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Editors: Managing Editor: Editorial Assistant: Contents Info Published by |
Volume 5, Number 3, July - September 2001
Case Report: Autoimmune Hepatitis in a Male-to-Female Transsexual Treated with Conjugated Estrogens
By Vin Tangpricha, M.D., Nezam H. Afdhal, M.D., Stuart R. Chipkin, M.D.
Citation: Tangpricha V., Afdhal N.H., Chipkin S.R. (2001) Case Report: Autoimmune Hepatitis in a Male-to-Female Transsexual Treated with Conjugated Estrogens. IJT 5,3, http://www.symposion.com/ijt/ijtvo05no03_03.htm
Estrogen hormone in male-to-female transsexuals is a major component of
therapy in the treatment of gender dysphoria. There are many adverse reactions
to estrogen therapy that require close monitoring. We describe a case of
autoimmune hepatitis that may have been exacerbated by estrogens: this is an
additional adverse effect of estrogens on liver function that has not
previously been reported. We recommend routine liver function tests to screen
for such adverse reactions.
Keywords: autoimmune hepatitis, estrogen,
transsexualism.
We present an interesting case of autoimmune hepatitis type I in a
male-to-female transsexual that we follow in our clinic. A discussion about
this rare condition follows.
A 38-year-old genetic white male presented to our endocrinology clinic for initiation of estrogen therapy for the treatment of gender dysphoria. Her evaluation by psychiatry met the criteria for transsexualism. She was healthy with no previous liver disease. Her family history was negative. She did not take any medications. She denied any use of over the counter medications or herbal supplements. She reported casual use of alcohol on weekends and denied tobacco or intravenous drug use. She also denied having multiple sexual partners or having had blood transfusions. Her occupation was mainly clerical, and involved no exposure to chemicals. Head, neck, and chest examinations were normal at baseline. Her abdomen was non-tender with no hepatosplenomegaly. A genital examination revealed normal male genitalia and normal sized testicles. There was no lower extremity edema. Initial laboratory investigations revealed: creatinine 0.9 mg/dl (0.8 – 1.3), total cholesterol 178 mg/dl, HDL cholesterol 62 mg/dl, AST 22 U/L (5 – 40), ALT 24 U/L (5 – 40), total bilirubin 0.9 mg/dl (0.1 – 1.2), albumin 5.1 g/dl (3.5 – 5.2), total testosterone 422 ng/dl and estradiol 21 pg/ml.
She was initiated on conjugated estrogens (PremarinÔ ) 0.625 mg daily for the first month. This was increased to 2.5 mg by the third month. After four months of therapy with conjugated estrogens, she presented with one week of nausea and dark urine with no abdominal pain. An examination revealed mild scleral icterus. Her abdomen was non-tender with no hepatosplenomegaly. Laboratory investigations revealed: alkaline phosphatase 111 U/L (35 –120), total bilirubin 3.5 mg/dl (0.1 – 1.2), direct bilirubin 1.9 mg/dl (0 – 0.4), albumin 4.3 g/dl (3.5 – 5.2), AST 1665 U/L (5 – 40), ALT 3880 U/L (5 -40), GGT 179 U/L (10 – 60), total testosterone 143 ng/dl and estradiol 429 pg/ml. Her estrogen therapy was discontinued immediately.
Liver ultrasound was normal. Serologies for Ebstein Barr virus, cytomegalovirus and hepatitis A, B, C viruses were negative. Ferritin was elevated at 1012 ng/ml (10 – 322). Anti-nuclear antibodies (ANA) were positive at 1:320 titer in a homogenous speckled pattern. Anti-smooth muscle and liver-kidney microsomal antibodies were negative. Serum immunoglobulins were elevated with IgG of 2210 mg/dl (694 – 1618) and IgA of 396 mg/dl (68 – 263). MRI of the liver revealed no evidence of Budd-Chiari syndrome. A liver biopsy revealed chronic active hepatitis with focal piece-meal necrosis involving portal areas and early bridging fibrosis (see Figure 1a). Iron staining of the liver biopsy was not compatible with hemachromatosis.
A clinical diagnosis of type I autoimmune hepatitis was made. She was started on prednisone 40 mg daily with a sub-optimal response in her transaminases. After four months, azathioprine 75 mg daily was added. After two months of combination therapy, she self discontinued the prednisone therapy and continued only on azathioprine. The transaminases gradually improved and normalized 11 months after the initial presentation. The patient requested re-initiation of estrogen therapy. The risks were explained and concerns over possible permanent damage were expressed. Nevertheless, the patient wished to pursue estrogen therapy. A second trial of conjugated estrogen using Premarin at 1.25 mg daily was attempted six months after normalization of transaminases. Anti-androgen therapy with spironolactone could only be tolerated at 50 mg daily because of severe nausea. Her dose was slowly increased stepwise over one year to Premarin 2.5 mg daily. However, her transaminases increased to two-to-three times normal, which resolved after discontinuation of estrogens.
