 18 months (Nunes et
al, 2001; Deira et al, 1997; Hagley et al, 1993; Rahmat et al, 1985; Zimran
et al, 1983).
4.D POSITIVE DECHALLENGE: Yes.
4.E POSITIVE RECHALLENGE: Yes.
4.E.1 Cross sensitivity between enalapril and captopril is documented
(Hagley et al, 1992; Shionoiri et al, 1987). Therefore, in patients who
develop hepatotoxicity while taking one angiotensin converting enzyme
inhibitor, other agents in this class should be avoided (Hagley et al,
1992;
Kitai et al, 1991). However, drug-induced hepatitis did not recur with
delapril treatment in a hemodialysis patient with congestive heart failure
who previously suffered from medication-induced liver disorder when treated
with captopril and enalapril (Shionoiri et al, 1987).
5 MONITORING PARAMETERS
5.A LABORATORY:
5.A.1 Serum transaminase as part of routine clinical monitoring of
underlying disease for which ACE inhibitors are being used. Median
elevations 2-to-5-times upper limit of normal described in 15 reported
cases. LDH was minimally elevated in all cases; a markedly elevated serum
bilirubin along with a normal LDH may be an important diagnostic clue
(Schattner et al, 2001).
5.A.2 Signs (jaundice, pruritus, yellow eyes) are common but not universal,
present in 16 of 19 reported cases.
6 CLINICAL MANAGEMENT
6.A PROPHYLACTIC MEASURES:
6.A.1 None known
6.B PHARMACOLOGIC:
6.B.1 Immediate withdrawal of ACE inhibitor therapy.
6.B.2 Cross-sensitivity highly likely; alternative antihypertensive class
or
agents should be substituted for further ACE inhibitor use (angiotensin II
receptor antagonists). ACE inhibitor rechallenge may be considered after
symptom resolution but only with careful monitoring (Schattner et al,
2001).
7 PREDISPOSING RISK FACTORS
7.A DOSE-RELATED: No.
7.A.1 Review of 14 cases of CAPTOPRIL-associated hepatotoxicity noted
cholestatic jaundice in 9, mixed cholestatic-hepatocellular in 4, and
hepatocellular in 1. In the 9 cases of cholestatic jaundice, mean captopril
doses were 225 milligrams (mg) daily (range 75 to 600 mg) (Rahmat et al,
1985).
7.B DURATION-RELATED: No.
7.B.1 In an early literature review of cases, mean onset of jaundice in
patients with mixed hepatocellular-cholestatic jaundice occurred at 150
days
(21 to 300 days)(Rahmat et al, 1985). In 19 cases reported between
1982-1992, duration of therapy prior to detection was a mean of 14 weeks
(median 1 month; range 5 days to 12 months) (Hagley et al, 1993).
7.C AGE GROUP: Mean age 61 to 63 years (Schattner et al, 2001; Hagley et
al,
1993).
7.D GENDER RELATED: No; 8 men, 9 women in one series (Hagley et al, 1993);
overall, 60% of cases women (Schattner et al, 2001).
7.E DISEASE STATES: Among 19 cases, primary and underlying conditions
included hypertension in 14; 3 congestive heart failure; 5 renal failure (4
requiring dialysis); 2 seropositive hepatitis-B (Hagley et al, 1993).
7.F OTHER: Hepatotoxicity has been reported for angiotensin converting
enzyme (ACE) inhibitors in each of the functional classes (phosphoryl,
sulfhydryl, carboxyl) (Hilburn et al, 1993).
8 PROBABLE MECHANISM
8.A MECHANISM: Unknown.
8.A.1 The presence of fever, eosinophilia, rash or combination of all these
symptoms, as well as the short interval between administration and hepatic
injury, suggests a hypersensitivity mechanism (Rahmat et al, 1985). In a
single case report of lisinopril-induced acute hepatitis, findings of
