copper deposition in the descemet membrane of the cornea , known as kayser - fleischer ring , is a rare finding in daily practice . if present , it is usually assumed to be pathognomonic for wilson 's disease ( wd ; a hepatolenticular degeneration and autosomal recessive movement disorder ) , but a kayser - fleischer ring is also rarely seen in other diseases , mainly of hepatic or hematological origin , indicating an imbalance of copper homeostasis [ 1 , 2 ] . copper is virtually totally incorporated into ceruloplasmin while small amounts are bound to serum albumin . in wd , ceruloplasmin deficiency leads to copper depositions in the cornea and brain via a consecutive rise of free serum copper . frequently , a kayser - fleischer ring can be detected prior to the appearance of neurological symptoms   and an efficient diagnosis and treatment of copper accumulation may prevent the development of the movement disorder . contraceptives with estrogenic effects are known to elevate serum copper and ceruloplasmin levels [ 4 , 5 ] . the underlying pathomechanism is not fully understood , but several authors propose an increase of ceruloplasmin as a direct effect of estrogen and , consequently , a rise of total copper content in the serum [ 4 , 5 ] . whatever the mechanism , the alteration of copper homeostasis is not listed in the drug information of oral contraceptives . however , in the last years , 3 cases with corneal deposition due to chronic intake of contraceptives have been reported , showing that changes in serum copper can be of clinical importance [ 6 , 7 ] . a 68-year - old woman with a 4-year history of alzheimer 's disease ( ad ) was admitted to the university eye hospital in freiburg , germany , for surgery of a bilateral pterygium and cataract . preinterventional slit - lamp examination revealed a yellow - greenish deposition in the posterior corneal stroma and the descemet membrane at the limbus of both corneas ( fig . urine copper ( 58.5 g/24 h ) , serum copper ( 106 g / dl ) and ceruloplasmin ( 38 mg / dl ) levels as well as transaminases and bilirubin were within the normal ranges . the tremor syndrome had been present since the patient 's adolescence and , in the light of a positive family history , it was judged to be an essential tremor . due to progressive ad (  probable ad according to nincds - adrda criteria ) , anomia and apraxia were present . the cognitive state of the patient was evaluated by mini - mental state examination , where she reached 10 of 30 points , with 4 points for orientation ( time , town , country , district ) , all 3 points for the registration of 3 words , 1 point for language ( name a pencil ) and 2 points for the 3-stage command ; all speaking for a moderate to severe impairment . the patient reported a daily 2-mg postmenopausal hormone estradiol intake over the past 22 years until one year before . magnetic resonance imaging ( mri ) revealed brain atrophy of the temporal and parietal lobes ( fig . neurosonography of the midbrain and basal ganglia displayed a right accentuated hyperechogenicity of both lentiform nuclei ( fig . 1d ) . in line with the clinical diagnosis , positron emission tomography ( pet ) studies revealed typical features of ad ( fig . 2 ) : [ f]fluorodeoxyglucose ( fdg ) pet demonstrated a pronounced bilateral temporoparietal hypometabolism , while c - labeled pittsburgh compound - b ( [ c]pib ) pet showed strong binding to cortical fibrillar amyloid- depositions in an ad - typical distribution . the enzyme atp7b facilitates the transfer of copper into the golgi apparatus of hepatocytes , where copper is incorporated into ceruloplasmin . in wd , a mutation of the copper - transporting gene atp7b leads to secondary ceruloplasmin deficiency with a reduced half - life . free serum copper accumulates in tissues like the eye ( kayser - fleischer ring , sunflower cataract ) , brain ( mainly basal ganglia ) , kidney and liver . a kayser - fleischer ring can be detected in approximately 60% of presymptomatic patients with wd , whereas virtually every patient with wd and neurological symptoms presents corneal copper deposition [ 3 , 8 ] . furthermore , a kayser - fleischer ring has been reported in other hepatic and hematological diseases [ 1 , 2 ] . in the latter cases , therefore , a relative surplus of free serum copper seems to be the common factor for tissue accumulation , rather than the absolute amount of copper or ceruloplasmin . an increase of ceruloplasmin and serum copper due to chronic estrogen administration has been known since 1966 [ 4 , 5 ] . moreover , both serum copper and ceruloplasmin are elevated during pregnancy , a physiologic state of raised estrogen levels . several authors suggest an estrogen - induced increase of ceruloplasmin and , secondary to that , a rise of the amount of total copper [ 4 , 5 ] . an explanation for a missing clinical manifestation of these increased serum copper levels might be that copper is incorporated into ceruloplasmin , preventing the accumulation of free serum copper . however , the occurrence of copper depositions in the cornea due to long - lasting estrogen intake argues for a direct impact of estrogens on copper uptake , since ceruloplasmin remains normal in these cases [ 6 , 7 ] . hardman et al .   