Muriel Buxton-Thomas

Hereditary fibrinogen A α-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation

Variants of fibrinogen A alpha-chain (AFib) cause the most common type of hereditary renal amyloidosis in Europe and, possibly, the United States as well. Variant fibrinogen is produced in the liver, and solitary renal allografts fail within 1 to 7 years with recurrent amyloidosis. We assessed 22 AFib patients for combined liver and kidney transplantation (LKT) and report the clinical features and outcome. Twenty-one had E526V and 1, the R554L variant. Coronary atherosclerosis was identified in 68% and systemic atheromatosis in 55%. Vascular atheroma excised at endarterectomy and endomyocardial biopsies contained purely variant fibrinogen amyloid. Half had autonomic neuropathy. Six of 9 patients who underwent LKT are alive (67%), with good allograft function and no amyloidosis at median 67 months (range, 33-155 months) of follow-up. Serial technetium-99m-labeled dimercaptosuccinic acid ((99m)Tc-DMSA) renal scintigraphy in 2 cases of preemptive LKT demonstrated preserved native kidney residual function at 5 years. Four explanted livers were used successfully for domino transplantation. Fibrinogen amyloidosis is a systemic amyloid disease with visceral, vascular, cardiac, and neurologic involvement. LKT is curative; however, cardiovascular amyloidosis may preclude this option. Our data encourage evaluation of preemptive solitary liver transplantation early in the course of amyloid nephropathy to prevent hemodialysis and kidney transplantation.

Cystatin C, an easy and reliable marker for assessment of renal dysfunction in children with liver disease and after liver transplantation

Renal dysfunction of variable severity is being increasingly recognized as a major complication of calcineurin inhibitors (CI), in some patients even necessitating renal transplantation. Close and effective monitoring of the renal function is indicated. Current methods for this monitoring are calculation of the glomerular filtration rate (GFR) based on creatinine or exogenous substances like 51Cr‐EDTA. The first method is unreliable in children and the second is expensive and cumbersome. Cystatin C has been shown to be an accurate marker of glomerular filtration but has not been evaluated in a large cohort of pediatric patients before and after liver transplantation (LT). We evaluated the accuracy of cystatin C in 62 children (30 male) with LT, who had their 51Cr‐EDTA measured on 40 occasions prior to LT and on 47 occasions after LT. The reciprocal of cystatin C correlated better with 51Cr‐EDTA GFR (r = .78) than the reciprocal of creatinine (r = .40). Diagnostic accuracy in the identification of reduced GFR was assessed by ROC analysis. Cystatin C yielded the highest area under the ROC curve (AUC) in all groups assessed. From these data a cutoff level of cystatin C predicting 51Cr‐EDTA GFR < 80 ml/min/1.73m2 was calculated. A level of 1.06 mg/L was found to have a sensitivity of 91% and a specificity of 81%. Applying this cutoff level in our patient group would have avoided 51Cr‐EDTA GFR estimation in 43 of the 87 estimations. In conclusion, the use of this simple test could be recommended as screening of renal dysfunction in children with liver disease and after LT. (Liver Transpl 2005;11:344–349.)

Bone mineral density and height gain in children with chronic cholestatic liver disease undergoing transplantation.

Background. Osteodystrophy is a well-described complication of chronic liver disease. Previous reports in adults and children undergoing liver transplantation (LT) were discordant, with the former showing no improvement of bone disease in the first year after transplantation and the latter demonstrating remarkable benefit from it. Our aim was to perform a pilot study on osteodystrophy in children undergoing LT and evaluate the contribution of growth on bone mineral density (BMD) changes. Methods. We studied six patients (two male), with a median age at transplantation of 8.8 (range 3.8–16.6) years. Indications for transplantation were biliary atresia and progressive familial intrahepatic cholestasis (three patients each). BMD was studied with dual-energy x-ray absorptiometry and biochemical markers of liver and bone function in patients before and at 3, 6, and 12 months after LT. Results. Median L2-L4 spinal BMD was 0.54 g/cm2 (range 0.29–0.87) before LT, and 0.58 g/cm2 (0.27–0.86) at 3 months, 0.66 g/cm2 (0.36–1.00) at 6 months, and 0.76 g/cm2 (0.44–1.02) at 12 months after LT (P =0.005). Median height was 133 (range 93–167) cm before LT, and 134 (93–167) at 3 months, 136 (97–167) at 6 months, and 139 (102–167) at 12 months after LT. There was direct correlation between height gain and total body BMD improvement (r =0.929, P =0.007). Conclusion. BMD in children with chronic cholestatic liver disease improves remarkably by 12 months after LT. Catch-up growth in children can account for the different effect of LT on bone density between adult and pediatric populations in the first year after surgery.

Transdermal hormone replacement therapy improves vertebral bone density in primary biliary cirrhosis: results of a 1-year controlled trial

Background : Retrospective studies have suggested that hormone replacement therapy may reduce the rate of bone loss in primary biliary cirrhosis, but no controlled data are available.

