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Pii: s1054-139x(02)00355-5JOURNAL OF ADOLESCENT HEALTH 2002;31:378–380 Wilson Disease Manifested Primarily as Amenorrheaand Accompanying Thrombocytopenia Wilson disease (WD), referred to as hepatolenticular which revealed normal findings. No further exami- degeneration and occurring primarily as neurologi- nation was performed. After 2 months, the patient cal and liver disease, is an inherited disorder that has was admitted to the hospital with pruritus of 2 weeks various clinical presentations [1–3]. The altered gene duration and jaundice for a week. The patient’s is localized on the long arm of chromosome 13.
course has been marked by normal growth (height Mutations in the Wilson gene are common and 90. percentile, weight 25. percentile for age). There include small insertions or deletions. In the cases of was no history of consanguinity in the family. How- unidentified tubular dysfunctions, hemolytic ane- ever, 21 years ago, the patient’s 9-year-old sister had mias, and urolithiasis, this disease should be kept in died 15 days after the development of jaundice, mind as the possible etiology. Amenorrhea has been having been diagnosed as having cirrhosis.
reported in untreated women with WD [1,2,4 – 8].
On physical examination, slight jaundice, pretibial Although thrombocytopenia, as a result of hyper- edema, and clubbing were recorded. Dry skin with splenism and/or as a side effect of D-penicillamin excoriation marks were remarkable. She had hepato- therapy, has been well-documented, the association megaly of 2 cm and splenomegaly of 1 cm. Breast of idiopathic thrombocytopenia and WD has been and pubic hair development was concomitant with published in only one case previously .
Tanner stage 4. The laboratory results were as fol- We present an adolescent patient with secondary lows: Hab: 8.2 g/dL, Hct: 26%, WBC: 3500/mm3, amenorrhea, and thrombocytopenia in the absence of platelets: 63,000/mm3 (in subsequent controls; 79 hypersplenism as the initial presentation.
000/mm3, 66,000/mm3 and 87,000/mm3), reticulo-cytes: 1%, Coombs (Ϫ). The platelet function tests were normal and the antithrombocyte antibodieswere negative. Erythrocyte sedimentation rate: 55 DK, a 14 year-old girl, had amenorrhea for 3 months mm/h. Serum iron: 51 g/dL, ferritin: 319 g/dL.
despite having had regular menses for 2 years. Sincethe patient refused the gynecologic examination, Total protein: 6.4 g/dL, albumin: 2 g/dL, total bili- only an abdominal ultrasound scan was performed rubin: 3.86 mg/dL, direct bilirubin: 2.37 mg/dL.
ALT, AST and GGT were elevated 3 times, 6 times,and 4 times normal values, respectively. Alkaline Department of Pediatrics (C¸.A.), Division of Gastroenterology (T.E., phosphatase and uric acid were slightly decreased E.M.G., T.K. F.C¸., G.T.T.) and Division of Hematology-Oncology (72 IU/L and 2 mg/dL, respectively). Prothrombin (H.A.), Cerrahpas¸a Medical Faculty, University of Istanbul, Istanbul,Turkey. activity was 53%. Immunoglobulins were slightly Address correspondence to: Tu¨lay Erkan, M.D., Vis¸nezade mah. elevated (IgG: 2005, IgA: 626, IgM: 183 mg/dL).
Kirec¸hane sok. Tu¨rker apt. no:9/4, Bes¸iktas¸ 80 690 Istanbul, Turkey. Alfa-1 antitrypsin level was normal. Autoantibodies Manuscript accepted December 13, 2001. such as ANA, AMA, SMA, LKM1 were negative.
Published by Elsevier Science Inc., 360 Park Avenue South, New York, NY 10010 Viral markers including HBsAg, anti-HBc IgM, anti copper in 24-hour urine excretion and in dry liver HBs, anti-HAV IgM, IgG, anti-HCV, HCV RNA and tissue. Before treatment, the platelet count was found antibodies for parvovirus, cytomegalovirus, and Ep- to be low with lack of increased number of stein-Barr were found negative. Total serum copper megakaryocytes in the bone marrow aspiration sug- value was normal, ceruloplasmin level was below gesting that the thrombocytopenia was not exclu- the normal values (Ͻ20 mg/dL; N: 20 –55 mg/dL).