found evidence that estrogen has a direct impact on the atp7a transporter of human placental cells , leading to a stimulation of the copper transport via an increase of atp7a - mrna expression . transferring these data to enterocytes , where atp7a plays a crucial role for the regulation of copper uptake , estrogen could upregulate atp7a - mrna , inducing an increased copper uptake via the intestine . this seems plausible , since an adequate copper supply to the embryo under physiologic conditions must be on the basis of an elevated intestinal copper uptake of the expectant mother . therefore , we propose that the increase of ceruloplasmin after estrogen treatment is secondary to an enhanced copper uptake . however , in patients with a kayser - fleischer ring under estrogen therapy , this hepatic compensatory mechanism seems to be disturbed , possibly due to having a defect on the ceruloplasmin gene or being heterocygotes for wd . new findings suggest an association of an atp7b polymorphism and sporadic ad which might be of interest in this context , since this polymorphism results in a disturbed function of the copper transporter , leading to an increased level of free serum copper . since in our case estradiol therapy was discontinued one year ago , ceruloplasmin and serum copper were at normal levels . we did not restart estradiol therapy to prove the pathomechanism because of ethical considerations mentioned below . however , in the 3 cases previously described , the causality between estrogen intake and enhanced serum copper has been described [ 6 , 7 ] . in wd , copper accumulation can be diagnosed by basal ganglia sonography , showing hyperechogenicity of the lentiform nucleus . in our patient , neurosonography of the basal ganglia revealed a right accentuated hyperechogenicity of both lentiform nuclei , supporting copper deposition in the basal ganglia , without presenting neurological symptoms compatible with wd . walter et al .   also found this hyperechogenicity in 2 of 3 presymptomatic patients with wd . this could be explained by the time lag ranging from 7 to 37 years between copper accumulation ( with secondary neurodegeneration due to oxidative stress ) and overt neurological symptoms . susceptibility - weighted mri showed no incidence of copper accumulation in the brain , but abnormal mri findings in presymptomatic wd seem to be rare . the role of copper in the pathogenesis of ad is still controversial , but there is increasing evidence that besides iron and zinc , free serum copper is involved in the aggregation of amyloid--forming amyloid plaques . moreover , a meta - analysis confirmed increased serum copper levels in patients with ad . copper is a redox - active metal and plays an important role as a catalyst in the production of reactive oxygen species . furthermore , copper is assumed to build complexes with tau protein , the second pathologic hallmark of ad . it seems noteworthy that the copper transporter atp7a is present in the brain . a co - release of amyloid- and copper into the synaptic cleft increases the probability of building a redox - active amyloid--copper complex leading to oxidative stress , which enhances the forming of amyloid plaques . estrogen therapy could have an impact on the expression of the atp7a transporter in the brain as well , but this has not been demonstrated yet . although a case report like ours does not necessarily provide evidence for causal relationships , it allows , nevertheless , formulating hypotheses for further investigations and research . certainly , it can not be proven that the occurrence of ad in the present case is due to estrogen therapy . however , it is very tempting to assume a causal role after more than 20 years of estradiol intake leading to a kayser - fleischer ring and presumed copper depositions in the basal ganglia and given the crucial role of copper in the pathogenesis of ad pathology . furthermore , this hypothesis might offer a partial explanation for the observation that postmenopausal estrogen therapy is associated with a higher risk of mild cognitive impairment , which is commonly the first stage of ad . in conclusion , we suggest that augmented atp7a - mrna in the intestine as a direct effect of estrogen therapy facilitates the absorption of copper , leading to increased serum copper levels . in some patients , hepatic function might be unable to cope with an increased copper load , resulting in corneal copper depositions and cerebral copper accumulation in the basal ganglia . furthermore , similar to findings in wd patients , we demonstrate hyperechogenicity of both lentiform nuclei , indicating cerebral copper accumulation in the basal ganglia in our patient . increased levels of free serum copper might have an impact on ad , since the same atp7a transporter for copper homeostasis is present in the brain and copper plays a crucial role in oxidative stress , the formation of amyloid plaques and tau aggregation . although we can not provide evidence for causality in the present case , we want to stimulate further investigations on the impact of estrogen on copper homeostasis and the link between serum copper and the pathophysiology of ad , since this might have consequences for monitoring hepatic regulatory mechanisms in patients receiving estrogens .
we present a patient with chronic postmenopausal estrogen intake with presence of kayser - fleischer ring in the cornea and alzheimer 's disease and discuss the pathophysiological mechanisms of estrogen intake and copper accumulation in various tissues , including the central nervous system . 
 sonography was compatible with copper accumulation in the basal ganglia , but the patient showed no clinical signs of wilson 's disease . 
 magnetic resonance imaging and positron emission tomography revealed a typical pattern for alzheimer 's disease . 
 we propose increased copper levels as a direct effect of estrogen intake due to an augmented atp7a - mrna in the intestine . 
 moreover , we discuss the impact of elevated free serum copper on accompanying alzheimer 's disease , knowing that copper plays a crucial role in the formation of amyloid plaques and tau aggregation . 
 this might offer a partial explanation for the observation that postmenopausal estrogen therapy is associated with a higher risk of mild cognitive impairment and alzheimer 's disease .