Wilson’s Disease Presenting with Severe Thrombocytopenia and Urinary Symptoms: Case Report and Literature Review

Volume 5 • Issue 6 • 1000222 J Nephrol Ther ISSN: 2221-0959 JNT, an open access journal Wilson’s Disease Presenting with Severe Thrombocytopenia and Urinary Symptoms: Case Report and Literature Review Zakharova EV1* and Golovkin BA2 1Head of Nephrology Unit, City Clinical Hospital n.a. S.P. Botkin, Moscow, Russian Federation 2Consultant Gastroenterologist, City Clinical Hospital n.a. S.P. Botkin, Moscow, Russian Federation


Introduction
"Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver" was the title of S.A. Kinnear Wilson doctoral thesis, published in 1912 and describing the condition, actually bearing his name -Wilson's disease [1,2]. The role of copper metabolism in the pathogenesis of Wilson's disease, the genetic defect and autosomal recessive pattern of inheritance were determined more than 3 decades later -between 1948 and 1993. It was shown, that loss of function of the metal-transporting P-type adenosine triphosphatase (ATPase), caused by mutation of ATP7B gene, leads to decreased excretion of copper into bile, and in hepatic copper accumulation and damage.
Excess of copper is released into the bloodstream and deposited in also in the brain, cornea and kidneys. In addition, this defect results in decreased copper incorporation into ceruloplasmin, increasing the total copper load in these organs. As a consequence, clinical presentation in the patients with Wilson's disease includes extrahepatic manifestations, such as neuropsychiatric symptoms, renal abnormalities, and many others [2][3][4][5][6][7][8][9][10].
Hepatic manifestations is the initial clinical manifestation in 40-50% of patients and include asymptomatic liver and spleen enlargement with or without slightly elevated liver enzymes, acute transient hepatitis, acute liver failure, which may be complicated by severe Coombsnegative haemolytic anaemia, and progressive cirrhosis. Neurologic manifestations present at the onset in 40-60% of cases, with the wide range of symptoms: tremor, dysarthria, chorea, tics, myoclonus, seizures, headache, peripheral polyneuropathy, emotional lability sleep dysfunction etc. Psychiatric manifestations include personality changes, depression, cognitive impairment and other changes. Ophthalmologic manifestations are typically presented by pigmented corneal rings, also known as Kayser-Fleischer rings, due to the copper deposition within Descemet's membrane. Another manifestation is sunflower cataract. Bone and joint involvement may manifest with spontaneous fractures and joint pain. Haemolytic anaemia due to the copper-induced damage of erythrocytes may be accompanied by thrombocytopenia; the latter may also be seen without anaemia. Thrombocytopenia was described in a patient with combination of Wilson Disease and antiphospholipid syndrome [9][10][11][12][13][14][15][16][17][18][19].
Variety of extrahepatic clinical presentation often lead to diagnostic errors, and delays in diagnosis and initiation of treatment are common even in patients with a positive family history [14]. and sleep loss. Patient's mother reported his emotional lability and aggressiveness. He also had high-grade fever, resolved on antibiotics within 3 days.

Abdomen, kidney and lymph nodes ultrasound
Liver enlarged, with parenchymal hyperechogenicity and coarse texture. Vena Porte diameter 14 mm, cholehepatic d`uct diameter 3 mm. Gall bladder and pancreas otherwise normal. Spleen enlarged up to 187х88 mm, normal echogenicity and structure, splenic vein diameter 8 mm. Kidneys enlarged with parenchymal hypoechogenicity: RD 140х65 mm, RS 154х65 mm; parenchyma 28 mmмм. No cyst, stones or dilatation of renal pelvis. Ascites, retroperitoneal or peripheral lymph nodes not found

Diagnostic considerations and additional work-up
Teenager male presented with the symptoms of systemic disease with CNS, skin, liver, spleen and kidneys involvement and severe throbocytopenia. As the first step we ruled out systemic lupus erythematosus, suspected on the basis of thrombocytopenia, neuropsychiatric disturbances, proteinuria, microhaematuria, and palmar erythema (patient did not meet ACR criteria), primary antiphospholipid syndrome (absence of thrombotic events, negative serology) and infectious endocarditis (ECHO-CG did not show any valvular abnormalities). There were no data favoring any kind of thrombotic microangiopathy (LDH normal, no anemia) or autoimmune hemolysis (no anemia, Coombs test negative). Neuropsychiatric symptoms, "dark" urine at the onset and urobilinuria were suggestive for acute porphyria, but Erlich test turned to be negative. Due to severe thrombocytopenia, idiopathic thrombocytopenic purpura or haemoblastosis were suspected, but bone marrow smear showed all three hematopoietic lineage enhanced proliferation.

Final diagnosis
Finally, combination of hepatosplenomegaly with the dilatation of vena portae and splenic vein, palmar erythema, vascular spiders, encephalopathy, urobilinuria with slightly elevated serum bilirubin level, decreased serum uric acid level lead us to the putative diagnosis of Wilson's disease. Patient was seen by ophthalmologist and slit lamp investigation confirmed presence of Kayser-Fleischer rings. Serum ceruloplasmin was tested and proved to be as low as 43 mg/L (normal range 200-600 mg/L). Serum copper test and urine 24-hour copper excretion were ordered, and the patient, diagnosed with Wilson's disease, was referred to the Hematology Research Center, Division of Orphan Diseases, for specific treatment. Subsequently additional tests showed decreased total serum copper level, and increased urinary copper excretion. The patient was started on penicillamine and his condition markedly improved within 2 months.

Discussion
This case demonstrates the difficulties in diagnostics of Wilson's disease due to unusual initial presentation. Asymptomatic liver disease and relatively mild neuropsychiatric abnormalities did not allow considering Wilson's disease as a "first choice" diagnosis. Severe thrombocytopenia as a leading symptom demanded differential diagnosis with systemic lupus erythematous, thrombotic microangiopathies and idiopathic thrombocytopenic purpura. Acute hepatic porphyria could not be excluded because of "dark" urine at the onset in combination with neuropsychiatric abnormalities, absence of hematuria at admission and urobilinuria without significant bilirubin elevation, this diagnosis was canceled only after negative Erlich test. Thus, Wilson's disease was suspected only after step by step rule out    of all above mentioned conditions, and confirmed by ceruloplasmin decrease, Kayser-Fleischer rings detection, and increase of urinary copper excretion. Family history with unspecified disabling illness of patient's aunt was also confirmative to the diagnosis.
Kidney damage, presenting with "dark" urine (probably due to uraturia, rather than to hematuria), moderate proteinuria and transient microhaematuria, is confirmed by low serum uric acid level. Absence of uric acid crystals in urine, kidney stones and electrolyte disturbances do not exclude tubular dysfunction, typical for Wilson's disease.
The most interesting finding is severe thrombocytopenia without anemia, rarely reported in the literature, and probably may be explained by hypersplenism, as no proof for DIC or antiphospholipid syndrome was found during detailed investigation.

Conclusion
Wilson's disease has to be considered in differential diagnostics of cases with even mild urinary abnormalities combined with extra renal symptoms like hepatic, CNS, skin, skeletal and blood involvement, along with other systemic diseases.