A case report of nifedipine-induced hepatitis with jaundice
Yusuf et al. BMC Res Notes
A case report of nifedipine-induced hepatitis with jaundice
Dimas Yusuf 2
Joanna Christy 0
David Owen 1
Meghan Ho 2
David Li 3
Martin J. Fishman 2
0 Beedie School of Business, Simon Fraser University , Vancouver, BC , Canada
1 Department of Pathology, Faculty of Medicine, University of British Columbia , Vancouver, BC , Canada
2 Department of Medicine, Faculty of Medicine, University of British Columbia , Vancouver, BC , Canada
3 Department of Family Practice, Faculty of Medicine, University of British Columbia , Vancouver, BC , Canada
Background: Nifedipine is a generic, well-known and commonly-prescribed dihydropyridine calcium channel blocker used in the treatment of hypertension and Prinzmetal's angina. A known but very rare and serious adverse effect of nifedipine is clinically-apparent hepatitis which can take months to resolve. Case presentation: Here we present a case of nifedipine-induced hepatitis in a 78-year-old Caucasian female with no prior history of liver or autoimmune disease. We discuss our investigative and management approach, and present a review of prior cases. We offer an approach for patients who present with signs of acute liver injury with jaundice and high elevations in serum transaminases. Conclusion: Not much is known about nifedipine-induced hepatitis due to its rare occurrence. Its prevalence is unknown. The disease appears to afflict older men and women. It can present acutely (within days) or subacutely (within 4-8 weeks after medication start) and in an idiosyncratic manner. Chronic or latent cases have also been described, some diagnosed as late as 3 years after medication start. Common symptoms include jaundice, nausea, chills, rigors, diaphoresis, fatigue, and abdominal pain. Laboratory investigations often reveal profound elevations in AST, ALT, GGT, and conjugated bilirubin. Peripheral blood smear may demonstrate eosinophilia. Histology from liver biopsy typically demonstrates infiltration of immune cells, cholestasis, and a picture of steatohepatitis. Treatment involves immediate discontinuation of the drug with supportive care. Thus far, all published instances of nifedipineinduced hepatitis were self-limiting without mortality due to fulminant liver failure. However, this disease can take months to resolve. There is no randomized evidence for other treatments such as corticosteroids.
Nifedipine; Calcium channel blocker; Side effect; Drug-induced hepatitis; Drug-induced liver injury; DILI; Jaundice; Hepatocellular; Liver biopsy; Adverse events
Nifedipine-induced hepatitis is a rare type of
druginduced liver injury (DILI), which has been a subject of
increased scrutiny in the medical community over the
last several years. Broadly speaking, DILI is a serious
complication of medication use, with a prevalence of up
to 14 out of 100,000 people [
]. It is implicated in up to
33% of patients who present with acute liver injury [
and has been cited as the most common cause of acute
liver failure—about 52% of all cases according to one
The majority of DILI—up to 75% in one prospective
study—is due to acetaminophen ingestion [
notable causes include antibiotics—especially
] and fluoroquinolones [
] —as well as
medications from other classes such as anti-epileptics
(Table 1). DILI is typically dose-dependent, and
occasionally idiosyncratic. Dose-dependent DILI is most
commonly caused by large and often supratherapeutic
doses of hepatotoxic drugs, in particular acetaminophen.
Conversely, idiosyncratic DILI is not dose-dependent.
DILI has a broad range of clinical presentations, from
subclinical (or chronic hepatitis) to fulminant liver
failure requiring transplantation or even death [
Histologically it is a diverse phenomenon, with findings that
can resemble autoimmune hepatitis, cholestasis,
steatosis, fibrosis, phospholipidosis, hepatic vein thrombosis,
These medications are commonly associated with drug-induced liver injuries. Acetaminophen, amoxicillin-clavulanate, amiodarone, atorvastatin, and captopril
account for the vast majority of cases. In particular, acetaminophen, isoniazid, propylthiouracil, phenytoin, valproate, and fluoroquinolones account for the vast
majority of drug-induced fulminant liver failures [
biliary sclerosis, granulomatous hepatitis, peliosis hepatis
and cirrhosis [
]. Rarely, DILI is also associated with
hepatic neoplasms, in particular adenomas,
angiosarcomas, and hepatocellular carcinomas [
]. For these
reasons, DILI can be thought of as a “great imitator” of
liver disease and should be suspected in any patient with
acute or chronic hepatitis of unclear etiology.
