J Clin Pharm Ther. 2014 Oct;39(5):573-6.

A case of synthetic oestrogen-induced autoimmune hepatitis with microvesicular steatosis.

Morii K, Nishisaka M, Nakamura S, Oda T, Aoyama Y, Yamamoto T, Kishida H, Okushin H, Uesaka K.

Department of Hepatology, Japanese Red Cross Society Himeji Hospital, Himeji, Hyogo, Japan.




Drug-induced liver injury (DILI) is a leading cause of acute liver failure in developed countries. Hepatotoxicity is a well-recognized adverse effect associated with synthetic oestrogens, which can cause cholestasis. The current report describes ethinyloestradiol (EE2)-associated highly unusual adverse effects of autoimmune hepatitis (AIH) and microvesicular steatosis (MS). DILI that fulfils the criteria for AIH is referred to as drug-induced autoimmune hepatitis (DIAIH). MS is a potentially severe liver lesion that results from mitochondrial dysfunction. We explore the pathophysiological mechanisms underlying DIAIH and MS.


A 51-year-old woman presented with jaundice, increased liver enzymes and IgG, and positive ANA. She had been taking EE2 for 3 years. Liver biopsy showed prominent interface hepatitis with MS. A drug-lymphocyte stimulation test (DLST) using EE2 was positive. The liver biochemical parameters had normalized after the EE2 discontinuation; however, they exacerbated 5 months post-onset. Repeated liver biopsy showed interface hepatitis with no MS. Considering EE2-induced DIAIH, corticosteroids treatment was initiated. Then, all liver biochemical parameters had normalized, and the corticosteroids were successfully withdrawn. The patient continued to be in complete remission over the next 3 years.


Five remarkable points should be emphasized: (i) a long latency interval, despite the acute presentation; (ii) exacerbation of liver biochemical parameters, even after drug cessation; (iii) the paired liver biopsies indicating continuing inflammation and disappearance of toxic features; (iv) a positive DLST and the absence of fibrosis consistent with DIAIH and not AIH; and (v) a rare histological feature of MS. Intense immunoallergic reactions were likely triggers of MS in the current case. A possibility of DIAIH should be considered in cases of DILI which exhibit overt jaundice, autoantibodies, intense histological inflammation and a long latency period.


autoimmune hepatitis; drug-induced liver injury; microvesicular steatosis; synthetic oestrogen

PMID: 24989642




Drug-induced autoimmune hepatitis

Drug-induced liver injury (DILI) is a leading cause of acute liver failure in developed countries. If accompanied by jaundice, DILI is associated with 9–12% mortality in large, global DILI registries. The latency period tends to be longer in severe cases than in mild cases. DILI that manifests with autoimmune hepatitis (AIH)-compatible features is referred to as“drug-induced AIH”(DIAIH). In a recent large cohort of AIH patients, 9.2% were shown to have DIAIH.([1]) Strikingly, many drugs that cause DILI, such as minocycline, diclofenac, and synthetic estrogens, are also implicated in DIAIH, with a relatively high incidence. The pathogenesis of DIAIH is presumed to result from reactive drug metabolites that produce self-mimicking neoantigens, which then activate lymphocytes that misdirect the immune responcse against self-antigens.


Microvesicular steatosis of the liver

Microvesicular steatosis (MS) is a potentially severe liver lesion that is frequently associated with acute liver failure, and that results from mitochondrial dysfunction.([2]) Certain drugs, such as amiodarone and tetracycline, can induce MS by impairing mitochondrial function. Synthetic estrogens can precipitate nonalcoholic steatohepatitis in genetically predisposed individuals; however, it is unclear synthetic estrogens can induce MS. Previous studies have inconsistently reported the beneficial effects of estradiol on chronic liver disease, which are based on its antifibrogenic and wound-healing effects.


Hepatotoxicity associated with synthetic estrogens

Although DILI can cause nearly any type of liver disease, certain drugs are related to specific clinical phenotypes. Hepatotoxicity associated with synthetic estrogens is more likely to be cholestasis other than the different types. However, the current report describes a patient with ethinylestradiol (EE2, synthetic estrogen)-associated DILI who presented with highly unusual clinicopathogical features of AIH and MS.


Five remarkable aspects regarding the present case of DIAIH

First, despite the acute presentation, with 7 days from the onset of symptoms to the peak of laboratory abnormalities, this case had a long latency interval, spanning 3 years. This long latency is consistent with autoimmunity because a long period of time is required for self-specific lymphocytes to expand sufficiently due to negative selection in the thymus.