sively owing to hypersplenism. The anemia that was Twenty-four hour urine excretion of copper was diagnosed initially disappeared without any treat- 288.1 g/dL (N Ͻ 100 g/dL) and the urine exam- ment or transfusion, although thrombocytopenia ination showed dibasic aminoaciduria. Serum urea persisted. It is evident that gross splenomegaly is not and creatinin values were normal. A hormone assay necessary to produce hypersplenism, but the pa- revealed abnormally low concentration of follicular tient’s bone marrow aspiration findings did not stimulating hormone (FSH) (2.23 mIU/mL), luteiniz- show hypercellularity suggesting hypersplenism (ex- ing hormone (LH) (0.21 mIU/mL) and estradiol (Ͻ20 cept erythroid hyperplasia). In patients with portal pg/mL). The concentrations of prolactin, T3, T4 and hypertension, the thrombocytopenia is generally ow- TSH, testosterone, free testosterone and androsteno- ing to hypersplenism. Also, the absence of anti- thrombocyte and viral antibodies excluded respec- Ophthalmologic examination with slit-lamp mi- tively the diagnosis of autoimmune thrombocytopenia croscopy detected Kayser-Fleischer rings. Abdomi- and viral infections frequently associated with mild nal ultrasonographic examination showed minimal ascites with irregular echogenity of the liver and The platelet function abnormalities in WD have hydrops of the gallbladder. The dimensions of the been well-recognized [10,11]. Owen et al.  stud- uterus were normal and no major follicle in the ied platelet function and coagulation profiles of 16 ovaries was observed. No endometrial echogenity WD patients and observed some abnormality of platelet aggregation in 15. The platelet function tests The needle biopsy of liver showed severe hepato- were normal in our patient. Also, Hoagland et al.
cellular necrosis, inflammatory changes and fibrosis.
, reported that 52% of patients with WD had Hepatic copper content was 578.18 g/g (N Ͻ 50 thrombocytopenia and 30% had leucopenia. Twenty- g/g). Upper gastrointestinal tract endoscopy re- four of these patients, who had thrombocytopenia, vealed no varices. Cranial tomography was normal, did not have splenomegaly. In the literature, there is however magnetic resonance imaging showed hy- only one case of an adult patient with idiopathic perintensity of the basal ganglia. We had no oppor- thrombocytopenia associated with WD . Splenec- tunity for electron micropscopic examination or ge- tomy was recommended because of poor response to netic mutational identification. Two subsequent bone corticosteroids and the liver biopsy performed dur- marrow aspirations showed erythroid hyperplasia ing the operation revealed chronic aggressive hepa- and normocellularity with normal megakaryocytes, titis. Further investigations showed low level of serum ceruloplasmin and the presence of Kayser- Zinc treatment was started initially. D-penicilla- Fleischer rings and thereupon the diagnosis of WD mine was also commenced but, as the patient’s thrombo- cyte count rapidly fell from 87,000 to 58,000/mm3, In advanced stages of chronic liver disease, serum the treatment was suspended. Trientine was com- thrombopoietin level may be decreased . Al- menced at a dose of 1 g/day. No clinical or biochem- though it is difficult to speculate in the absence of the ical manifestations of toxicity were observed. Also, serum thrombopoietin, it is possible that low levels the avoidance of foods with high copper content was might have caused thrombocytopenia. Thrombopoi- advocated. At 30 months follow-up, the patient is etin is mainly produced by the liver and the regula- doing well with normal ovulatory function and with tory mechanism of thrombopoietin gene expression thrombocyte count around 98,000/mm3.
in hepatocytes is not clear. But Yamashita et al. using various growth factors and cytokines onthrombopoietin mRNA expression in adult rat hepa-tocytes in primary cultures, showed that among them only hepatocyte growth factor/scatter factor The patient was diagnosed as WD owing to the low (HGF/SF) enhanced thrombopoietin mRNA expres- level of ceruloplasmin, the presence of corneal Kay- sion. On the other hand, HGF is a copper-binding ser-Fleischer rings along with increased level of protein . In WD as the copper level in liver rises, JOURNAL OF ADOLESCENT HEALTH Vol. 31, No. 4 possibly related to the decrease in HGF, thrombopoi- Minor manifestations such as isolated thrombocyto- etin production can decrease and could be the reason penia or amenorrhea as a presenting feature of WD is for thrombocytopenia in WD. As this has not been interesting and extremely unusual. Because treat- studied, it is not possible to know whether the ment is capable of reversing these changes and thrombocytopenia in our patient was owing to liver restoring a normal menstrual cycle, early diagnosis is damage or this relationship between copper and important. Thus, we support the recommendation that adolescents with amenorrhea or children with Primary or secondary amenorrhea has been re- thrombocytopenia without any obvious cause, ported in women with chronic liver disease and in almost all untreated women with WD [6,7,15]. Inthese patients, as in ours, because the concentrationsof FSH and LH were low, gonadotropin-releasing stimulation test can be done in order to identify 1. Sokol RJ, Narkewicz MR. Copper and iron storage disorders.
