Escitalopram-induced hepatitis:A case report

INTRODUCTION

Depression is a common mental disorder worldwide and a leading cause of non-fatal health loss,affecting more than 264 million people[1].

They arrive exactly at 8:00 a.m. to take her home, but she has been ready since before seven. She has taken a shower -- not an easy task lying down on a shower stretcher. She isn’t allowed to sit up yet without her body brace1, but regardless, here she is, clean and freshly scrubbed and ever so anxious to go home. It has been two-and-a-half months since she has seen her home -- two-and-a-half months since the car accident. It doesn’t matter that she is going home in a wheelchair or that her legs don’t work. All she knows is that she is going home, and home will make everything okay. Even Dorothy says so: “Oh, Auntie Em, there’s no place like home!” It’s her favorite movie.

Thus her desire and curiosity were excited to such an extent that at last she said: Take me to your ship; I shall go there myself and view your master s treasures

Among the antidepressants,selective serotonin reuptake inhibitors are often prescribed as a first-line treatment.They increase the intrasynaptic levels of serotonin by inhibiting the neurotransmitter's reuptake into the presynaptic neuron.However,the benefits of antidepressants are known to be minimal or ever non-existent in patients with mild to moderate symptoms,uselessly exposing them to potential adverse drug reactions[2].Drug-induced liver injury is a rare complication of antidepressants and is a concern mainly for tricyclic and tetracyclic antidepressants[3].

So that evening, when the Princess came once more with her sleeping-drink, he pretended to drink, but threw it away behind him, for he suspected that it was a sleeping-drink

Here we present a case of cholestatic and cytolysis liver injury due to escitalopram,a selective serotonin reuptake inhibitor,and a VigiBasestudy.

CASE PRESENTATION

Chief complaints

The 68-year-old Caucasian male patient,was prescribed escitalopram 5 mg/d by his general practitioner for a minor depressive episode;the posology rose to 10 mg/d one week later.The patient developed clinical icterus with pale stools and dark urine three days later,without any pain or hyperthermia.

History of present illness

The patient was admitted to the emergency unit three days later.He was then transferred to the gastroenterology and hepatology unit,where an etiologic investigation was performed[4].

But to this day I do not know what strange impulse made me take George to see her and to tell her, before I had confided13 in another living soul, of our engagement

Pharmacovigilance analysis of hepatitis and cholestasis induced by escitalopram was investigated using Vigibase,which is the most extensive pharmacovigilance database.It contains more than 24 million individual case safety reports(ICSRs)submitted by national pharmacovigilance centers from countries all over the world within the World Health Organization pharmacovigilance program.

History of past illness

The patient had no history of past illness,chronic treatment or known allergies.

34.Troll: Trolls originated in Scandinavian folklore. They are large and powerful monsters, enemies to humans. Some protagonists in folklore seek the treasures hidden by trolls in their castles or simply to rescue another human captured by a troll. They are similar to ogres in that they have low intelligence and can often be defeated through a battle of wits. They travel at night and live in darkness since their greatest weakness is sunlight. Direct sunlight will cause them to either burst or turn to stone (Jones 1995). Trolls also appear on this site in The Three Billy Goats Gruff.Return to place in story.

Personal and family history

No notable personal or family history.

Physical examination

A physical examination was unremarkable,except for palpable hepatomegaly,eliminating an obstructive cause.Etiologies such as cholangitis,pancreatic carcinoma or edema,cholelithiasis and trauma were not found.

Laboratory examinations

Normochromic and normocytic anemia,a subtle inflammatory syndrome,cholestasis with conjugated hyperbilirubinemia and cytolytic hepatitis were observed(Table 1).The presence of conjugated bilirubin and the absence of hemolysis excluded pre-hepatic jaundice.A viral cause was improbable due to the absence of hyperthermia,and human immunodeficiency virus(HIV),hepatitis viruses(HAV,HBV,HCV,HEV),cytomegalovirus(CMV)and herpes simplex viruses(HSV)serologies were negative.Autoantibodies and serum immunoglobulin levels were not screened.