A 78-year-old Caucasian female presented to a
community hospital in Canada with jaundice, scleral icterus,
and mild epigastric discomfort. She reported a 4-day
history of progressive fatigue with intermittent
nausea and vomiting, diminished appetite, as well as loose,
lightly coloured, and foul-smelling stools. She had no
evidence of coagulopathy or encephalopathy. Her past
medical history included essential hypertension,
dyslipidemia, and chronic obstructive pulmonary disease. She
had no history of liver disease, intravenous drug use,
excessive alcohol consumption, recent travel, infectious
symptoms, or constitutional symptoms. She had no
exposure to poisonous mushrooms or other common
hepatotoxic agents. Her medications were atorvastatin
20 mg daily which she had been taking for many years,
a course of clarithromycin for community-acquired
pneumonia completed 28 days prior to admission, and
nifedipine 10 mg daily for hypertension which was
started 14 days prior to admission. She did not take any
alternative or complementary therapies.
Physical examination revealed a slightly distended
abdomen with diffuse tenderness to palpation,
particularly in the epigastric region, and jaundice with scleral
icterus. There was no rebound tenderness, guarding, or
hepatosplenomegaly. She did not have any other
stigmata of liver disease and the rest of her physical
examination was unremarkable.
Initial laboratory investigations revealed profound
elevations in all liver enzymes, bilirubin, and LDH—all
indicative of significant hepatocellular injury:
• ALT 1912 U/L (29× upper limit of normal or
• AST U/L (42× ULN).
• ALP 439 U/L (3× ULN).
• GGT 352 U/L (6× ULN).
• Conjugated bilirubin 119 μmol/L (24× ULN).
• Total bilirubin 134 μmol/L (7× ULN).
• LDH 408 U/L (1.7× ULN).
Her INR was between 1.1 and 1.3 throughout the
hospitalization, PTT was 27 s, and albumin was slightly
low at 31 g/L (normal > 34 g/L). Lipase was within
normal range at 288 U/L, and creatine kinase was normal
at 31 U/L.
Her complete blood count was within normal
limits. There was a mild monocytosis of 1.4 giga/L. Her
electrolytes were within normal range. Creatinine was
65 μmol/L with an estimated glomerular filtration rate
(eGFR) of 76 mL/min. Her lactate, anion gap, random
blood glucose, and extended electrolytes were all also
within normal limits.
Other laboratory investigations ruled out many
infectious, metabolic, and autoimmune causes of acute liver
injury. Serologies (IgM) for Epstein–Barr virus (EBV) and
cytomegalovirus (CMV) were negative. Serologies for the
human immunodeficiency virus (HIV) and hepatitis A, B,
C, and E viruses (e.g. hepatitis A IgM, HBsAg, Anti-HBs,
anti-HBc, anti-HBc IgM, anti-HCV, HBeAg) revealed
no sign of current infection. Anti-liver kidney
microsome type 1 (anti-LKM1) antibody, anti-mitochondrial
antibody (AMA), anti-smooth muscle antibody (ASMA),
ceruloplasmin, and immunoglobulins were negative.
Alpha-1 antitrypsin was also negative. The ANA titre was
1:80, a non-specific finding in the context of the patient’s
A computed tomography (CT) scan of the patient’s
abdomen revealed that her hepatic parenchyma was
unremarkable, with no evidence of hepatic obstruction,
biliary duct dilatation, thrombosis, or malignancy (Fig. 1).
Incidentally, the patient was discovered to have a
prominent Riedel’s lobe of the liver and sigmoid diverticulosis.
A follow-up abdominal ultrasound revealed that her liver
had a heterogeneous echotexture. The gallbladder was
markedly thickened and edematous but decompressed.
The patient was admitted to hospital. Suspicious that
her liver injury may be statin-induced, her atorvastatin
was held on admission. Nifedipine was also held on
Although her liver enzymes continued to steadily
improve during the admission, the patient’s clinical
condition deteriorated during the first 14 days of
hospitalization with worsening fatigue, jaundice, mild hypotension
and development of a generalized, pruritic urticarial
eruption that partially responded to antihistamines. The
patient then developed an acute COPD exacerbation
treated with a 5-day course of prednisone, oral
moxifloxacin, nebulized ipratropium and salbutamol, and
Given the ongoing elevation in liver enzymes and
jaundice, an ultrasound-guided core liver biopsy was
performed. The biopsy demonstrated portal tract and
central zone inflammation with necrosis and plasma cell
infiltrates, which was consistent with a
hypersensitivitymediated drug-induced hepatitis (see Fig. 2).