jaundice preceded by fever and myalgia, associated with serum anti-smooth
muscle suggest an immunoallergic mechanism (Larrey, 1990). Altered hepatic
eicosanoid metabolism related to antagonism of kininase II and consequent
failure to inactivate bradykinin has also been proposed. Speculatively,
this
lead to imbalanced production of prostaglandin subtypes known to have
inhibitory effects on bile flow (A-1 and E-2, eg) (Hagley et al, 1993). All
proposed mechanism, however, await confirmation.
9 DOCUMENTATION
9.A QUALITY: Excellent
10 LITERATURE REPORTS
10.A Review of 14 cases of captopril-associated hepatotoxicity noted
cholestatic jaundice in 9, mixed cholestatic-hepatocellular in 4, and
hepatocellular in 1. In the 9 cases of cholestatic jaundice, mean captopril
doses were 225 milligrams (mg) daily (range 75 to 600 mg) with jaundice
occurring in 7 to 150 days (mean, 46 days) (Rahmat et al, 1985). Biopsy
reports in an additional 12 cases showed 8 cholestatic patterns, 2 mixed, 2
hepatic necrosis, and 1 hepatocellular injury (Hagley et al, 1993). The
mean
onset of jaundice in patients with mixed hepatocellular-cholestatic
jaundice
occurred at 150 days (21 to 300 days). The presence of fever, eosinophilia,
rash or combination of all these symptoms, as well as the short interval
between administration and hepatic injury, suggests a hypersensitivity
mechanism (Rahmat et al, 1985).
10.B Asymptomatic, mild elevations in serum aspartate aminotransferase
(AST)
(SGOT) and alanine aminotransferase (ALT) (SGPT) were reported in one
patient receiving ZOFENOPRIL 30 to 60 mg/day (Lacourciere & Provencher,
1989). Liver function test elevations to 3-times normal with trandolapril
occur in less than 1% (Prod Info Mavik(R), 2000). ALT increased from 23 to
274 IU, AST rose from 14 to 126 IU, and serum lactate dehydrogenase (LDH)
was increased from 341 to 505 IU in 1 patient following 8 weeks of oral
ramipril 2.5 mg/day (Fukiyama et al, 1987). Two cases of IMIDAPRIL-related
elevated liver function tests are reported (Saruta et al, 1995), while
liver
enzyme elevations without clinical hepatotoxicity occurred in 2 of 85
patients receiving ALACEPRIL 50 to 100 milligrams/day (Ogihara et al,
1991).
These abnormalities generally resolved within 2 weeks following
discontinuation of the drug (Saruta et al, 1995; Lacourciere & Provencher,
1989).
10.C Hyperamylasemia associated with reversible cholestatic jaundice was
reported in a 74-year-old woman following approximately four weeks of
captopril therapy (25 to 50 milligrams (mg) three times daily) for heart
failure. Jaundice worsened over the next few days (bilirubin, 7.2
mg/deciliter) and amylase levels increased to 2000 IU. Captopril was
discontinued resulting in prompt improvement. There were no signs of acute
pancreatitis (Zimran et al, 1983).
10.D Cholestatic jaundice was described in a 54-year- old male with heart
failure following approximately 3.5 months of CAPTOPRIL therapy (25
milligrams (mg) three times daily). CAPTOPRIL was added to other
medications
(digoxin, isosorbide, furosemide) due to inadequate control of heart
failure. The patient presented with jaundice and elevations in hepatic
function tests (bilirubin, alkaline phosphatase, SGPT and SGOT). Captopril
was withdrawn after 6 days of hospitalization, resulting in resolution of
symptoms and a reduction in bilirubin levels. Hepatic biopsy on the ninth
day of hospitalization demonstrated marked cholestasis with mild portal
