Acute Hepatotoxicity Caused by Enalapril: a Case Report

case reports
Acute Hepatotoxicity Caused by Enalapril: a Case Report
Gustavo Henrique da Silva1, Almerinda Vieira Fernandes Ribeiro Alves2, Pedro Duques2, Tiago Sevá-Pereira2,
Elza Cotrim Soares2, Cecilia Amelia Fazzio Escanhoela1
1) Department of Pathology; 2) Department of Medicine, Faculty of Medical Sciences, State University of Campinas
(UNICAMP), Sao Paulo, Brazil
Abstract
A case of enalapril-induced acute hepatotoxicity with
an unusual morphology is described. This morphology
was characterized by macro- and microvesicular steatosis
associated with neutrophil infiltration and Mallory bodies,
occasionally with satellitosis. These alterations were most
abundant in zone 1 of the periportal region, less common in
zone 2 and rare in zone 3. There was also confluent periportal
necrosis with sinusoidal fibrin deposits associated with
intense ductal metaplasia and an infiltrate of inflammatory
cells that included plasmocytes and a few eosinophils, as
well as focal biliary damage. This morphology, that may be
referred as „predominantly periportal steatohepatitis”, was
distinct from that associated with non-alcohol and alcoholinduced steatohepatitis, both initiated in acinar zone 3 and
subsequently extended to other zones.
Keywords
ACE inhibitors – enalapril – acute hepatotoxicity – liver
steatosis.
Introduction
During the last 20 years, angiotensin-converting enzyme
(ACE) inhibitors have been extensively used to treat
cardiovascular disorders, including hypertension. These
drugs are generally well tolerated [1, 2]. However, hepatic
injuries, which are rare [3, 4], have been reported in patients
treated with captopril [5-8], lisinopril [9, 10], ramipril [2] and
enalapril [1,11-14,15-18]. In this report, we describe a case
of acute hepatotoxicity that involved unusual morphological
alterations referred to as “predominantly periportal
steatohepatitis” in an individual treated with enalapril.
Received: 04.04.2009Accepted: 17.04.2009
J Gastrointestin Liver Dis
June 2010 Vol.19 No 2, 187-190
Address for correspondence:
Gustavo Henrique da Silva
Department of Medicine, Faculty of Medical Sciences, State University of Campinas, Sao Paulo, Brazil
Email: [email protected]
Case Report
A 44-year-old white man presented with a history of
jaundice during the last 30 days and hepatic encephalopathy
that was preceded by intermittent bouts of fever during the
previous three months. The patient had a 10-year history
of systemic lupus erythematosus (SLE), had been using
corticoids for one year (40 mg/day) and had been taking
enalapril (Pressotec®, 10 mg/day) for 2.5 years to treat
hypertension. In the previous three months, the dose of
enalapril had been increased to 20 mg/day. To treat the
recurrent fever, the patient had used paracetamol on an
irregular basis. The patient reported that in the course of his
professional duties he had been in contact with petroleum
derivatives, including toluene, kerosene, paint thinner,
ethyl acetate and alcohol. In the days immediately prior
to the onset of jaundice, he had manipulated pesticides
that included Madaldrin-Pikapau (a formicide), Mirex-Ssulphluramide (a fungicide) and Tanidil® (an ectoparasiticide
for veterinarian use). The patient was not overweight (64 kg)
and his body weight index (BWI) was 21.63. He showed
elevated transaminases (AST, ALT), g-glutamyltransferase
(g-GT) and alkaline phosphatase (AP) (Table I); antinuclear
antibodies, anti-DNA and viral markers were negative.
The patient was admitted to hospital and isolated from
all possible hepatotoxic agents. He underwent a liver biopsy
a few days after admission and was kept on corticoids and
supporting treatment, resulting in the normalization of serum
enzyme levels. The biopsy revealed periportal confluent
necrosis, sinusoidal deposition of fibrin, focal biliary damage
and intense ductal metaplasy with macro- and microvesicular
steatosis associated with neutrophil infiltration and Mallory
bodies, occasionally with satellitosis. These alterations were
greatest in zone 1 but extended to zone 2 and, more rarely,
to zone 3 (acinar zone) (Fig. 1). The patient was discharged
from hospital after 26 days and re-initiated his treatment
with enalapril. Three weeks later he presented again with
fever and increased serum transaminase and bilirubin levels.