Plasma cell infiltration of the liver, seen in our patient’s
liver biopsy, can be a sign of autoimmune hepatitis.
However, in this case, we felt that the overall histologic
pattern of liver damage was not consistent with what would
be typically seen in autoimmune hepatitis. This, coupled
with the absence of immunological markers associated
with autoimmune hepatitis, made the diagnosis of
autoimmune hepatitis less likely.
In addition, the patient’s presentation is very
consistent with published cases of nifedipine-induced hepatitis,
which have suggested that symptoms typically manifest
within 2 weeks of initial exposure. This patient’s
symptoms began 10 days after she started taking the drug.
During our patient’s third week of hospital stay, her
bilirubin and liver enzymes began to normalize. Her
jaundice, abdominal pain, and urticaria resolved, and
her energy improved. She remained in hospital for 2
additional weeks for supportive care and rehabilitation.
She was discharged home after 5 weeks of
hospitalization with full resolution of her liver disease and return
to baseline functioning.
The limitation of our diagnosis was that it largely
relied on the exclusion of other diagnoses. While it
remains possible that there was another etiology, we
felt the odds were small. One way to confirm the
diagnosis would be to re-challenge the patient with
nifedipine after she has recovered from the illness, to see if a
similar reaction recurred. However, given the severity
of the patient’s liver injury, we did not have the option
to do this.
The patient’s other medications—in particular
atorvastatin and clarithromycin—have also been associated
with drug-induced hepatitis. However, for various
reasons discussed below, we felt that nifedipine was the
most likely cause.
The possibility that the patient’s liver injury was
caused by atorvastatin was strongly considered,
however ultimately, we believe this to be less likely as the
patient had been taking atorvastatin for years with no
complications. Twelve weeks after the patient was
discharged from hospital, the patient was re-challenged
with atorvastatin at gradually increasing doses and
experienced no liver injury.
Clarithromycin has been known to cause liver
enzyme elevations in 1–3% of patients exposed to the
drug, and rarely, it can also cause fulminant
hepatitis similar to nifedipine. One key difference is that a
number of deaths have been reported in the literature
for clarithromycin, whereas none have been reported
for nifedipine [
]. The histology of both statin and
clarithromycin-induced hepatitis can be similar to
the histology of nifedipine-induced hepatitis. All can
exhibit signs of cholestasis [
] and infiltration of
immune cells [
]. Despite these similarities, the
diagnosis of clarithromycin-induced hepatitis was felt to
be less likely for our patient as she has been exposed
to clarithromycin on multiple occasions for COPD
exacerbations over the past several years, and none of
her previous exposures to clarithromycin has resulted
in drug-induced liver injury. Furthermore, the onset
and peak of liver injury in relation to the timing of
clarithromycin exposure is not typical of
clarithromycin-induced liver injury—at least for the ones that have
been reported. A recent review of the literature on this
topic demonstrated that the vast majority of fulminant
liver injuries caused by clarithromycin occur within
days of administration, usually within 1 week [
Onset of fulminant liver injury that occurs 3 weeks
after discontinuation of clarithromycin has virtually
Discussion and conclusions
Nifedipine is a dihydropyridine calcium channel blocker,
initially developed in Germany in the 1970s [
remains a commonly prescribed medication for
hypertension and Prinzmetal angina. Common side effects
include facial flushing (up to 25%), peripheral edema (up
to 30%), dizziness or lightheadedness (up to 27%), and
gastrointestinal symptoms such as nausea and heartburn
(up to 11%) [
]. A very rare but known adverse effect
of nifedipine is drug-induced liver injury, which has
been described in the literature in nine case reports and
reviews that were published between 1979 and 1999 [
14, 15, 17, 19–23
Characteristics of nifedipine‑induced hepatitis
Not much is known about nifedipine-induced hepatitis
due to its rare occurrence. The disease appears to afflict
older men and women, with an age range of 59–80 years
old as per published case reports [
13, 14, 16–21
14, 15, 17–22
14, 15, 17, 19–23
Nifedipine-induced hepatitis is often acute and
idiosyncratic, with symptoms occurring as rapidly as within
12 h to as late as 1 month after initial ingestion [
Indolent cases have been described, diagnosed as late as
3 years after initial ingestion [
presenting symptoms are jaundice, nausea, chills, rigors,
diaphoresis, fatigue, and abdominal tenderness.