inflammation. The patient continued to receive digoxin, furosemide and
isosorbide without further complication (Tabibian et al, 1987).
10.E A 55-year-old man with no history of liver disease presented with
jaundice, fever, myalgia, and an increase in serum aminotransferase enzymes
after receiving LISINOPRIL 20 mg daily for 2 weeks. After 4 weeks of
therapy, jaundice worsened and ascites developed. Lisinopril was
discontinued; there were no drugs other than lisinopril likely to be
responsible for hepatitis in this patient. Despite discontinuation of
lisinopril, the patients' course worsened over the following week,
resulting
in increased ascites, leg edema, confusion, and coma. Histologic exam
showed
evidence of extensive centrilobular hepatic necrosis and cholestasis. The
patients' subsequent course, over the next few weeks, was marked by
progressive improvement of liver function and gradual resolution of hepatic
encephalopathy. Despite improved liver function, the patient died a month
later as a result of post-surgical complications following surgery for a
perforated duodenal ulcer (Larrey, 1990).
10.F ENALAPRIL was associated with a fatal case of liver failure which
appeared 3 years into therapy for hypertension. First symptoms of malaise
and chills appeared 5 days prior to admission, with jaundice of the eyes
and
skin apparent 2 days before admission. Aspartate aminotransferase was 834
U/L and alanine aminotransferase was 936 U/L. Multiple tests for
immunologic
or organic-related causes for liver toxicity were negative. Enalapril was
withdrawn immediately. However, hepatic enzymes remained severely elevated
at 3 weeks, declining dramatically by 6 weeks (142 and 113 U/L,
respectively) but accompanied by Grade I encephalopathy and worsening renal
failure (BUN to 100 mg/dL; serum creatinine to 2.6 mg/dL). Liver
transplantation was performed 7 weeks after admission, but the patient died
2 weeks later due to multiorgan failure (Jeserich et al, 2000).
10.G FOSINOPRIL was implicated as the causative agent of acute cholestatic
liver injury (histological pattern of pure cholestasis) in a 61-year-old
man
who had been treated for 21 days. Lymphocyte transformation assay was
reactive to fosinopril, but negative for his other medications, metoprolol
and diazepam. While serum enzyme concentrations had been normal in the
month
prior, at admission total bilirubin was 19-times normal, and other enzymes
were elevated by 1.5- to 3- times normal. During the 2 months
hospitalization, a number of serious complications were encountered
(malnutrition requiring nutritional support; gastrointestinal bleeding;
acute, reversible renal failure with dialysis). Pruritus was present for 6
months, controlled with naltrexone (10 to 50 mg daily). Bilirubin declined
over 4 months to within normal range, but alkaline phosphatase, peaking at
5-times normal, remained at twice normal levels at 18 month follow-up
(Nunes
et al, 2001). Liver enzyme elevations of 6- to 20-times normal, as well as
biopsy findings of biliary tract damage with cholestasis, eosinophilic
infiltrates and spotty hepatocellular necrosis were noted within 3 months
after FOSINOPRIL. Though the patient was a heavy drinker, alcoholic
hepatitis was not appreciated. Within 4 weeks after drug withdrawal and
alcohol abstinence, liver enzymes returned to normal (Romero-Gomez et al,
2001).

