|Year : 2021 | Volume
| Issue : 1 | Page : 70-72
Isotretinoin Hepatotoxicity or Isotretinoin Induced Autoimmune Hepatitis?
Fatma Ilknur Varol1, Mukadder Ayse Selimoglu1, Nese Karadag2, Sukru Gungor1
1 Department of Pediatric Gastroenterology, Hepatology and Nutrition, Faculty of Medicine, Inonu University, Malatya, Turkey
2 Department of Pathology, Faculty of Medicine, Inonu University, Malatya, Turkey
|Date of Submission||22-May-2020|
|Date of Decision||27-May-2020|
|Date of Acceptance||29-Jun-2020|
|Date of Web Publication||31-Dec-2020|
Fatma Ilknur Varol
Department of Pediatric Gastroenterology, Hepatology and Nutrition, Faculty of Medicine, Inonu University, Malatya
Source of Support: None, Conflict of Interest: None
While isotretinoin, a drug used for the treatment of severe nodulocystic acne, is known to be hepatotoxic, an association with autoimmune hepatitis (AIH) has not been suggested so far. A 17-year-old girl diagnosed with AIH following isotretinoin use for acne vulgaris is presented, and the differences between isotretinoin hepatotoxicity and isotretinoin triggered AIH were discussed. To conclude this case, we want to underline that induction of an AIH by isotretinoin, even though so far unreported, is possible and thus the drug should be used with care, especially in patients with another autoimmune disease.
Keywords: Autoimmune hepatitis, hepatotoxicity, isotretinoin
|How to cite this article:|
Varol FI, Selimoglu MA, Karadag N, Gungor S. Isotretinoin Hepatotoxicity or Isotretinoin Induced Autoimmune Hepatitis?. Indian J Paediatr Dermatol 2021;22:70-2
|How to cite this URL:|
Varol FI, Selimoglu MA, Karadag N, Gungor S. Isotretinoin Hepatotoxicity or Isotretinoin Induced Autoimmune Hepatitis?. Indian J Paediatr Dermatol [serial online] 2021 [cited 2021 Jan 16];22:70-2. Available from: https://www.ijpd.in/text.asp?2021/22/1/70/305817
| Introduction|| |
Autoimmune hepatitis (AIH) is a chronic necroinflammatory liver disorder of unclear origin characterized by liver-specific and nonspecific antibody production, increased immune globulin synthesis, and histologically, a dense mononuclear cell infiltrate of the portal spaces., Nitrofurantoin and minocycline are two of the best known drugs that have been documented to cause AIH. Viruses have also been shown to trigger AIH. Similarities between viral proteins and self-proteins may be responsible for this trigger function and/or high cytokine levels accompanying infection may also play a role in immune reaction.
While isotretinoin, a drug used for the treatment of severe nodulocystic acne, is known to be hepatotoxic, an association with AIH has not been suggested so far. A case of AIH following isotretinoin use for acne vulgaris is presented, and the differences between isotretinoin hepatotoxicity and isotretinoin triggered AIH were discussed.
| Case Report|| |
A 17-year-old girl who had started isotretinoin (Roaccutane®) treatment, 30 mg b., i.d., after a baseline check of liver enzyme levels (aspartate transaminase [AST] 36U/L and alanine aminotransferase [ALT] 43U/L) had experienced an increase of those enzyme levels during the 3rd week of the treatment (AST 102U/L and ALT 130U/L). Her dose schedule was then reduced to 20 mg b., i.d., and the medication was discontinued 1 week later as the enzyme elevation persisted (AST 98U/L, ALT 141U/L). Values of 145U/L and 214U/L for AST and ALT, respectively, determined 1 month after the discontinuation, prompted a referral to our clinic for an investigation of the cause of the persisting enzyme elevation.
The patient reported using levothyroxine therapy for hashimoto thyroiditis. There was no other medication she used; her family history was unremarkable.