Imaging examinations

Hepatic ultrasonography was unremarkable.

FINAL DIAGNOSIS

Considering the lack of probing results from the etiologic investigation and the spontaneous resolution of symptoms after treatment was withdrawn,the only possible remaining cause was drug-induced cholestatic and cytolytic hepatitis due to escitalopram.

TREATMENT

Our case illustrates how inappropriate prescriptions can have severe consequences on both patients(hospitalizations)and the health care system(evitable social security costs).

OUTCOME AND FOLLOW-UP

The chronopathology was as follows: The symptoms started to appear ten days after initiation of treatment.Pruritus resolved two days after escitalopram withdrawal.Clinical jaundice disappeared ten days after withdrawal.Liver function tests normalized a month after withdrawal.It should be noted that bilirubin levels normalized more rapidly than transaminase levels,which is not common in clinical practice,especially in drug-induced liver injury(DILI)[5].However,we are unable to explain this phenomenon.

DISCUSSION

Case report description

We used the Roussel Uclaf Causality Assessment Method(RUCAM)to quantify the strength of the association between cholestatic hepatitis and treatment with escitalopram[6,7].The RUCAM comprises seven criteria: The time to onset of reaction after drug start,clinical course,risk factors,concomitant drugs with hepatotoxic properties,non-drug causes,and published information on hepatotoxicity and the response to any new administration to the suspected drug.The RUCAM score ranges from -8 to +14.A higher score means a higher probability of DILI as it is collapsed into the following five-category scale: Highly probable(>8),probable(6-8),possible(3-5),unlikely(1-2),and excluded(≤ 0).

According to the RUCAM,the iatrogenic cause of both hepatitis(10/14)and cholestasis(9/14)in our case was highly probable(Supplementary material).

Literature review

Eligible studies were identified through electronic searches of Medline and Embase(1966 to May 2020),using different sets of keywords.The first set consisted of “escitalopram” and “citalopram”;the second set of “cholestasis” and “hepatitis”,the third one(optional)of “iatrogeny” and “drug-induced”.

One cold evening during the holiday season, a little boy about six or seven was standing1 out in front of a store window. The little child had no shoes on and his clothes were mere2 rags. A young woman passing by saw the little boy and could read the longing3 in his pale blue eyes. She took the child by the hand and led him into the store. There she bought him new shoes and a complete suit of warm clothing.They came back outside into the street and the woman said to the child, “Now you can go home and have a very happy holiday.”The little boy looked up at her and asked, “are you God, Ma’am?”She smiled down at him and replied, “No son, I’m just one of His children.”The little boy then said, “I knew you had to be some relation.”

Approximately two-thirds(64.6%)of the cases of hepatitis or cholestasis related to escitalopram found in Vigibaseconcerned female patients.At first sight,this might indicate gender-based differences in the hepatic toxicity of escitalopram.However,it is well established that depression has a higher prevalence in women than in men:A recent United States national data study found a similar ratio[15].Furthermore,the exact ratio applies to the number of cases of adverse drug reactions notified with escitalopram(69.3% of cases were female patients): It is unlikely that the hepatotoxicity of escitalopram differs according to gender.

Milkiewicz[12]have made assumptions on the pathophysiological mechanism involving the hepatocellular redistribution of multidrug-resistant protein 2,one of the key canalicular proteins responsible for transporting several organic anions,including bilirubin glucuronides,from the hepatocyte to bile.However,the exact mechanism of such hepatotoxicity remains unclear and needs to be investigated.

The moderate daily intake of alcohol(less than 10 g/d)and the absence of damaged hepatocytes,cirrhosis or carcinoma excluded hepatocellular jaundice.