REFERENCES:
1. Deira JL, Corbacho L, Bondia A et al: Captopril hepatotoxicity in a case
of renal crisis due to systemic sclerosis Nephrol Dial Transplant 1997;
12:1717-1718.
2. Fukiyama K, Omae T, Kaneko Y et al: Efficacy and safety of ramipril (HOE
498) in the treatment of hypertension: dose finding study Am J Cardiol
1987;
59:121D-124D.
3. Gonzalez de la Puente M, Calderon E, Espinosa R et al: Fatal
hepatotoxicity associated with enalapril (letter). Ann Pharmacother
2001;35:1492.
4. Hagley MT, Benak RL & Halisz DT: Suspected cross-reactivity of
enalapril-and captopril- induced hepatotoxicity Ann Pharmacother 1992;
26:780-781.
5. Hagley MT, Hulisz DT & Burns CM: Hepatotoxicity associated with
angiotensin-converting enzyme inhibitors. Ann Pharmacother 1993;
27:228-231.
6. Hilburn RB, Bookstaver D & Whitlock WL: Comment: angiotensin-converting
enzyme inhibitor hepatotoxicity: further insights (letter) Ann Pharmacother
1993; 27:1142.
7. Jeserich M, Ihling C, Allgaier H-P et al: Acute liver failure due to
enalapril. Herz 2000; 25(7):689-693.
8. Kitai E, Sandiuk A & Zalewski S: Enalapril-induced immunologic
impairment
of hepatic function. J Fam Pract 1991; 33:301-302.
9. Lacourciere Y & Provencher P: Comparative effects of zofenopril and
hydrochlorothiazide on office and ambulatory blood pressures in mild to
moderate essential hypertension. Br J Clin Pharmacol 1989; 27:371-376.
10. Larrey D, Babany G, Bernuau J et al: Fulminant hepatitis after
lisinopril administration. Gastroenterology 1990; 99:1832-1833.
11. Nissan A, Spira RM & Seror D: Captopril-associated pseudocholangitis: a
case report and review of the literature. Arch Surg 1996; 131:670-671.
12. Nunes ACR, Amaro P, Macoas F et al: Fosinopril-induced prolonged
cholestatic jaundice and pruritus: first case report Eur J Gastroenterolo
Hepatol 2001; 13(3):279-282.
13. Ogihara T, Ishikawa H & Mikami H: Effect of alacepril on quality of
life
in the treatment of hypertension. Curr Ther Res 1991; 49:862-869.
14. Product Information: Capoten(R), captopril. Bristol-Myers Squibb Co,
Princeton, NJ, (PI revised 04/1996) reviewed 05/2000.
15. Product Information: Monopril(R), fosinopril sodium. Bristol-Myers
Squibb Co, Princeton, NJ (PI revised 08/1999) reviewed 05/2000.
16. Product Information: Mavik(R), trandolapril. Knoll Pharmaceutical Co,
Mount Olive, NJ (PI revised 06/1997) reviewed 05/2000.
17. Romero-Gomez M, Miralles EJ, Diaz EG et al: Hepatotoxicity induced by
fosinopril (letter). J Hepatol 2001; 35(2):309-310.
18. Schattner A, Kozak N & Friedman J: Captopril-induced jaundice: report
of
2 cases and a review of 13 additional reports in the literature. Am J Med
Sci 2001; 322(4):236-240.
19. Tabibian N, Alpert L & Alpert E: Captopril-induced liver dysfunction.
South Med J 1987; 80:1173-1175.
20. Zimran A, Abraham AS & Hershko C: Reversible cholestatic jaundice and
hyperamylasaemia associated with captopril treatment. Br Med J 1983;
287:1676.

Most recent revision:  12/2001

On Metronidazole, only one report on suspected liver ADR is listed so that
is rare:

1. A hemodialysis patient developed hepatotoxicity while receiving
metronidazole 250 milligrams orally twice daily for 4 days. The patient had
symptoms of right upper quadrant pain, nausea, vomiting and drowsiness. The
patient developed marked increases in serum aminotransferases: aspartate
aminotransferase 1,450 IU/L (normal less than 27 IU/L). No laboratory
evidence of cholestasis was noted, however. Symptoms resolved and liver
function test returned to normal values within 15 days of discontinuing
metronidazole (Hestin et al, 1994).

It is therefore unlikely that metronidazole would have caused any of the
symptoms described (Meyler's Siden Effects of Drugs 14th Ed).

Kirsten

Kirsten Myhr, MScPharm, MPH
Head of Eastern Region Drug Information Centre

RELIS Ost
Ulleval University Hospital
N-0407 OSLO
Tel: +47 23 01 64 11  Fax: +47 23 01 64 10
kirsten.myhr@relis.ulleval.no (w)
myhr@online.no (h)
www.relis.no


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