Biochemically, the initial pattern of liver injury is
profound elevation of liver enzymes and conjugated
bilirubin. Peripheral blood smear may reveal eosinophilia [
Data from published cases reflect an average elevation of
AST of 17× ULN, ALT 7× ULN, GGT 16× ULN, and
conjugated bilirubin of 14× ULN. Total bilirubin was
also frequently elevated but to a lesser degree at 5× ULN,
as were LDH (3× ULN) and ALP (3× ULN) (Table 2).
Immunological markers of autoimmune hepatitis, ANA,
ASMA, AMA, and anti-LKM1 are typically negative or
On liver biopsy, a multitude of findings have been
described in the literature. There is often a general
impression of “hypersensitivity” [
] or “subacute
]. Signs of cholestasis and centrilobular necrosis
have been observed [
]. Other features include an
alcoholic-like picture with steatosis, hypertrophic
hepatocytes and Mallory bodies [
], and an expansion of portal
tracts with a mixed inflammatory infiltration of
lymphocytes, histiocytes, neutrophils, and eosinophils [
these latter findings, the parenchyma architecture may
be preserved with mild infiltration of lymphocytes,
neutrophils, and eosinophils [
]. The findings of
nifedipineinduced hepatitis are similar to the findings of liver injury
from verapamil, another calcium channel blocker [
This table summarizes the findings of prior case reports of nifedipine-induced hepatitis in the literature. Jaundice, nausea, anorexia, chills, rigors, and abdominal pain
appear to be the most common presenting symptoms. Biochemically, there is a pattern of general transaminitis with marked elevations in AST, GGT, and conjugated
In case reports where repeat liver biopsies were
obtained following clinical and biochemical resolution of
the liver injury, histological changes seen during the
illness—in particular steatosis and Mallory
bodies—typically resolve [
Diagnosis, management, and outcome of severe drug
induced liver injury
DILIs are one of the few etiologies of liver injury that
can result in very high elevations of liver enzymes that
exceed 1000 U/L (Table 3). The main treatment for DILI
is prompt discontinuation of the offending drug.
Switching patients to another drug from the same class is not
entirely safe as cross-reactions frequently occur. For
instance, in one case of nifedipine-induced hepatitis,
the patient’s jaundice recurred after he was started on
amlodipine, another dihydropyridine calcium channel
While the majority of DILIs will resolve with prompt
discontinuation of the offending drug, DILIs can worsen
nonetheless and progress to liver failure that requires
transplantation. Long-term sequelae of DILI include
ongoing impaired liver function, progression to
cirrhosis, and rarely, the development of hepatic
malignancies. Mortality rates for DILI vary greatly depending on
the offending drug and patient population, but has been
reported as up to 60% in the published literature [
Fortunately, nifedipine-induced liver injury tends to have a
favorable outcome, and no cases of mortality or liver
transplantation have been reported in the literature [
Additional therapeutic options are available to
clinicians in select situations. Acetaminophen toxicity can
be treated with n-acetyl cysteine (NAC) [
Valproateinduced hepatitis can be managed with activated
charcoal and emergent hemodialysis [
Analysis of the United States Network for Organ
Sharing (UNOS) liver transplant database revealed that DILI
accounted for 15% of liver transplants secondary to acute
liver failure. Most (76%) of the recipients were female.
Acetaminophen accounted for 49% of DILI-related liver
transplants, followed by isoniazid (17.5%),
propylthiouracil (9.5%), phenytoin (7.3%) and valproate (7.3%). A
marker for increased severity and poorer prognosis was
described by Hyman Zimmerman and recently validated
by two different groups in studies involving a large
number of patients with suspected DILI. Named Hy’s rule,
it includes the presence of jaundice with a concomitant
elevation in serum bilirubin (≥ 2× ULN) and serum
transaminases, in particular ALT (≥ 3× ULN) [
Hepatitis is a rare adverse effect of nifedipine. It typically
affects older individuals who recently began taking the
medication. Presenting symptoms include jaundice,
nausea, chills, rigors, diaphoresis, fatigue, and right upper
quadrant abdominal pain. Laboratory investigations
In general, consider: total IgG, gamma-globulin level, anti-soluble liver antigen or liver
pancreas (anti-SLA/LP) antibody, liver biopsy
Anti-nuclear antibody (ANA), anti-smooth muscle antibody (ASMA), anti-actin antibody
(AAA), anti-dsDNA antibody, anti-soluble liver antigens (SLA) antibody, anti-neutrophil
cytoplasmic antibody (ANCA), anti-mitochondrial antibody (AMA)
Anti-liver kidney microsomal 1 (anti-LKM1) antibody, anti-liver cytosol antigen (anti-LC1),
atypical p-ANCA (pANNA), anti-soluble liver antigens (SLA)
CBC, lactate, hypercoagulopathy workup, age-appropriate malignancy workup, abdominal
ultrasound, CT, or MRI
The above are causes of liver injury that can result in liver enzyme elevations that exceed 1000 U/L, or 25 times the upper limit of normal
reveal elevations in bilirubin and liver enzymes.