The patient had no complaints, and her physical examination was normal. Complete blood count values were normal; blood chemistry showed AST 122 and ALT 140U/L, total and direct bilirubin, respectively, 1.54 and 0.57 mg/dL, total protein 8 g/dL and albumin 3 g/dL. Immunoglobulin (Ig) G level was 2224 mg/dL (normal range: 724–1611 mg/dL). Antinuclear antibody was positive, as were anti-smooth muscle antibody and anti-liver kidney microsome antibody, both at 1:100. Anti-thyroid peroxidase antibody was 44.5 IU/mL (normal: 0–35); anti-thyroglobulin 241 IU/mL (0–40) and a test for anti-insulin antibody were positive. Free thyroxine (T4) level was 1.03 ng/dL (0.8–1.9), and thyroid-stimulating hormone was 2.03 μIU/mL (0.4–4). Serology was negative for hepatitis A, B, C, and cytomegalovirus; alpha-1 antitrypsin, alpha-fetoprotein, and ceruloplasmin levels were within the normal ranges. An ultrasound examination of the liver was unremarkable. Liver biopsy revealed the presence of severe portal, and periportal plasmocyte-rich infiltration and marked lobular necroinflammatory activity, compatible with AIH [Figure 1] and [Figure 2].
|Figure 1: Portal inflammation, piecemeal necrosis and striking lobular necroinflammatory activity H and E, ×10|
Click here to view
Prednisolone treatment was initiated. Azathioprine was added after observing a drop in the enzyme levels. Transaminases normalized within a month. The patient is currently being followed up.
| Discussion|| |
While AIH etiology is unclear, the disease is known to be triggered by exogenous factors such as viruses and drugs, including phytopharmacologicals. Several clinical observations support the idea that drugs may be potential triggers for some patients., Certain drugs have been suggested to trigger autoimmune reactions even following their discontinuation, including oxyphenisatin, methyldopa, nitrofurantoin, pemoline, minocycline, atorvastatin, thienylic acid, dihydralazine, and anti-tumor necrosis factor α., The hepatic injury results from an immune response targeting proteins in the liver., Circulating antibodies and hypergammaglobulinemia are often present, as in idiopathic AIH; liver biopsy often shows an interface hepatitis with marked plasmocytic infiltrates. Response to corticosteroid treatment supports the diagnosis; a recurrence of symptoms and signs following the discontinuation of corticosteroids provides a differential diagnosis between drug-induced AIH and idiopathic hepatitis. Björnsson et al. indicate that one of the most significant findings in patient series with drug-induced AIH is the absence of relapse following the discontinuation of corticosteroid treatment. Current studies also fail to observe relapses over 36 months of overall follow-up after the interruption of corticosteroid treatment.
Available data on drug-induced AIH consist mainly of case reports and small series of cases. Hepatitis induced by nitrofurantoin and minocycline is well documented. Nitrofurantoin-induced hepatitis has been reported in the US in a series of five patients in the 1970s and in six patients in Netherlands in the 1980s.
A review by Björnsson et al. showed that approximately 9% of AIH cases were drug induced. Of those, over 90% seemed to be linked to the use of either nitrofurantoin or minocycline.
Isotretinoin is preferred for severe inflammatory acne and for cases resistant to antibiotics and topical treatment. It was shown that isotretinoin might cause hepatic injury (for example, liver enzyme level elevation) and changes in blood lipid profile (elevation of triglycerides, total and high-density lipoprotein (HDL) cholesterol, and reduced HDL cholesterol). The decision to continue the treatment with isotretinoin is made on the basis of AST, ALT, and triglyceride level measurements which are performed 1 month after starting the treatment and quarterly thereafter. Vieira et al. reported that most of the patients did not experience any clinical consequences despite aminotransferase level increase and only one had an ALT elevation to more than twice the normal upper limit. Acute hepatic toxicity appears to be a rare adverse effect. As for chronic hepatic toxicity, while it could not be evidenced in prospective studies, elevation of liver function test results due to drug exposure is not always entirely reversible.
In summary, AIH was suspected because this was a 17-year-old adolescent girl with a history of another autoimmune disease (Hashimoto's thyroiditis), elevated transaminases, inversion of the albumin/globulin ratio, high IgG level, positivity for autoantibodies, and a suggestive histologic appearance of the liver biopsy. The occurrence of the event immediately following isotretinoin treatment led to the suspicion that this was the triggering agent. A prompt recovery of elevated transaminase values following the interruption of isotretinoin administration has been observed in the published literature; no case was reported, however, of an agent inducing autoimmunity.
In the case reported here, the possibility of a drug-induced autoimmune reaction instead of hepatotoxicity was supported by the very short duration of isotretinoin use, the failure of transaminases to normalize following the interruption of isotretinoin, and the response of transaminase to immune suppression.
To conclude this case, we want to underline that induction of an AIH by isotretinoin, even though so far unreported, is possible and thus the drug should be used with care, especially in patients with another autoimmune disease.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]