Bone mineralization in children with Wilson’s disease

Background

The goal of this study was to determine bone mineralization in children with Wilson’s disease (WD).

Methods

Twenty-seven patients (16 males) and two age- and gender-matched healthy children for each patient were enrolled in the study. Bone mineral content (BMC, grams) and density (BMD, g/cm²) at lumbar 1–4 vertebrae were measured by dual-energy X-ray absorptiometry. Urinary calcium excretion was calculated in 19 patients. The effect of cirrhosis and hypercalciuria on BMC and BMD was also evaluated in WD patients.

Results

There was no statistically significant difference between patients and healthy controls regarding mean BMC (33.0?±?13.9 vs. 35.8?±?13.8 g) (p?=?0.940) and mean BMD values (0.66?±?0.16 vs. 0.71?±?0.18 g/cm²) (p?=?0.269), respectively. Nine (47.4 %) patients had hypercalciuria. Hypercalciuric patients had statistically significant lower BMC and BMD values than those without hypercalciuria. A significant difference continued to be present after age, weight, height, and pubertal stage adjustment was done, but disappeared after weight, height, follow up duration, and pubertal stage adjustment was done. The presence of cirrhosis did not affect BMC and BMD significantly in WD patients.

Conclusions

BMC and BMD in children with WD were normal. The presence of hypercalciuria but not cirrhosis may affect BMC and BMD negatively in the patients.     

Genetics of Wilson’s disease: a clinical perspective

Hepatic Wilson??s disease is often a difficult diagnosis to confirm. This review examines the current role of genetic tests for Wilson??s disease and is aimed at clinicians caring for patients with this disease. We discuss how genetic testing is carried out for Wilson??s disease, indications for these tests, and genetic counseling for the family. In contrast to the advances in diagnosis of Wilson??s disease by testing for ATP7B mutations, genotype-phenotype correlations are not yet sufficiently established. The non-Wilsonian copper overload syndromes causing cirrhosis in children are another important area for study. The review also identifies further areas for research into the genetics of Wilson??s disease in India.     

Concordance rates of Wilson’s disease phenotype among siblings

Wilson’s disease (WD) is an autosomal recessive disorder characterized by the functional disruption of adenosine triphosphatase 7B (ATP7B), which results in positive copper balance. Although the primary manifestations of the disease are hepatic or neurological in scope, the factors that cause a very diverse picture of WD are not well researched. We compared the first clinical presentation, ages of onset and diagnosis, copper metabolism parameters, and ceruloplasmin levels between index cases (ICs) and their siblings. We examined 73 ICs and 95 siblings from 73 families, including a total of 168 patients with biochemical and genetically confirmed WD diagnoses. We observed an 86 % concordance rate of primary clinical symptoms among ICs with hepatic symptoms and their siblings. There was 66 % concordance among ICs with neurological symptoms and their siblings. No differences regarding age at onset of symptoms or copper metabolism parameters at diagnosis were identified between hepatic ICs and their siblings. The age at symptom onset did not differ between neurological ICs and their siblings, although ICs presented lower ceruloplasmin and serum copper levels. These results demonstrate a high intra-familial concordance of the clinical and biochemical presentation of WD, suggesting that similar factors shared within the same families strongly influence the disease presentation.     

Hepatic Wilson’s disease: Initial treatment and long-term management

Opinion statement This article is based on the experience of 320 patients with Wilson’s disease who were seen between the years 1954 and 2000. These patients were seen at The Boston City Hospital, 1954 thru 1955, University College Hospital, London,1955 thru 1957; Addenbrooke’s Hospital, Cambridge, 1967 thru 1987, and The Middlesex Hospital London, 1988 thru 2000. Wilson’s disease is not strictly a gastroenterologic disease but a genetically determined metabolic disease that is mediated by a failure of copper excretion through the bile. The mutation carried on chromosome 13q14.3: it involves a copper-carrying ATPase (ATPase 7B); more than 250 mutations are now known. The first organ to be affected is the liver, then many other tissues, principally the brain but also the eyes, the kidneys, the bone marrow, and the osteoskeletal system. It is with the hepatic form of the disease that this article is concerned. The hepatic illness may be acute, subacute or chronic; it may be progressive or, apparently, self-limiting. In 10% of patients hemolysis may also be found which can later lead to the formation of pigment gallstones. The management of liver disease is not considered in this article, which is strictly confined to the therapeutic options available for the elimination of copper and the long-term welfare of the patient. It must be remembered that all close relatives of the patient must be screened for the presymptomatic stage of the disease so, if they are found to be homozygous carriers for the mutation, they can be started on preventive treatment.     

