A Case Report of a Patient with Wilson ’ s Disease and Coincidental Sarcoidosis

Wilson’s disease (WD) or hepatolenticular degeneration is an inherited autosomal recessive disease characterized by a defect in the biliary copper excretion, leading to copper accumulation in many organs. The gene responsible for WD encodes a coppertransporting ATPase (ATP7B) and was identified on chromosome 13q14.3. ATP7B protein resides mainly in hepatocytes and is involved in the transmembrane transport of copper within hepatocytes. The defective ATP7B function causes a decreased hepatocellular excretion of copper into bile and eventually an excessive copper deposition mainly in the liver and the brain, leading to the hepatic and neurological features of WD. An additional phenomenon is an altered incorporation of copper into the copper-transporting glycoprotein ceruloplasmin that may lead to an Abstract


Introduction
Wilson's disease (WD) or hepatolenticular degeneration is an inherited autosomal recessive disease characterized by a defect in the biliary copper excretion, leading to copper accumulation in many organs.The gene responsible for WD encodes a coppertransporting ATPase (ATP7B) and was identified on chromosome 13q14.3.ATP7B protein resides mainly in hepatocytes and is involved in the transmembrane transport of copper within hepatocytes.The defective ATP7B function causes a decreased hepatocellular excretion of copper into bile and eventually an excessive copper deposition mainly in the liver and the brain, leading to the hepatic and neurological features of WD.An additional phenomenon is an altered incorporation of copper into the copper-transporting glycoprotein ceruloplasmin that may lead to an On the other hand, sarcoidosis is an idiopathic granulomatous disease affecting multiple organ systems.The disease presents with neurologic manifestations (neurosarcoidosis) in only 5% of patients, 97% of whom also have extraneural disease.The organs most often affected are the lungs (90%), followed by the lymph nodes, skin, eyes, upper respiratory tract, bones, joints, bone marrow, spleen and liver.The prevalence of sarcoidosis varies between 15-20/100.000 in northern Europeans and 1-5/100,000 in southern Europeans [Rybicki BA, Iannuzzi MC, 2007].
We report the case of a patient who presented with tremor and was diagnosed with both Wilson's disease and sarcoidosis.To our knowledge, this is the third reported case of coexistence of Wilson's disease and sarcoidosis.

Case Report
A 34 year old Caucasian female was admitted to our department because of rest and intention tremor for the last 1.5 years.The tremor initially involved the right arm and then affected also the left arm and the head.The tremor gradually worsened, compromising skilled activities such as writing.Tremor was exacerbated by physical and psychological stress and improved with mild alcohol consumption.The patient had been previously treated with propranolol 30 mg tid under the diagnosis of "essential tremor" without any clinical improvement.Her family history was unremarkable and there was no consanguinity between the patient's parents.Her past medical history included hypothyroidism, surgical removal of an endometrial polyp, menstrual irregularities since adolescence and iron deficiency anemia.The patient was a highschool graduate and had worked as a private employee.A detailed occupational and environmental history didn't reveal any extrinsic factors, such as exposure to various metals, that could be associated with the presenting symptoms.She also reported mild anxiety and depression.
The neurological examination revealed rest, position and task-dependent tremor in the distal upper extremities and a subtle head tremor with rotating features.Mild bradykinesia of the upper limbs, particularly of the left arm, was also noticed.Furthermore, bilateral cogwheel rigidity after activation and a dystonic posture of the left arm (abduction of the little finger) were present.There were no dysautonomic symptoms.The deep tendon reflexes were symmetrical and there were no pyramidal signs or abnormal pyramidal reflexes.The eye movement examination showed mild slowing of horizontal saccades.The glabellar tap sign was negative.Romberg test was negative and the pull test positive (one step backwards).Sensory testing did not reveal any deficits and the muscle strength was normal.A Mini Mental State Examination and an Alzheimer's disease Assessment Scalecognitive subscale test (MMSE/ADAScog) were performed and revealed normal cognitive function.Although the patient mentioned occasional symptoms of anxiety and depression, there was no official evaluation on this aspect since her symptoms were considered very mild.
The complete blood count showed microcytic hypochromic anemia and the white blood cells were at the lower limits of the normal range.Routine blood chemistry including liver function tests was normal (ALT 15 U/l, AST 21 U/l , gamma-GT 26 U/l, ALP 55 U/l bilirubin 0,68 mg/dl, Prothrombin time 13, INR 1.1 ).The patient was euthyroid and serum prolactin levels were also within the normal range.Serum ceruloplasmin levels were low (15.5 mg/dl, reference range 22-58) and serum copper levels were also low (0.6 mcg/ml, reference range 0.7-1.4).Copper levels in a 24h urine collection were increased (400 μg/24h, reference range < 100 μg/24h).Because these findings were suggestive of Wilson's disease, slit lamp examination was performed and revealed Kayser-Fleischer rings in both eyes with normal visual acuity and normal findings in fundoscopy.