Enalapril use was once again discontinued and after six
weeks the serum enzyme levels had returned to normal.
188
Silva et al
Table I. Biochemical data upon admission and at subsequent intervals.
Admission
Two
Four
Six
Nine
Reference
values
1.9
2.9
-
3.2
-
3.4-4.8
Glucose (mg/dl)
77
106
-
-
-
70-109
Sodium (mEq/l)
131
135
-
-
-
133-145
Potassium (mEq/l)
4.2
4.4
4.2
3.7
-
3.3-5.1
Aspartate aminotransferase (AST,
U/l)
859
68
453
38
20
37
Alanine aminotransferase (ALT, U/l)
370
64
285
35
23
40
Alkaline phosphatase (U/l)
668
137
747
150
100
40-129
Gama-glutamyltransferase (U/l)
1210
329
1073
484
301
9-40
72
27
-
-
-
49
Creatinine (mg/dl)
1.09
0.65
0.8
-
0.93
1.2
Conjugated bilirubin (mg/dl)
13.1
-
5.51
-
-
0.2
Unconjugated bilirubin (mg/dl)
3.3
-
1.35
-
-
0.8
Total bilirubin (mg/dl)
16.4
-
6.86
-
-
1
Albumin (g/dl)
Urea (mg/dl)
Time (months) after admission
Fig 1. A – Periportal steatosis and associated focal parenchymal infiltrate of inflammatory
(predominantly polymorphonuclear) cells (H-E, x40). B – Detail of (A) (H-E, x400). C – Confluent
periportal necrosis with sinusoidal deposits of fibrin (H-E, x100). D – Portal infiltration of
inflammatory cells, mainly plasmocytes, with focal damage to biliary ducts (H-E, x200).
Discussion
Although there were many potentially hepatotoxic
chemicals involved in this case, the clinical signs and
laboratory findings following the re-introduction of enalapril
therapy, together with the total recovery in hepatic function
when treatment with enalapril was interrupted, confirmed
this drug to be the cause of hepatotoxicity.
An overdose of acetaminofen (paracetamol) can result in
perivenular necrosis (acinar zone 3), with panacinar necrosis
leaving only small portions of normal tissue in the periportal
region [4, 19]. This damage profile is completely different
from that seen here.
Intoxication by diazinnon (Madaldrin-Pikapau®, an
organophosphate) results in manifestations typical of
poisoning by organophosphates, including the cholinergic
syndrome [20], but was not present in our patient. Poisoning
by Mirex-S-Sulphluramide ® (N-ethyl-perfluorooctane
sulfonamide), a fungicide with intrinsic hepatotoxicity,
causes typical periportal steatosis in rats [21], similar to that
seen here. However, the patient had had only minimal contact
with this agent. In addition, such hepatic damage has been
Acute hepatotoxicity caused by enalapril
reported exclusively in rats, with no descriptions in humans.
Intoxication by Tanidil® [an ectoparasiticide (Carbaril)
- associated with cipermetrine] can result in transitory
disturbances in carbohydrate metabolism, protein synthesis
and normal detoxification functions. In addition, Carbaril
causes transitory inhibition of cholinesterase activity [22].
Our patient showed none of these alterations.
The patient had been on corticoid therapy (40 mg/
day) for one year, and this could have contributed to the
development of steatosis. In addition, the patient had recently
been in contact with organic solvents that cause direct or
indirect hepatotoxicity, possibly involving auto-immune
mechanisms. However, since the patient´s contact with these
substances had been minimal, they were not considered to
be the principal cause of the damage observed.
The histological analysis of hepatic tissue excluded
chronic hepatitis caused by SLE since this is normally
characterized by autoimmune responses, e.g., a portal
infiltrate of lymphomononuclear inflammatory cells rich
in plasmocytes, with intense parenchymal involvement,
including the formation of pseudo-rosette hepatocytes.