Recent clinical features of Wilson’s disease with hepatic presentation

Background We carried out this study to evaluate recent clinical features of Wilsons disease (WD) with hepatic presentation, especially in terms of age, degree of liver injury, and association with hepatocellular carcinoma (HCC).Methods Sixteen patients with hepatic manifestations were diagnosed with WD in the period 1976–2003. We divided this period into two periods, past and recent. The diagnosis was based on the presence of Kayser-Fleisher rings, low serum copper levels, low serum ceruloplasmin levels, increased urinary copper concentrations before or after D-penicillamine challenge, and increased hepatic copper concentrations. This retrospective study was done at Ehime University Hospital.Results Four patients, including a pair of siblings, had a family history of WD. Four patients had parental consanguinity. There were 6 patients aged over 40 years in the recent period, whereas no patients in the past period were over 40. Four patients had neurological manifestations. Ten patients had liver cirrhosis and 5 had chronic hepatitis. Two had fatty liver without obesity. All patients in the past period had liver cirrhosis. Three patients with liver cirrhosis were found to have HCC during the follow up. All patients were treated with either D-penicillamine or trientine chloride, or both. However, four patients had to discontinue these agents due to the side effects.Conclusions Recently, the number of patients diagnosed with WD has been increasing, not only in terms of those with classical-type WD but also in terms of elderly patients or patients with non-cirrhotic liver injury such as fatty liver and chronic hepatitis. The various clinical features of WD should be recognized and particular attention should focus on HCC as a complication.     

A case of Wilson’s disease with characteristic laparoscopic findings

A 44-year-old male was pointed out liver function abnormality by medical check-up. Blood examination and computed tomography showed liver cirrhosis. Then, he was referred to our hospital for further examination. After blood test, viral markers revealed previous infection of hepatitis B virus (HBV). We estimated the etiology of his liver disease as previous HBV infection. On laparoscopic examination, his liver surface was nodular with mixed yellowish nodules and ash gray to copper-colored nodules in the diameter of 3–10 mm. There were large regenerative nodules in segments 3 and 4. Large regenerative nodules and irregular steatosis were contradictory to HBV-related liver cirrhosis, so then we supposed Wilson’s disease. The amount of copper excretion in the urine was 326.6 μg (>100 μg/24 h). After D-penicillamine administration, urinary copper excretion increased to 2151.5 μg/24 h. Though hepatic copper concentration was 174.5 μg/g wet tissue (>200 μg/g wet tissue), his laboratory data fulfilled the Leipzig diagnostic criteria proposed by EASL. Laparoscopic examination with liver biopsy has advantages to survey many disease-specific findings on liver surface and to obtain adequate liver sample. Laparoscopic examination is one of the effective procedures for diagnosing relatively rare liver disease like Wilson’s disease.     

Hepatocellular carcinoma in a non-cirrhotic patient with Wilson’s disease

We report the exceptional case of hepatocellular carcinoma in a non-cirrhotic patient, whose Wilson’s disease was diagnosed at the unusual age of 58 years. The liver histology revealed macrovesicular steatosis with fibrosis, but no cirrhosis. The disease was treated with D-penicillamine for 3 years until acute discomfort in the right upper quadrant led to detection of multifocal hepatocellular carcinoma, which was successfully resected. The histological examination confirmed the malignant nature of the 4 lesions, which were classified according to Edmondson and Steiner as poorly differentiated hepatocellular carcinoma grade 3. The non-tumoral parenchyma showed 80% steatosis with ballooned cells, lobular inflammation, septal fibrosis but no cirrhosis. Hepatocellular carcinoma is rare in Wilson’s disease, especially in the absence of cirrhosis. The literature’s 28 published cases are reviewed and the contributory role of copper in the hepatocarcinogenic process is discussed.     

Brain proton magnetic spectroscopy in long-term treatment of Wilson’s disease patients

We reported the brain proton magnetic resonance spectroscopy (MRS) findings in 27 Wilson’s disease (WD) patients treated more than 6 years in neurological (nWD) and hepatic (hWD) subgroups. We investigated 4 hWD patients, with no improvement and 8 with marked improvement; and 8 nWD patients with marked improvement and 7 with no improvement of clinical status. In nWD patients with improvement the MRS showed significantly higher Cho/Cr, Glx/Cr ratios levels. In hWD patients with no improvement the lower Cho/Cr and in nWD significantly lower NAA/Cr and higher Cho/Cr and Lip/Cr ratios were detected. In nWD patients with improvement the spectroscopic pattern, can be related to gliosis. In patients with no neurological improvement a persistent neuronal dysfunction can occur, perhaps as a result of copper or iron deposition.     