We used Vigibaseto describe the characteristics of the hepatobiliary disorders associated with escitalopram[8].We searched for all ICSRs presenting at least one adverse drug reaction from a defined list related to escitalopram with a minimal set of data(Table 2),submitted from the 14 November 1967 to 7 May 2020.A total of 481 ICSRs were analyzed,but only 127 ICSRs matched our specific criteria of cholestasis and/or hepatitis(Table 2),presumably caused by escitalopram.For each of those 127 ICSRs,we collected the following data:Age and sex of the patient,time between the introduction of escitalopram and the hepatobiliary disorder,withdrawal of escitalopram,necessity for hospitalization and the recovery from hepatobiliary disease after it was diagnosed.

We also performed a disproportionality analysis from the data extracted from Vigibasebetween the adverse reactions “hepatitis acute(PT)” or “cholestasis(PT)” and escitalopram treatment using the case/non-case method.The strength of the association was quantified by crude reporting OR with their 95% confidence interval[9,10].Statistical methods are detailed in Supplementary material.

Statistical significance was defined as a-value threshold of 0.05.Statistical analyses were performed in SAS 9.4(SAS Institute,Cary NC,United States).

In addition,we reviewed the reference lists in the articles.Voican[3]wrote a review for clinicians on antidepressant-induced liver injury.Helmut[11]described a case of cholestasis and acute hepatitis three weeks after introducing citalopram in a 56-year-old woman.Milkiewicz[12]described a case of cholestasis and acute hepatitis two months after introducing citalopram 10 mg/d(posology rose to 20 mg/d one month later).Finally,Ng[13]described a case of cholestasis two weeks after the introduction of escitalopram and olanzapine in a 56-year-old woman.

The mean duration between the introduction of escitalopram and the occurrence of hepatitis or cholestasis was ten days +/- seven days.

“It must have fallen off before I got here,” I said to the kids. “I’ll probably find it back at the bus depot（，） .” Without a word, Charlie returned to his seat. When he got off at his stop, he didn’t so much as glance at me. That summer Charlie moved away...

With regard to the 127 ICSRs included for the characterization of hepatitis or cholestasis secondary to the intake of escitalopram,most of the patients were women(64.6%).The median(interquartile)age was 35years old.

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Cases of cytolytic hepatitis(28 ICSRs - 22.0%)seemed to be more frequent than cases of cholestasis(19 ICSRs - 15.0%).Only 2 ICSRs(1.6%)corresponded to mixed cholestatic and cytolytic hepatitis.

The toxicity of escitalopram did not seem to be dose-dependent: In almost half of cases the prescribed posology was 10 mg/d(49.0%),followed by 20 mg/d(17.6%),5 mg/d(8.6%)and 15 mg/d(5.5%).

The vast majority of cases included in the international pharmacovigilance database lacked data such as the chronology of healing after the withdrawal of escitalopram.However,from our case,we can hypothesize that clinical recovery occurs within a few days and biological normalization within a fewweeks.

Among the 9372588 ICSRs included in the disproportionality analysis,13071 involved escitalopram.Most of the patients were women(69.3%).Patient age was mainly between 45 and 64 years old(57.0%)followed by 65 and 74 years(21.3%),18 and 44 years(13.9%),and ≥ 75 years(7.8%).A signal was found between acute hepatitis or cholestasis and exposure to escitalopram(Table 3).

The duck swam toward them, and Hansel got on her back and bade his little sister sit beside him. No, answered Gretel, we should be too heavy a load for the duck: she shall carry us across separately. 56 The good bird did this, and when they were landed safely on the other side, and had gone for a while, the wood became more and more familiar to them, and at length they saw their father s house in the distance. Then they set off to run, and bounding into the room fell on their father s neck. The man had not passed a happy hour since he left them in the wood, but the woman had died.57 Gretel shook out her apron so that the pearls and precious stones rolled about the room, and Hansel threw down one handful after the other out of his pocket. Thus all their troubles were ended, and they lived happily ever afterward.58

Cholestasis is not mentioned in the summary of product characteristics(SmPC)of escitalopram in the EU or the United States.It should be noted that the American SmPC mentions a risk of delayed hyperbilirubinemia when taking escitalopram,with no further notice(incidence not known).Hepatitis is mentioned in both the European and American SmPC of escitalopram,with an unknown incidence.