Use of extracorporeal liver assist device and auxiliary liver transplantation in fulminant hepatic failure

The case history of a 14-year-old boy with fulminant hepatic failure secondary to non-A, non-B hepatitis who fulfilled selection criteria for orthotopic liver transplantation is described. Two forms of liver support were used (extracorporeal liver assist device and an auxiliary partial orthotopic liver transplantation) to provide additional time to allow spontaneous recovery to occur. During the 66 h of extracorporeal haemoperfusion through the device, haemodynamic stability was maintained along with improvements in serum bilirubin (555 to 381 mumol/l), and international normalized ratio (INR) (3.7 to 2.9). Deterioration in these parameters was observed following cessation of treatment and 10 h later, after a donor liver had become available, an auxiliary transplant was performed. Clinical recovery, though initially slow, was eventually complete, with histopathological and scintigraphic evidence of full liver regeneration at 3 months. Withdrawal of his immunosuppressive drugs began at 6 months and was complete by 14 months after auxiliary transplantation. He has since remained well with normal liver function tests. Temporary liver support may provide additional time for spontaneous recovery of the native liver to occur in selected cases of fulminant hepatic failure, even when criteria are fulfilled for orthotopic liver grafting.

Bilateral orbital metastases from a neuroendocrine tumor

When neuroendocrine tumors metastasize to the orbit, they usually do so as solitary lesions, sometimes involving an extraocular muscle. A 70-year-old woman with a known neuroendocrine tumor had bilateral painful proptosis, orbital soft tissue swelling, and ophthalmoplegia. Imaging showed masses within all the extraocular muscles. Orbital biopsy disclosed metastatic neuroendocrine tumor cells within the connective tissue.

Diurnal, Week-to-Week, and Long-Term Variation in Urine Deoxypyridinoline Cross-Link Excretion in Healthy Older Women

OBJECTIVES: To establish a reference range for morning and afternoon excretion of urinary deoxypyridinoline (DPD) in apparently healthy older women selected from a volunteer database. To assess the extent of diurnal variation and short and long‐term within‐subject longitudinal variation.

Striatal 123I-Ioflupane SPECT abnormality in sporadic Creutzfeldt–Jakob disease

A 61-year-old man presented with a 9 month history of progressive coordination, speech and memory problems as well as a 20 lb weight loss. He had fatigue, daytime somnolence and anxiety. Past personal and family medical histories were non-contributory. Examination demonstrated poor recall [Mini Mental State Examination (MMSE) 27/30, losing three points for memory]. He had an unsteady gait, could not tandem walk, had a fine upper limb postural tremor and had mild limb apraxia. The remainder of his neurological exam was normal. Investigations for a cerebellar syndrome were initiated. Full blood count, electrolytes, liver enzymes, B12, folate, thyroid-stimulating hormone (TSH), free T4, autoantibodies (mitochondrial, anti-gastric parietal cell, liver kidney microsomal, anti-smooth muscle, antinuclear antibody, anti-neutrophil cytoplasmic antibody), immunoglobulins, serum protein electrophoresis, copper, caeruloplasmin, manganese, neuronal antibodies (anti Ri, Yo, Hu), voltage-gated K channel antibodies, TSH receptor binding antibody and thyroid peroxisome antibodies were normal or negative. Cerebrospinal fluid (CSF) glucose and protein were normal, and there were no cells. The diagnosis of multiple system atrophy-cerebellar phenotype was considered. One year into the illness, dopamine transporter imaging (DAT) using 123I-Ioflupane single-photon emission computed tomography (SPECT) showed equivocally abnormal appearance qualitatively. After standard processing protocols, which involves attenuation correction during reconstruction, quantification of specific to non-specific ratios showed reduced caudate and putamen uptake bilaterally (see Fig. 1 for qualitative appearance and ratios), the right putamen having the lowest ratio. Subsequent brain magnetic resonance imaging (MRI) revealed T2 hyperintensity and corresponding restricted diffusion of the basal ganglia and thalami bilaterally as well as the cingulate gyri, right middle frontal gyrus and left parietal cortex, suggestive of sporadic Creutzfeldt–Jakob disease (CJD) (Fig. 2). Electroencephalogram (EEG) was normal. Within weeks, startle myoclonus developed, and he died shortly thereafter. Autopsy confirmed the diagnosis of sporadic CJD. A single published case of DAT in CJD also revealed reduced pre-synaptic putaminal uptake [1], and together with our case, suggests dopaminergic pathway dysfunction in CJD. These in vivo findings are in agreement with a recent pathologic study of the nigrostriatal pathway in sporadic CJD in which Vital et al. [2] found both preand post-synaptic cell loss in the nigrostriatal system. The loss of dopaminergic neurons in the substantia nigra correlated with the loss of neurons in the caudate and putamen. Interestingly, the patient previously reported by Ragno et al. [1] had an extrapyramidal syndrome while our patient had a cerebellar syndrome yet also had abnormal DAT imaging. In our patient, the DAT imaging appearance was not felt to be typical of idiopathic Parkinson’s disease. C. Hinnell M. Samuel (&) Department of Neurology, King’s College Hospital, 9th Floor, Ruskin Wing, Denmark Hill, London SE5 9RS, UK e-mail: m.samuel@nhs.net