Major Depressive Disorder in an International Multisite Wilson Disease Registry.

BACKGROUND AND AIMS: Psychiatric symptoms are frequently reported in Wilson disease (WD); however, systematic assessments with validated measures are lacking. OBJECTIVE: We aim to report the prevalence and clinical correlates for major depressive disorder (MDD) as resulting from a multisite international WD registry. METHODS: All patients enrolled in the WD registry received structured psychiatric evaluations (Mini International Neuropsychiatric Interview, Patient Health Questionnaire-9, Generalized Anxiety Disorder-7 scale, Perceived Stress Scale), laboratory tests, hepatology, and neurological assessments. We present the analysis of the data collected at enrollment for the first 3 years (N = 62). RESULTS: Thirty-seven percent (23) had a lifetime history (MDD), and 6% (4) met the criteria for an active major depressive episode. Depression was self-reported in 30.51% (19) at WD diagnosis. Patients with MDD had worse mental health quality-of-life (QOL) scores (median 43 vs 53.6, P = 0.006), higher severe anxiety (13.04% vs 0), higher perceived stress (median 18 vs 9, P < 0.003), and higher levels of neuroticism (median 8 vs 5.0, P = 0.002). We found no significant difference in physical health QOL and severity of neurological or liver disease. There was no significant difference in copper parameters or liver tests in those with MDD and without. The limitations of our study consist of the small sample size, the cross-sectional report, and the lack of brain copper measurements. CONCLUSIONS: Lifetime MDD is highly prevalent in WD and associated with worse mental health QOL. We did not find a significant association among liver disease, neurological disease laboratory tests, and MDD. Screening for depression should be considered in patients with WD.

The Effect of Mental Health, Neurological Disease, and Liver Disease on Quality of Life in Patients With Wilson Disease.

BACKGROUND: Wilson disease (WD) is a chronic disorder of copper metabolism which may affect patient's quality of life (QOL). OBJECTIVE: Our aim was to assess the relationship between mental QOL (M-QOL) and physical QOL (P-QOL) and severity of the liver, neurological disease and mental health in patients with WD. METHODS: At enrollment into our multisite international WD registry, adults (n = 62) were administered examinations assessing QOL (Short-Form 12-Item Health Survey), cognition, and mood. Patients also underwent hepatology and neurological assessments. RESULTS: Patients had lower M-QOL than P-QOL scores, P = 0.0006. Patients with major depressive disorder (n = 22) had worse M-QOL scores, P = 0.0017 but not P-QOL. We found no association with impaired cognition (n = 37) and QOL. The P-QOL scores have a moderate negative association with neurological disease severity based on the Unified Wilson Disease Rating Scale score (total [r = -0.38, P < 0.003], part 2 [r = -0.50, P < 0.0001], and part 3 [r = -0.37, P = 0.004]). M-QOL was not associated with Unified Wilson Disease Rating Scale scores. Worse P-QOL, but not M-QOL, was found in higher cirrhosis severity indicated by Child-Pugh (r = -0.80, P = 0.002) and Model for End Stage Liver Disease scores (r = -0.64, P = 0.03). CONCLUSIONS: M-QOL was associated with depression but not cognitive impairment, neurological disease, or liver disease severity, suggesting that mental health issues may affect overall QOL independent of the degree of liver or neurological disease. P-QOL was affected by the severity of neurological and liver disease but not mental health but also contributes to overall QOL in WD. An appreciation of the range of problems that affect QOL in adults with WD will help health care providers address issues that could improve overall well-being. The Short-Form 12-Item Health Survey may provide a useful instrument for QOL surveillance in WD.

Direct Measurement of ATP7B Peptides Is Highly Effective in the Diagnosis of Wilson Disease.

BACKGROUND & AIMS: Both existing clinical criteria and genetic testing have significant limitations for the diagnosis of Wilson disease (WD), often creating ambiguities in patient identification and leading to delayed diagnosis and ineffective management. ATP7B protein concentration, indicated by direct measurement of surrogate peptides from patient dried blood spot samples, could provide primary evidence of WD. ATP7B concentrations were measured in patient samples from diverse backgrounds, diagnostic potential is determined, and results are compared with biochemical and genetic results from individual patients. METHODS: Two hundred and sixty-four samples from biorepositories at 3 international and 2 domestic academic centers and 150 normal controls were obtained after Institutional Review Board approval. Genetically or clinically confirmed WD patients with a Leipzig score >3 and obligate heterozygote (carriers) from affected family members were included. ATP7B peptide measurements were made by immunoaffinity enrichment mass spectrometry. RESULTS: Two ATP7B peptides were used to measure ATP7B protein concentration. Receiver operating characteristics curve analysis generates an area under the curve of 0.98. ATP7B peptide analysis of the sequence ATP7B 887 was found to have a sensitivity of 91.2%, specificity of 98.1%, positive predictive value of 98.0%, and a negative predictive value of 91.5%. In patients with normal ceruloplasmin concentrations (>20 mg/dL), 14 of 16 (87.5%) were ATP7B-deficient. In patients without clear genetic results, 94% were ATP7B-deficient. CONCLUSIONS: Quantification of ATP7B peptide effectively identified WD patients in 92.1% of presented cases and reduced ambiguities resulting from ceruloplasmin and genetic analysis. Clarity is brought to patients with ambiguous genetic results, significantly aiding in noninvasive diagnosis. A proposed diagnostic score and algorithm incorporating ATP7B peptide concentrations can be rapidly diagnostic and supplemental to current Leipzig scoring systems.