Few cases have proved that hepatic cholestasis can rarely be caused by citalopram[11,12].Since citalopram is a racemic composed of 50% R-citalopram and 50% escitalopram,it was plausible that such a rare adverse event could be due to escitalopram.Only recently,Ng[13]described a case of cholestasis due to escitalopram in a 56-year-old woman: The first clinical signs of cholestasis appeared two weeks after escitalopram was initiated.The RUCAM score showed a probable iatrogenic cause.The patient was treated with other drugs,and olanzapine was introduced four days before escitalopram.Olanzapine is also labelled as a cause a cholestasis[14],and up to 28% of patients experience elevated hepatic enzymes.Therefore,in the case presented by Ng[13],it may well have participated in hepatic toxicity.In our case,escitalopram was the only drug taken by the patient,and thus its sole contribution to hepatic toxicity is certain,making this case unique.

The pharmacovigilance analysis confirmed that escitalopram could rarely cause acute hepatitis and cholestasis.However,the ICSRs in Vigibaselack data,especially the course of clinical recovery and biological normalization after escitalopram withdrawal.Therefore,when confronted with hepatitis or cholestasis due to escitalopram,health practitioners must spontaneously report it to their local or national pharmacovigilance center and provide as many details as possible.

An interesting aspect of our case is that the general practitioner prescribed escitalopram for a minor depressive episode.A psychiatrist reexamined the patient during his hospitalization and diagnosed mild depression,with no need for an antidepressant drug.Thus,our case highlights something well established:Antidepressants are minimally helpful,if not useless and dangerous,in patients with mild to moderate depressive symptoms[2].General practitioners and physicians should be aware of the ineffectiveness and harm of serotoninergic antidepressants in patients with non-severe depression.

CONCLUSION

Treatment with escitalopram was immediately stopped.

Although extremely rare,escitalopram can cause drug-induced hepatitis and cholestasis,generally within a week after initiation.Therefore,physicians must be aware of this rare but severe adverse effect.The SmPC of escitalopram should be updated to alert for this risk and give clear clinical guidelines.In the case of hepatitis or cholestasis,if an iatrogenic cause cannot be excluded,escitalopram must be immediately withdrawn and then contraindicated if its responsibility is ascertained.

FOOTNOTES

Wabont G wrote the manuscript;all authors contributed equally to this work and have read and approved the final manuscript.

The study participant provided informed written consent prior to study enrollment.

It is true that she never said so positively, but she certainly allowed the Princess to believe it, because she thought a little disappointment would be good for her

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The authors followed the CARE checklist guidelines.

Then she picked up one gift, held it in her hand as if it were a fragile bird, and walked toward me. At my knee, her beautiful blue eyes looked into mine. She stretched her prize to me and said, One finger, Nana!

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.It is distributed in accordance with the Creative Commons Attribution NonCommercial(CC BYNC 4.0)license,which permits others to distribute,remix,adapt,build upon this work non-commercially,and license their derivative works on different terms,provided the original work is properly cited and the use is noncommercial.See: http://creativecommons.org/Licenses/by-nc/4.0/

France

Soon after that she had a little daughter, who was as white as snow, and as red as blood, and her hair was as black as ebony; and she was therefore called Little Snow-white5. And when the child was born, the Queen died.

Guillaume Wabont 0000-0002-2594-0993;Laurie Ferret 0000-0002-7338-1014;Nicolas Houdre 0000-0003-2023-0594;Antoine Lepied 0000-0002-6935-0856;Johana Bene 0000-0002-1137-1830;Etienne Cousein 0000-0003-1875-3273.

Wang JJ

Webster JR

Wang JJ