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A subsequent magnetic resonance imaging of the brain revealed, on T2 weighted images, small dispersed hyperintense lesions in the cerebral hemispheres (especially in the basal ganglia) and the midbrain around the cerebral aqueduct.Other findings included atrophy of the brain parenchyma with enlargement of the subarachnoid spaces and the ventricular system, and atrophy of the vermis and the cerebellar hemispheres (Figure 1).

Discussion
The presence of low ceruloplasmin levels, Kayser-Fleischer ring, high 24-hour urine copper excretion, the brain MRI and the liver biopsy findings strongly support the diagnosis of Wilson's disease in our patient [European Association for Study of Liver, 2012] , [Roberts EA, Schilsky ML, 2008].Genotype testing for Wilson's disease was not performed.At the same time, the findings from the chest X-ray and CT scan, the bronchoalveolar lavage and the biopsy of mediastinal lymph nodes as well as the increased serum ACE levels and the elevated 24h urine calcium excretion were all suggestive of pulmonary sarcoidosis.Therefore, our patient appears to have both Wilson's disease and pulmonary sarcoidosis.
To our knowledge, this is the third case of coexistence of Wilson's disease and sarcoidosis that has been reported [Danks DM et al., 1990], [Giouleme O. et al., 2009].The first report by Danks et al. in 1990, described a forty-three year-old male who presented with symptoms and signs of cirrhosis and no neurologic symptoms and was finally diagnosed with Wilson's disease.He had a history of pulmonary sarcoidosis which had been diagnosed nine years earlier and treated with corticosteroids.The second patient, described by Giouleme et  It was thought that portopulmonary hypertension was a vascular consequence of the advanced liver disease caused by Wilson's disease.The authors' further investigation of the acute pericarditis provided evidence of sarcoidosis, as another factor of secondary pulmonary arterial hypertension.This was indicated by patient's rapid improvement of pericarditis after corticosteroid treatment, at one-month follow-up visit, and by gradual decrease of mean pulmonary arterial pressure, at threemonth follow-up visit.Reported patient had symptoms of sarcoidosis as well as the symptoms of Wilson's disease.
The frequency of the overlapping cases is expected to be very low, given the prevalence of sarcoidosis and the prevalence of Wilson's disease.
Furthermore, these two rare entities don't seem to share common pathways and their association appears incidental.It is interesting though that elevated serum copper levels can be found in various cancers, immune system diseases and lymphoproliferative disorders.Donghi et al. in 1995 reported an increase of serum copper concentration in Löfgren syndrome (a type of acute sarcoidosis with bilateral hilar lymphadenopathy and erythema nodosum).The authors concluded that, although the finding of an increase of serum copper in patients with mediastinal adenopathies is usually indicative of Hodgkin's disease, it can be related also to other conditions such as sarcoidosis.[Donghi et al., 1995].On the other hand, environmental and occupational exposure to aerosolized copper and other metals (aluminum, barium, beryllium, cobalt, copper, gold, lanthanides, titanium, and zirconium) has been strongly correlated with granulomatous lung diseases that mimic sarcoidosis.[Newman LS. 1998

Conclusion
In the case discussed here, the coexistence of Wilson's disease with a seemingly idiopathic disorder such as sarcoidosis raises the question whether there is a potential link between these two diseases.One possible assumption is that the excessive copper due to Wilson's disease could have acted as an intrinsic factor that triggered an immunologic response in an immunologically predisposed patient and led to the manifestation of sarcoidosis.In any case, the coexistence of both diseases raises special considerations regarding the follow-up and Medicine __________________________________________________________________________________________________________________ ______________ Arnaoutoglou Marianthi, Kiryttopoulos Andreas, Kalliolia Eirini, Tziomalos Konstantinos and Orologas Anastasios (2014), International Journal of Case Reports in Medicine, DOI: 10.5171/2014.221927

Figure 1 :
Figure 1: Brain Magnetic Resonance Imaging of the Patient

Figure 2 :
Figure 2: Chest X-ray showing enlarged upper mediastinum and computed tomography scan showing bilateral hilar lymphadenopathy _____________________________________________________________________________ ______________ Arnaoutoglou Marianthi, Kiryttopoulos Andreas, Kalliolia Eirini, Tziomalos Konstantinos and Orologas Anastasios (2014), International Journal of Case Reports in Medicine, DOI: 10.5171/2014.221927 future monitoring of the patient since they could share common hepatic or neurological manifestations.