Second, even after drug cessation, sustained elevation in liver biochemical parameters, serum IgG level, and ANA concentration was observed. Most patients with DILI recover rapidly when the incriminated drug is discontinued. In contrast, chronic DILI after drug cessation has been reported in approximately 6% of all DILI cases. It is conceivable that chronic DILI has an autoimmune mechanism.

Third, paired liver biopsies allowed us to compare the histological features observed at early onset and 7 months later (Figure 1-3). In clinical practice, the diagnostic investigation of a suspected DILI is generally based on clinical and biochemical examinations, along with the response to drug cessation, and liver biopsy is not consistently performed.



Figure 1. Liver biopsy specimen obtained at the onset. Moderate magnification. Hematoxylin-eosin (HE) staining.



Figure 2. Liver biopsy specimen obtained at the onset. High magnification. HE staining.


Fourth, a histological feature of MS was observed, which was defined by numerous small vacuoles in hepatocytes, centrally positioned nuclei, and swollen hepatocytes (Figure 1-2).

Fifth, a positive drug-lymphocyte stimulation test (DLST) and the histological analysis confirmed a diagnosis of DIAIH. DLST, an immunological test that measures the proliferation of T cells in response to a drug in vitro, has high specificity for previous in vivo sensitization to a drug.


Histological features of the liver

Prior biopsy showed prominent interface hepatitis, with an inflammatory infiltrate that primarily consisted of lymphocytes and plasma cells. Lobular hepatitis disrupted the liver cell plates, but no fibrosis was present. Bile duct injuries with lymphocytic infiltration and epithelial disarray were additionally identified (Figure 1). At a higher magnification, small vacuoles were diffusely noted in the hepatocytes, although the nuclei maintained their central position. Hepatocellular cholestasis was also evident (Figure 2).

Subsequent biopsy showed lymphocytic and plasmacytic infiltration in the portal triad, extending into the lobule. In contrast to the first biopsy, toxic features, such as cholestasis, steatosis, or bile duct injuries were not identified (Figure 3).


Figure 3. Liver biopsy specimen obtained 7 months post-onset. Low magnification. HE staining.


Plausible mechanisms underlying synthetic estrogen-associated DIAIH and MS

Administration of exogenous estrogen might alter the immunological milieu. Increased estrogen concentrations may induce cell proliferation, including the proliferation of macrophages and fibroblasts, and stimulate the expression of B cell-activating factor and activation-induced deaminase.([3]) Estradiol is also reported to reduce the number of regulatory T-cells and to induce pro-inflammatory cytokines, such as interleukin-6.

In an experimental analysis, repeated estradiol administration impaired the mitochondrial structure and fatty acid oxidation; in vivo, however, the liver’s weight increased to compensate for the impairment of fatty acid oxidation, so fatty liver did not occur. The direct toxicity of EE2 was not deemed to be the main inducer of MS. Immune-mediated processes can also affect mitochondrial function by influencing tumor necrosis factor-α/Fas ligand and by activating caspase-8. Intense immunoallergic reactions were most likely the cause of the MS observed in the present case.



Many drugs can cause DIAIH with a relatively high incidence. Clinicians should strongly consider a possibility of DIAIH in the case of DILI which exhibits overt jaundice, autoantibodies, intense histological inflammation, and a long latency period. Autoimmunity as a sequela of idiosyncratic DILI should not be underestimated, particularly in the case of drugs previously shown to induce DIAIH.



Kazuhiko Morii, M.D. and Ph.D.,

Department Manager of Hepatology

Japanese Red Cross Society Himeji Hospital

1-12-1 Shimoteno, Himeji, Hyogo 670-8540, Japan

E-mail: moriikazuhiko@gmail.com



Figure 4. Author and the Hepatology department staffs



[1]. Björnsson E, Talwalkar J, Treeprasertsuk S, Kamath PS, Takahashi N, Sanderson S, Neuhauser M, Lindor K. 2010 Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology 51:2040-2048

[2]. Begriche K, Massart J, Robin MA, Borgne-Sanchez A, Fromenty B. 2011 Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver. J Hepatol 54:773-794

[3]. Cutolo M, Sulli A, Capellino S, Villaggio B, Montagna P, Seriolo B, Straub RH. 2004 Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus 13:635-638



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