Outcomes of Acute Liver Injury in Adults Due to Wilson's Disease: Is Survival Without Transplant Possible?

Wilson's disease (WD) is a rare cause of acute liver failure (ALF) that is thought to have a uniformly fatal outcome without liver transplantation (LT). Previous studies proposed diagnostic and prognostic criteria for WD-ALF. It is not known whether these apply to WD patients presenting as severe acute liver injury (ALI) without encephalopathy. From 2008 to 2018, 822 patients with ALI in the US Acute Liver Failure Study Group (ALFSG) registry were enrolled and prospectively followed. The diagnosis of WD-ALI was confirmed in 8 patients. Serum biochemical diagnostic ratios predicting WD-ALF (alkaline phosphatase [ALP]:total bilirubin(TB) and aspartate aminotransferase [AST]:alanine aminotransferase [ALT]) were determined in these patients, and predictors of prognosis for WD-ALI were evaluated. Of these 8 ALI-WD patients, 5 received an LT. Ratios of both ALP:TB of <4 and AST:ALT of >2.2 on study admission were met in 4 LT patients. All LT patients were female. The Model for End-Stage Liver Disease scores on admission were generally higher in LT patients. All transplanted patients had an initial revised WD score of >11 (>10 predicting poor outcome without LT in WD-ALF), whereas in non-LT patients, 2 had scores of 9, and 1 a score of 13. Also, 3 LT patients were started on chelation therapy, 2 were started on plasmapheresis, and 1 was started on Molecular Adsorbent Recirculating System therapy. All non-LT patients were treated with chelation. At 21 days, all patients were alive and discharged from the hospital. In conclusion, some patients with ALI due to WD may survive without LT. Revised Wilson index scores >10 predict poor outcome in most patients with WD-ALI, as they do for WD-ALF, and they correlate positively with the ALI model in this cohort. Biochemical ratios for WD diagnosis appear more applicable to ALF compared with WD-ALI.

Zinc Maintenance Therapy for Wilson Disease: A Comparison Between Zinc Acetate and Alternative Zinc Preparations.

We evaluate Wilson disease (WD) treatment with zinc acetate (U.S. Food and Drug Administration approved) and alternative zinc salts. Studies examining zinc therapy in WD are few, and data on alternative zinc salts are limited. We describe one of the largest recent studies of zinc therapy in WD. First, we conducted a single-center retrospective review of 59 patients with WD (age 6-88 years, 32 female patients) treated with zinc (50-150 mg) for 0.8 to 52 years (median, 26 years); most were on prior chelation therapy (n = 39). Second, we developed a survey to explore patients' zinc therapy experience. Primary endpoints were alamine aminotransferase (ALT) and urine copper excretion (µg/24 hours). Urine copper was categorized as low <25 µg (possible overtreatment), target 25-100 µg, or elevated >100 µg (possible noncompliance or treatment failure). The target range was reached in 81% of patients on zinc acetate, 73% on zinc gluconate, and 57% on alternative zinc. Low urine copper was not associated with a high ALT. ALT was normal in 77% of patients with target urine copper but only in 16% with urine copper >100 µg. ALT elevations were not significantly different between zinc salts (Kruskal-Wallis, P = 0.26). Our survey demonstrated the mean age of starting zinc was 26.8 years (3.5-65 years); most were treated with zinc acetate (45%) and zinc gluconate (42%). Before zinc treatment, 45% of patients were symptomatic; the majority of patients (80%) were asymptomatic on zinc. Gastrointestinal side effects were the predominant reason for changing zinc salts (38%), but most reported no side effects on current zinc therapy (67%). Conclusion: Effective treatment with zinc is possible in many patients with WD. The potential for treatment failure suggests close monitoring and consideration of alternative treatments are paramount for those without both a normal serum ALT and appropriate urine copper excretion.

Effects of single-agent and combination chemotherapy for gestational trophoblastic tumors on risks of second malignancy and early menopause.