Liver injury caused by toxins or chemicals is generally
associated with acute or chronic damage. Injury by cytotoxins
is characterized by necrosis, steatosis or both, whereas
cholestatic lesions are characterized by bile retention and may
or may not be associated with portal inflammation. Chronic
injuries include chronic hepatitis, steatosis, phospholipidosis,
veno-occlusive illness, cirrhosis, peliosis and neoplasia. Such
damage may involve intrinsic toxicity of the compound itself,
uncommon host susceptibility or a combination of both.
Uncommon susceptibility may result from immunological
idiosyncrasy (hypersensitivity reaction) or toxic reactions
to drug metabolites (metabolic idiosyncrasy) [23]. In this
regard, the mechanism by which ACE inhibitors cause
liver injury remains unclear, mainly because of the lack
of a suitable experimental model [23]. An immunological
idiosyncrasy could be involved and would concord with
the low incidence of this phenomenon, its occurrence at low
doses and the range of clinical manifestations (cutaneous
rash, fever, myalgia and eosinophilia) that may accompany
this response [7, 10]. On the other hand, a metabolic
idiosyncrasy could involve the sulphydryl group or terminal
proline ring of captopril; this ring structure also occurs for
lisinopril and enalapril [2].
The inhibition of bradykinin inactivation could result
in enhanced arachidonic acid release and conversion into
prostaglandins such as 16,16-dimethyl-prostaglandin E2 that
reduces bile flow in humans. Biliary stasis would increase
the leucotriene levels, resulting in hepatocellular and biliary
toxicity, as seen in animals with ligated biliary ducts [2, 6]. A
metabolic idiosyncrasy may also involve reactive metabolites
produced by the cytochrome P450 system, with direct or
immune-mediated toxicity; indeed, cytochrome P450 may
be involved in the activation of enalapril and glutathione
detoxification [11]. Modulation by enhanced eicosanoid
formation and increased hepatic bradykinin levels has also
been suggested [3, 6, 11]. In agreement with this, several
189
of the clinical and laboratory findings of our patient (fever,
cutaneous rash, myalgia and eosinophilia) must be thought of
as manifestations of an immunological idiosyncrasy [7, 10].
However, the long period between the beginning of enalapril
treatment and the first signs of liver damage suggests the
possibility of a metabolic idiosyncrasy [4].
In the present case, an enalapril dose of 10 mg/day was
apparently well-tolerated for 2.5 years. However, an increase
in the dose to 20 mg/day during the previous six months
coincided with the clinical alterations described here. Other
literature reports of hepatotoxicity caused by enalapril have
shown that the onset of clinical manifestations occurs within
a few weeks [12] to four years [11] after the start of treatment.
In a similar case, captopril at a dose of 25 mg/day was welltolerated for two years, but when the dose was increased to
50 mg/day the patient presented with jaundice and mental
confusion six weeks later.
There is little information on the hepatic morphological
alterations caused by enalapril and other ACE inhibitors.
Specifically for enalapril, the alterations reported include (a)
destructive cholangitis with ductopenia and insufficient ductal
proliferation evolving to chronic cholestasis [12], (b) minimal
cholestasis associated with a moderate inflammatory infiltrate
and fibrosis [11], (c) areas of focal necrosis, predominantly
centrolobular, with a parenchymal inflammatory infiltrate
and portal mixture containing eosinophils, lymphocytes,
plasmocytes and histiocytes arranged in a granuloma-like
formation [18], (d) sudden hepatitis with massive hepatic
necrosis [13], and (e) confluent necrosis, with architectural
collapse similar to the disorganization seen in halothaneinduced hepatotoxicity, including an inflammatory infiltrate
and moderate eosinophilia [1].
Hepatic damage associated with captopril includes
massive hepatic necrosis [5], portal widening with a chronic
inflammatory infiltrate and interface activity (active chronic
hepatitis) [5], and cholestatic alterations with biliary plugs
within canaliculi, feathery degeneration of hepatocytes
and portal inflammatory infiltrate of lymphomononuclear
cells with or without eosinophils [5, 8]. With regard to the
use of ramipril, the principal alterations involved include
cholangiodestructive injuries resulting in ductopenia, with
incipient evolution to biliary cirrhosis [2] while for lisinopril
the major changes involve centrolobular necrosis, cholestasis
and an inflammatory infiltrate of polymorphonuclear cells
with a portal and parenchymal localization [10].