Autoimmune serology are not expected to be positive.
Imaging is usually benign or non-specific. Liver biopsy often
shows a pattern of generalized inflammation, infiltration
of immune cells in hepatic structures, and cholestasis.
Patients will not improve unless the offending
medication is discontinued. Other calcium channel
blockers should be avoided if possible, as there have been
reports of cross-reactivity. Treatment is supportive, as
no treatments have been formally studied. Reassuringly,
the nifedipine-induced DILI appears to be self-limiting
although the elevations in liver enzymes can take months
to resolve. No deaths from nifedipine-induced hepatitis
have been reported in the literature.
In general, drug-induced hepatitis should be suspected
in all patients with acute or chronic liver injury of unclear
etiology. While most cases of drug-induced hepatitis
resolve with prompt discontinuation of the offending
agent, some may progress to fulminant and irreversible
liver failure. Markers for increased severity and poorer
prognosis include the presence of jaundice and elevation
in bilirubin (≥ 2× ULN) and ALT ≥ 3× ULN [
case serves as a reminder to clinicians to always consider
the possibility of drug-induced hepatitis in patients with
liver injury of unclear etiology.
ALP: alkaline phosphatase; ALT: alanine aminotransferase or alanine
transaminase; AMA: anti-mitochondrial antibody; ANA: anti-nuclear antibody; ANCA:
anti-neutrophil cytoplasmic antibody; Anti-LKM1: anti-liver kidney
microsomal type 1 antibody; ASMA: anti-smooth muscle antibody; AST: aspartate
aminotransferase; BPM: beats per minute; CMV: cytomegalovirus; COPD:
chronic obstructive pulmonary disease; CT: computed tomography; DILI:
drug-induced liver injury; EBV: Epstein–Barr virus; eGFR: estimated glomerular
filtration rate; g/L: grams per liter; GGT: gamma-glutamyl transpeptidase;
giga: unit prefix in the metric system denoting a factor of billion; HIV: human
immunodeficiency virus; IADL: instrumental activities of daily living; INR:
international normalized ratio; IV: intravenous; LDH: lactate dehydrogenase; mg:
milligram; mL: milliliter; mL/minute: milliliters per minute; mmol/L: millimoles
per liter; MRI: magnetic resonance imaging; NAC: N-acetyl cysteine; NSAID:
non-steroidal anti-inflammatory drug; PTT: partial thromboplastin time; U/L:
units per liter; ULN: upper limit of normal; umol/L: micromole per liter; UNOS:
United States Network for Organ Sharing; WBC: white blood cell.
DY obtained consent from the patient and her family and drafted the article.
DO assisted in diagnosing the case and manuscript preparation. JC and MH
assisted in the preparation and publication of the manuscript. DL was the
attending physician and provided much of the inspiration behind the article.
MJF assisted in diagnosing the case and provided additional clinical guidance.
All authors read and approved the final manuscript.
DY is an internist and alumnus of the University of British Columbia Faculty
of Medicine. JC is an alumnus of the Faculty of Land and Food Systems at
the University of British Columbia and an MBA student at the Beedie School
of Business. DO is a professor of pathology in the Department of Pathology
and Laboratory Medicine at the University of British Columbia and
consultant pathologist at Vancouver General Hospital. His major interest is the
morphologic aspects of gastrointestinal and pancreatic disease including
the influence of histopathologic appearances on the prognosis of malignant
neoplasms. MH is a general internist and alumnus of the University of British
Columbia Faculty of Medicine. DL is a family physician and clinical professor in
the Department of Family Medicine at the University of British Columbia. MJF
is a gastroenterologist and clinical professor in the Department of Medicine at
the University of British Columbia.
The authors declare that they have no competing interests.
We thank the patient and her family for giving us their permission to study
and publish this case for the advancement of medical knowledge and for the
benefit of future patients.
Availability of data and materials
This article contains all of the data and materials that were available to us and
utilized in the production of this article. No additional data or materials exist
beyond what is presented in this article.
Consent for publication
Express written consent was provided to the authors by the patient for the
publication of this case report.
Ethics approval and consent to participate
This study was self-funded by the authors. No outside source of funding exists.
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