PURPOSE: To assess the risks of second malignancy and early menopause in a large cohort of patients with gestational trophoblastic tumor who were treated with chemotherapy. PATIENTS AND METHODS: A survey of patients treated at Charing Cross Hospital between 1958 and 2000 was performed in 2006 to assemble incidence data for subsequent malignancies and the age at menopause. Treatment records were reviewed for the regimens and durations, and the incidence of subsequent malignancies was compared with that in the national age-matched population. RESULTS: Data were obtained for 1,903 patients, with a mean follow-up of 16.9 years. Eighty-six patients developed a subsequent malignancy compared with an expected number of 79 (standardized incidence ratio [SIR], 1.1; 95% CI, 0.9 to 1.3). The overall risk was low for patients treated with single-agent methotrexate and folinic acid (MTX-FA; SIR, 0.7; 95% CI, 0.5 to 1.1) and also for patients treated with etoposide, methotrexate, and dactinomycin followed by cyclophosphamide and vincristine on alternating weeks (EMA-CO) with an SIR of 0.9 (95% CI, 0.4 to 2.2), but there were significantly increased risks of oral cancer, melanoma, meningioma, and leukemia. The cumulative risk of early menopause was low after MTX-FA but was substantial after EMA-CO, reaching 13% by age 40 years and 36% by age 45 years. CONCLUSION: Subsequent cancer risks for patients cured of gestational trophoblastic tumors with modern chemotherapy appear similar to those of the normal population with no overall increased risk of malignancy after MTX-FA or EMA-CO. However, there was evidence of an increased risk of leukemia after EMA-CO and some evidence of other site-specific increased risks based on small patient numbers. All major treatments except MTX-FA increased the risk of early menopause.

Tumour lysis syndrome in a patient with intravascular spread from a recurrent epithelial ovarian cancer.

Tumour lysis syndrome is a potentially life-threatening oncological emergency most commonly encountered in patients with rapidly proliferating, treatment-responsive haematological malignancies. It is rarely observed in solid tumours and, to our knowledge, this is the first time that it has been reported in a cancer with an intravascular tumour extension. In this report, we describe a case of a woman who presented with recurrent ovarian cancer and was found to have tumour invading into her vasculature. The patient subsequently developed tumour lysis syndrome after receiving chemotherapy. The case highlights the importance of considering tumour lysis syndrome prophylaxis when treating patients with intravascular involvement from a solid malignancy even if, as in this case, it is a recurrent tumour. Included is a brief review of the literature. We propose that 'intravascular tumour invasion is recognised as an important risk factor for the development of tumour lysis syndrome.

Women's perspective of botulinum toxin treatment for overactive bladder symptoms.

INTRODUCTION AND HYPOTHESIS: This study aimed to evaluate the women's' views and expectations about outcomes and complications of botulinum toxin treatment for overactive bladder (OAB) symptoms. METHODS: Consecutive women with OAB symptoms and detrusor overactivity were requested to fill out a multiple choice questionnaire to assess whether they would consider botulinum and what outcomes as well as complications they would find acceptable to undergo this treatment. RESULTS: Two hundred sixty-one women, mean age of 58 (range, 38-78) years, were studied. Two hundred twenty-four were treatment-naive women (group A), while 37 were no responders to anticholinergics (group B). Only 49.6% of women in group A and 54% in group B would accept botulinum toxin. No significant differences were found between treatment-naive women and non-responders to anticholinergics (p > 0.05). CONCLUSIONS: Acceptance of botulinum toxin treatment involves a complex interaction of efficacy and possible complications. The balance of these factors changes the acceptability of the treatment.

Bladder sensations during filling cystometry are different according to urodynamic diagnosis.

PURPOSE: To determine the position and character of bladder filling sensations in women undergoing urodynamic investigations. MATERIALS AND METHODS: Women with lower urinary tract symptoms referred to urodynamic clinics of two tertiary referral teaching hospitals were prospectively studied. During filling cystometry the women were asked to describe the bladder sensations at the first sensation of bladder filling, first desire to void, strong desire to void, maximum bladder capacity and if the woman felt urgency. Women were also asked to define the time that the voiding could be delayed and to indicate the position of each sensation on a body map. Women were classified into four groups according to urodynamic diagnosis: detrusor overactivity (DO), urodynamic stress incontinence (USI), co-existing DO and USI (mixed) and inconclusive urodynamics; the latter was excluded from the study. Bladder sensations were compared between these groups using Chi squared and Kruskall-Wallis tests. RESULTS: Eighty-two women were studied. Women with DO and mixed urodynamic diagnosis predominantly described the bladder sensations as being perineal or vaginal in origin, whereas those with USI felt the sensations suprapubically. The character of bladder sensation was not significantly different between the diagnostic groups and the intensity increased with larger bladder volume. The duration that women could delay voiding was significantly different between different urodynamic groups. CONCLUSIONS: Bladder sensations experienced during cystometry are different in position and duration in relation to urodynamic diagnoses. This indicates that uniform descriptions of sensations during filling cystometry might not be appropriate to different urodynamic diagnoses.