None of the foregoing reports described morphological
alterations similar to those seen here, including the extensive
periportal necrosis. The few agents that typically produce
such injury include phosphorus, ferrous sulfate (high doses),
acetic acid (90%), allyl alcohol and its esters, Proteus
endotoxins, and certain compounds such as halothane [23];
none of these substances was involved in this case.
The present case clearly shows that enalapril can cause
significant and unusual hepatic morphological lesions,
and also highlights the need for close clinical monitoring,
possibly including hepatic histological analysis of patients
being treated with enalapril.
190
References
1. Jeserich M, Ihling C, Allgainer HP, Berg PA, Heilmann C. Acute
liver failure due to enalapril. Herz 2000; 27: 689-693.
2. Yeung E, Wong FS, Wanless IR, et al. Ramipril-associated
hepatotoxicity. Arch Pathol Lab Med 2003; 127: 1493-1497.
3. Hagley MT, Hulisz DT, Burns CM. Hepatotoxicity associated with
angiotensin-converting enzyme inhibitors. Ann Pharmacother 1993;
27: 228-231.
4. Zimmerman HJ. Hepatotoxicity. The adverse effects of drugs and
other chemicals on the liver. Philadelphia: Lippincott Williams &
Wilkins, 1999.
5. Bellary SV, Isaacs PE, Scott AW. Captopril and the liver. Lancet
1989; 26: 514.
6. Hagley MT. Captopril-induced cholestatic jaundice. South Med J
1991; 84: 100.
7. Rahmat J, Gelfand RL, Gelfand MC, Winchester JF, Schreiner GE,
Zimmerman HJ. Captopril-associated cholestatic jaundice. Ann Inter
Med 1985; 102: 56-58.
8. 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: 236-240.
9. Droste HT, de Vries RA. Chronic hepatitis caused by lisinopril. Neth
J Med 1995; 46: 95-98.
10 Larrey D, Babany G, Bernuau J, et al. Fulminant hepatitis after
lisinopril administration. Gastroenterology 1990; 99: 1832-1833.
11. Bas V, Erkan T, Çaliskan S, et al. Toxic hepatitis due to enalapril in
childhood. Pediatr Int 2003; 45: 755 -757.
Silva et al
12. Hartleb M, Biernat L, Kochel A. Drug-induced damage – a three-year
study of patients from one gastroenterological department. Med Sci
Monit 2002; 8: CR292-296.
13. Hurlimann R, Binek J, Oehlschlegel C, Hammer B. Enalapril
(Reniten)-associated toxic hepatitis. Schweiz Med Wochenschr 1994;
124: 1276-1280.
14. Kitai E, Sandiuk A, Zalewski S. Enalapril-induced immunologic
impairment of hepatic function. J Farm Pract 1991; 33: 301-302.
15. Lunel F, Grippon P, Cadranel JF, Victor N, Opolon P. Hepatite aigue
après la prise de maleate d’enalapril. Gastroenterol Clin Biol 1987;
11: 174-175.
16. Todd P, Levison D, Farthing MJ. Enalapril-related cholestatic
jaundice. J R Soc Med 1990; 83: 271-272.
17. Valle R, Carrascosa M, Cillero L, Perez-Castrillon JL. Enalaprilinduced hepatotoxicity. Ann Pharmacother 1993; 27: 1405.
18. Rosellini SR, Costa PL, Gaudio M, Saragoni A, Miglio F. Hepatic
injury related to enalapril. Gastroenterology 1989; 97: 810.
19. Gursoy M, Haznedaroglu IC, Celik I, Sayinalp N, Ozcebe OI, Dundar
SV. Agranulocytosis, plasmacytosis, and thrombocytosis followed
by a leukemoid reaction due to acute acetaminophen toxicity. Ann
Pharmacother 1996; 30: 762-765.
20. Diazinon (EHC 198, 1998). www.inchem.org.
21. Kendall MW. Light and electron microscopic observations of the
acute sublethal hepatotoxic effects of Mirex in the rat. Arch Environ
Contam Toxicol 1979; 8: 25-41.
22. Carbaryl (EHC 153, 1994). www.inchem.org .
23. Zimmerman HJ. Hepatotoxicity. Dis Mon 1993; 39: 675-787.