Brain proton magnetic spectroscopy in long-term treatment of Wilson’s disease patients

We reported the brain proton magnetic resonance spectroscopy (MRS) findings in 27 Wilson’s disease (WD) patients treated more than 6 years in neurological (nWD) and hepatic (hWD) subgroups. We investigated four hWD patients, with no improvement and eight with marked improvement; and eight nWD patients with marked improvement and seven with no improvement of clinical status. In nWD patients with improvement the MRS showed significantly higher Cho/Cr, Glx/Cr ratios levels. In hWD patients with no improvement the lower Cho/Cr and in nWD significantly lower NAA/Cr and higher Cho/Cr and Lip/Cr ratios were detected. In nWD patients with improvement the spectroscopic pattern, can be related to gliosis. In patients with no neurological improvement a persistent neuronal dysfunction can occur, perhaps as a result of copper or iron deposition.     

Influence of BDNF polymorphisms on Wilson’s disease susceptibility and clinical course

Susceptibility to Wilson’s disease (WD) and its clinical manifestations are thought to be affected by genetic factors, including polymorphisms. The role of brain-derived neurotrophic factor (BDNF) in the pathogenesis of neurodegenerative diseases is now widely discussed. The aim of the present study was to evaluate the frequency of the BDNF Val66Met (G-196A) and C-270T polymorphisms in WD patients and in healthy controls, and to determine the role of these polymorphisms in the clinical characteristics of WD. We found that the BDNF Val/Val (?196 G/G) and ?270 C/T genotypes occurred more frequently in WD patients than in healthy controls (66 % versus 45.5 %, p?=?0.0001, and 14 % versus 6 %, p?=?0.018, respectively). Similarly, symptomatic patients carried the BDNF Val/Val genotype more often than presymptomatic patients (75 % versus 53 %, p?=?0.0097). No association was detected between any of the determined polymorphisms and the dominant form of the disease or the age of onset for WD.     

The effect of gender on brain MRI pathology in Wilson’s disease

Gender influence on the clinical manifestations of Wilson’s Disease (WD) has been suggested; however, brain MRI pathology based on sexual dimorphism in WD has not yet been examined. The aim of this study was to analyse the effect of gender on brain MRI pathology according to the predominant form of WD. We retrospectively analysed the brain MR images of 204 newly diagnosed and untreated WD patients. The predominant form of the disease was neuropsychiatric (n?=?105), hepatic (n?=?67) or presymptomatic (n?=?32). Overall, neuroimaging pathologies were found in 64.2 % WD patients. The clinical form analysis revealed significant gender-related differences. In the neuropsychiatric form, men presented with cerebellar atrophy and cortical brain atrophy more often than women (25/58 vs. 11/47; p?<?0.05) and (23/58 vs. 12/47; p?=?0.09), respectively. In contrast, women tended to present with globus pallidus lesions more often than men (25/47 vs. 20/58; p?=?0.054). There were no gender differences observed in the hepatic form, but cortical brain atrophy presented more often in men than women (3/12 vs. 0/20; p?<?0.05) in the presymptomatic form. According to our findings, there is a gender-dependent brain vulnerability to copper toxicity. We speculate that these differences are potentially related to an oestrogen protective effect and are due to differences in gender-related clinical forms.     

Hirschsprung’s disease

Opinion statement Hirschsprung’s disease (HSCR) is the most common congenital malformation of the enteric nervous system and requires early diagnosis and surgical repair for the best comprehensive outcome. The early diagnosis of this disorder permits the use of primary endorectal pull-through (PERPT), which is now the definitive surgical therapy for HSCR. PERPT has become the preferred method of treatment for HSCR, and large numbers of successfully treated patients have been described in the recent medical literature. The rate of postoperative complications is generally similar to that following a two-stage surgical repair, but PERPT patients may be at a slightly higher risk for Hirschsprung’s-associated enterocolitis. Despite recent surgical advances in the treatment of HSCR, a two-stage surgical repair involving a temporary diverting colostomy may still be necessary in up to one third of patients. Candidates for a staged repair include those HSCR patients with long-segment or total colonic disease or when there has been a delay in diagnosis that results in a markedly dilated proximal colon or patient clinical instability. Internal anal sphincter hypertonicity, occurring either as isolated primary anal achalasia or as a postoperative complication, can be successfully managed by either botulinum toxin injections or anal myectomy. The measurement of colonic motility in surgically repaired patients with a long-standing postoperative abnormality of bowel function can identify several distinct motility disorders that are amenable to separate and individualized therapies. The single most important element in the management of HSCR remains the clinical judgement of the surgeon of record, who utilizes all discernible clinical data to elect the manner of surgical repair in a given patient.     