pituitary involvement. Liver damage is known to In: Suchy FJ, Sokol RJ, Balistreri WF (eds). Liver Disease in interfere with normal metabolism of estrogen. In this Children, 2nd Editon. Philadelphia: Lippincott Williams & case, the estradiol level was low, owing either to low concentrations of FSH and LH and/or inadequate 2. Schwarzenberg SJ, Sharp HL. Update on metabolic liver disease. Pediatr Clin North Am 1996;43:28 –32.
estradiol production. Estrogen is necessary to sustain 3. Gitlin N. Wilson disease: the scourge of copper. J Hepatol granulosa cell mitosis and FSH is required to permit the granulosa cell to aromatize the theca cell to 4. Baban NK, Hubbs DT, Roy TM. Wilson’s disease. South Med estrogen. So, endocrine microenvironment of the developing follicle remains estrogenic. The amount 5. Chu NS, Hung TP. Geographic variations in Wilson’s disease.
and activity of aromatase is critical in maintaining the health of the oocyte. Interference of the enzyme 6. Chu KK, Chen CL. Abatement of secondary amenorrhea in Wilson’s disease following liver transplantation. Transplant system aromatase by copper intoxication would propably cause poor estradiol production and poor 7. Kaushansky A, Frydman M, Kaufman H, Homburg R. Endo- ovulation . The liver damage in WD may prevent crine studies of the ovulatory disturbances in Wilson’s disease.
also the normal breakdown and metabolism of tes- tosterone which, in the presence of a normal produc- 8. Hartemann P, Leclere J, Thomas JL, Genton P. Gonadotropin- resistant ovary syndrome and Wilson’s disease. A case. Rev tion rate, will elevate the total testosterone levels, and these in turn may prevent normal function of the 9. Donfrid M, Jankovic G, Strahinja R, et al. Idopathic thrombo- ovulatory mechanism by arresting follicular matura- cytopenia associated with Wilson’s disease. Hepatogastroen- tion and producing atretic follicles . In this pa- tient low levels of FSH, LH, and estradiol were found 10. Owen CA, Goldstein NP, Bowie JW. Platelet function and coagulation in patients with Wilson disease. Arch Intern Med with normal levels of testosterone, free testosterone, and androstenodion. Despite inadequate breakdown 11. Hoagland HC, Goldstein NP. Hematologic (cytopenic) mani- and metabolism of testosterone, normal serum tes- festations of Wilson’s disease (hepatolenticular degeneration).
tosterone levels in our patient can be explained by the low levels of FSH-LH and the lack of the normal 12. Kawasaki T, Takeshita A, Souda K, et al. Serum thrombopoi- etin levels in patients with chronic hepatitis and liver cirrhosis.
ovarian follicular activity. As a result, the amenor- Am J Gastroenterol 1999;94:1918 –22.
rhea in WD probably originates from the hypotha- 13. Yamashita K, Matsuoka H, Ochiai T, et al. Hepatocyte growth lamic and/or pituitary and/or ovarian levels. In a factor/scatter factor enhances the thrombopoietin mRNA ex- study from Taiwan, amenorrhea was reported to be pression in rat hepatocytes and cirrhotic rat livers. J Gastro-enterol Hepatol 2000;15:83–90.
relatively more common among WD patients in Asia 14. Rahimi N, Etchells S, Elliott B. Hepatocyte growth factor . The wide spectrum of age of onset of the clinical (HGF) is a copper-binding protein: In a facile probe for features in WD may be related to the severity of the purification of HGF by immobilized CU(II)-affinity chroma- gene disruption by mutation. The mutations provide tography. Protein Expr Purif 1996;7:329 –33.
an explanation for some of the wide phenotype 15. Cundy TF, Butler J, Pope RM, et al. Amenorrhea in women with non-alcoholic chronic liver disease. Gut 1991;32:202– 6.
16. Louvet JP, Harman SM, Schreiber JM, Ross GT. Evidence of a In conclusion, WD is encountered in the differen- role of androgen in follicular maturation. Endocrinology 1975; tial diagnosis of amenorrhea or thrombocytopenia.
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