A third trial of estrogen therapy was initiated at low doses: estradiol
(EstraceÔ ) 2.0 mg daily. Her liver function
tests remained normal after nine months of therapy. A follow-up liver biopsy
revealed a decrease in fibrosis and lymphocytic infiltration (see Figure 1b).
She experienced very little feminization so a small dose of a transdermal
estrogen, EstradermÔ 0.05 mg/daily, was added
to her oral estrogen. The transdermal estrogen was prescribed in the hope of
avoiding first pass effect by the liver. However, her transaminases elevated to
three-to-four times normal. This normalized after discontinuation of all of her
estrogens. She is now stable on estradiol 2.0 mg daily and is being evaluated
for orchiectomy.
Estrogen therapy for the treatment of male-to-female transsexuals is associated with some potential adverse effects on liver function. The treatment of male-to-female transsexuals with estrogens has been associated with mild elevations in transaminases (Meyer et al., 1986; Van Kesteren et al., 1997). Liver adenomas have been reported in females treated with estrogens (Aldinger et al., 1977). Other causes of abnormal liver function, specifically in male-to-female transsexuals, include viral hepatitis and alcohol abuse (Van Kesteren et al., 1997; Asscheman et al., 1989).
We have presented a case of type I autoimmune hepatitis occurring in a male-to-female transsexual taking oral estrogens. The etiology of this rare liver disease is unknown. This condition occurs predominantly in young females of reproductive age (Czaja, 1996). A major clinical finding is the presence of serum autoantibodies (Czaja, 1996). Several antibodies define the type of autoimmune hepatitis. Type I is associated with positive anti-nuclear antibodies (ANA). A liver biopsy is required to confirm the diagnosis and exclude other etiologies (Czaja, 1996). Other criteria that are needed for the diagnosis include the absence of viral antibodies and other liver toxins (Johnson and MacFarlane, 1993). Treatment consists of corticosteroids alone or in combination with azothioprine (Czaja, 1996). However, treatment failure occurs in 9% of all cases and may require liver transplantation (Czaja, 1996).
Estrogens may play a role in triggering this autoimmune process: a higher prevalence of autoimmune hepatitis in pre-menopausal women has been noted by some authors (Herzog et al., 1997). This case indicates that there may be a potential adverse effect of estrogens on liver function in male-to-female transsexuals. We stress the need for careful surveillance of liver function during treatment of male-to-female transsexuals with estrogens, especially in the initial months of therapy. Liver function should be monitored every two months initially until the estrogen dose is stable; thereafter, every six months may be sufficient.
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| Figure 1a: Liver biopsy histology at the initial
presentation showing peri-portal lymphocytic infiltration and extensive
peri-portal fibrosis. |
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| Figure 1b: Follow-up liver biopsy histology two-and-a-half years later after treatment with prednisone and azathioprine with re-initiation of estrogens at lower dosages. There is a reduction in the inflammation and fibrosis. |
Aldinger, K., Ben-Menachem, Y., and Whalen, G. (1977) Focal nodular hyperplasia of the liver associated with high-dosage estrogens. Archives of Internal Medicine, 137(3): 357-359.
Asscheman, H., Gooren, L.J., and Eklund, P.L. (1989) Mortality and morbidity in transsexual patients with cross-gender treatment. Metabolism: Clinical and Experimental, 38(9): 869-873.
Czaja, A.J. (1996) Diagnosis and therapy of autoimmune liver disease. Medical Clinics of North America, 80(5): 973-994.
Herzog, D., Rasquin-Weber, A.M., Debray, D., and Alvarez, F. (1997) Subfulminant hepatic failure in autoimmune hepatitis type 1: an unusual form of presentation. Journal of Hepatology, 27: 578-582.
Johnson, P.J. and MacFarlane, I.G. (1993) Meeting report: International Autoimmune Hepatitis Group. Hepatology, 18: 998-1005.
Meyer, W.J., Webb, A., Stuart, C.A., Finkelstein, J.W., Lawrence, B., and Walker, P.A. (1986) Physical and hormonal evaluation of transsexual patients: a longitudinal study. Archives of Sexual Behavior, 15(2): 12-38.
Van Kesteren, P.J., Asscheman, H., Megens, J.A., and Gooren, L.J. (1997) Mortality and morbidity in transsexual subjects treated with cross-sex hormones. Clinical Endocrinology (Oxford), 47: 337-342.
Corresponding author: Vin Tangpricha M.D., Section of Endocrinology, Diabetes and Nutrition, Boston University School of Medicine, M-1024, 88 East Newton Street, Boston, MA 02118, Tel: (617) 638-8197, Fax: (617) 638-8898, Email: vin@bu.edu.