Whipple’s disease

Whipple’s disease is an infectious disease caused by a grampositive bacterium, Tropheryma whipplei. The first case was reported in 1907 by GH Whipple. Its classic symptoms are diarrhea and arthralgias, but symptoms can be various. Cardiac or central nervous system involvement, not always associated with digestive symptoms, may also be observed. For a long time, diagnosis has been based on duodenal biopsy, which is positive using periodic acid-Schiff staining. However, for patients without digestive symptoms, results can be negative, leading to a delay in diagnosis. For 10 years, a tool based on polymerase chain reaction targeting the 16S rDNA sequence has been used. In vitro culture of the bacterium, achieved 3 years ago, has allowed new perspectives for diagnosis and treatment. The natural evolution of the disease without treatment is always fatal. Current treatment is based on administration of trimethoprim-sulfamethoxazole for at least 1 year.     

Menetrier’s disease

Opinion statement Menetrier’s disease is a rare acquired disorder of the fundus and body of the stomach (ie, oxyntic mucosa) characterized by giant hyperplastic folds, protein-losing gastropathy, hypoalbuminemia, increased mucus secretion, and hypochlorhydria. Recent research implicates overproduction of transforming growth factor-α with increased signaling of the epidermal growth factor receptor (EGFR) in the pathogenesis. Activation of the EGFR, a transmembrane receptor with tyrosine kinase activity, triggers a cascade of downstream, intracellular signaling pathways that leads to expansion of the proliferative compartment within the isthmus of the oxyntic gland. The diagnosis of Menetrier’s disease is based upon characteristic histologic changes, including foveolar hyperplasia, cystic dilation of pits, and reduced numbers of parietal and chief cells. The best treatment for Menetrier’s disease is not clear. It seems reasonable to test and treat for cytomegalovirus and Helicobacter pylori, as 1) in children, evidence exists that the disease may be due to cytomegalovirus infection in up to one third of patients; and 2) in adults, there are anecdotal reports of resolution upon H. pylori eradication. More recently, therapies targeting increased signaling of the EGFR have shown promise, including somatostatin analogues and monoclonal antibodies (eg, cetuximab) directed against the EGFR. In refractory cases, gastrectomy is curative.     

Crohn’s disease complicated by adult-onset Still’s disease

A 31-year-old man with Crohns disease developed arthritis, spiking fever, and skin rash indistinguishable from that of adult-onset Stills disease. He was admitted to our hospital because of a periumbilical intestinal skin fistula. Crohns disease had been diagnosed in 1991, and had required intestinal resection twice, and schizophrenia had been diagnosed in 1993. He developed polyarthritis and spiking fever, accompanied by a macular skin rash on both forearms. Marked hepatosplenomegaly and bilateral pleural effusion were detected on computed tomography examination. These findings are indistinguishable from those of adult-onset Stills disease. Because his mental status had deteriorated following high-dose prednisolone on a previous admission, he was treated with an immunosuppressive agent on this occasion, with the treatment being successful. This is the first report of adult-onset Stills disease complicating Crohns disease. In patients with Crohns disease, polyarthritis and skin rash can easily be misdiagnosed as enteropathic arthritis with erythema nodosum associated with the Crohns disease. Although adult-onset Stills disease may not be fatal, early diagnosis is important because it can, in rare cases, result in life-threatening complications.     

Cushing’s disease

Cushing’s disease, i.e., pituitary ACTH-secreting adenoma causing excess glucocorticoid secretion, is a rare disease with significant mortality and morbidity. Timely diagnosis and appropriate treatment can alter the course of the disease and are therefore mandatory. First step of the diagnostic work-up is the endogenous glucocorticoid excess by measurement of urinary free cortisol, cortisol circadian rhythmicity or suppression by low doses of dexamethasone. In patients with equivocal results, second line tests, such as the dexamethasone-suppressed CRH test and desmopressin stimulation, usually enable the diagnosis to be confirmed. Measurement of plasma ACTH then allows the distinction between ACTH-dependent (e.g., pituitary or extrapituitary neuroendocrine tumors) and ACTH-independent causes (e.g., adrenal tumors). The last step in the diagnostic algorhythm is often the most fraught with problems as the distinction between Cushing’s disease and ectopic ACTH secretion relies on judicious interpretation of several diagnostic procedures. Positive responses to stimulation with CRH and inhibition by high doses of dexamethasone, if concurrent, enable a pituitary origin to be established whereas conflicting results call for inferior petrosal sinus sampling, the latter to be performed in experienced centres only. Visualisation of the tumor at pituitary imaging is helpful but not required for the diagnosis, as microadenomas often remain undectected by MRI and/or CT scan and, on the other hand, visualisation of a non-secreting incidentaloma may be misleading. Surgical removal of the pituitary tumor is the optimal treatment choice and should be attempted in every patient. Surgical failures as well as relapses can be treated by radiotherapy, medical therapy or, if necessary, bilateral adrenalectomy. Finally, patients cured of Cushing’s disease require long-term monitoring given the risk of relapse and clinical burden of associated ailments.