Phaeochromocytoma and paraganglioma.

Phaeochromocytomas and paragangliomas are rare catecholamine-producing neuroendocrine tumours which can potentially cause catastrophic crises with high morbidity and mortality. This best practice article considers the causes and presentation of such tumours, screening and diagnostic tests, management of these patients and consideration of family members at risk.

Intraoperative PTH Assay during Minimally Invasive Parathyroidectomy May Be Helpful in the Detection of Double Adenomas and May Minimise the Risk of Recurrent Surgery.

Background. Minimally invasive parathyroidectomy (MIP) is increasingly replacing the traditional bilateral neck exploration in the treatment of primary hyperparathyroidism (PHP). Intraoperative PTH (IOPTH) measurement has recently been introduced as a useful adjunct in confirming successful excision of abnormal parathyroid gland. Aims. We evaluate the safety, efficacy, and clinical usefulness of IOPTH measurement during MIP in a district general hospital. Methods. Retrospective review of eleven consecutive patients with PHP who underwent MIP with IOPTH, following preoperative assessment with ultrasound and sestamibi scans. Results. All patients had successful removal of the abnormal parathyroid gland. The concordance rate between ultrasound and sestamibi scan in localising the parathyroid adenoma was 82%. IOPTH measurement confirmed the removal of adenoma in all cases and, in one case, led to identification of a second adenoma, not localised preoperatively. The median hospital stay was 2 days (range 1-7 days). All patients remained normocalcaemic after a median of 6 months (range 1-10 months). Conclusions. Minimally invasive parathyroidectomy is a feasible, safe, and effective method for treatment of PHP. The use of IOPTH monitoring potentially offers increased sensitivity in detecting multiglandular disease, can minimise the need and risk associated with recurrent operations, and may facilitate cost-effective minimally invasive surgery.

Urinary levels of creatine and other metabolites in the assessment of polymyositis and dermatomyositis.

BACKGROUND: A simple and reliable method is needed to assess disease activity and monitor the efficacy of therapy in polymyositis (PM) and dermatomyositis (DM). This study used in vitro proton ((1)H) magnetic resonance spectroscopy (MRS) to explore whether excretion of urinary metabolites can be used as a reliable marker of disease in PM and DM patients. METHODS: Urine samples were obtained from PM/DM patients (n=34), healthy controls (50) and subjects with known muscle-wasting conditions including adult-onset muscular dystrophy (8), stroke patients (10), rheumatoid arthritis (RA) patients on steroids (13) and not on steroids (16) and patients with alcoholic myopathy (12). Levels of urinary metabolites were then correlated with creatine kinase (CK) activities and quadriceps muscle strength. RESULTS: Creatine was detected in the urine in 26 of 35 patients with PM/DM, four of 60 cases with other medical disorders (including one with adult-onset dystrophy, one with a stroke and two with RA who were not on steroids) and 10 of 50 healthy controls. The urinary creatine/creatinine ratio exceeded 0.4 in 20 patients with PM/DM but no patients with other medical disorders and no healthy controls. These differences were highly significant (P<0.001) by Kruskal-Wallis test (comparing all groups) and by Mann-Whitney U-tests (comparing individual groups with PM/DM cases). Citrate, glycine, choline-containing compounds and taurine levels were significantly increased in PM/DM when compared with controls. There were positive correlations between CK activities and choline-containing compounds (r=0.78, P=0.0006) and also between CK activities and betaine (r=0.57, P=0.026). CONCLUSIONS: This study shows significant differences in the urinary levels of creatine, choline-containing metabolites, betaine and citrate in PM/DM subjects compared with controls, although further work is required to elucidate the underlying metabolic processes.

HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome.

We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.

A comparative investigation into the effect of chronic alcohol feeding on the myocardium of normotensive and hypertensive rats: an electrophoretic and biochemical study.

We investigated whether the imposition of chronic alcohol in hypertension leads to greater biochemical and cellular abnormalities of the myocardium than those arising in normotension. Fifteen-week-old spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats were fed ethanol-containing diets for six weeks. Particular attention was focused on the composition of contractile proteins identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), fractional rate of protein synthesis, and synthesis rates relative to RNA (RNA activity) or DNA (cellular efficiency). In addition, myocardial enzymes and adenine nucleotides were measured. In both SHR and WKY rats chronic ethanol caused a general decrease in the contents of all nine contractile proteins with myosin heavy chain predominantly affected. Fractional rates of mixed (i.e., total) and myofibrillary proteins remained unaltered in both WKY rats and SHR, as were cellular efficiencies. The RNA activity was significantly reduced in ethanol-treated SHR but not in WKY rats. In ethanol-treated SHR, cardiac creatine kinase (CK) and malate dehydrogenase (MDH) activities were increased, AMP levels were elevated, whilst ATP levels and the energy charge were reduced. In WKY rats, the only significant change related to increased aspartate aminotransferase activities in response to alcohol feeding. Although there were only subtle differences between the response of the normotensive and hypertensive rats due to ethanol dosage, the reduced ATP levels and increased CK and MDH activities in SHR may reflect a greater susceptibility to ischaemic damage. Reduced contractile protein content, particularly myosin heavy chain, may contribute to contractile defects, a common feature of subclinical and clinical alcoholic cardiomyopathy.

Alternative genetic pathways in parathyroid tumorigenesis.

In this study 44 parathyroid tumors from 26 sporadic cases, 10 cases previously given irradiation to the neck, and 8 familial cases were screened for sequence copy number alterations by comparative genomic hybridization. In the sporadic adenomas, commonly occurring minimal regions of loss could be defined to chromosome 11 (38%), 15q15-qter (27%), and 1p34-pter (19%), whereas gains preferentially involved 19p13.2-pter (15%) and 7pter-qter (12%). Multiple aberrations were found in sporadic tumors with a somatic mutation and/or loss of heterozygosity of the MEN1 gene. The irradiation-associated tumors also showed multiple comparative genomic hybridization alterations and frequent losses of 11q (50%), and subsequent analysis of the MEN1 gene demonstrated mutations in 4 of 8 cases (50%). The adenomas from familial cases showed few alterations, and in 3 of these tumors a gain of 19p13.2-pter was seen as the only aberration. In this study numerical copy number alterations were frequently detected in sporadic and irradiation-associated parathyroid adenomas, although these tumors are benign. The majority of these alterations were found in tumors with confirmed involvement of the MEN1 gene locus in agreement with a role of the MEN1 gene in genomic stability. Furthermore, the frequent occurrence of MEN1 mutations (50%) in irradiation-associated parathyroid tumors suggests that inactivation of the MEN1 gene is an important genetic alteration involved in the development of parathyroid tumors in postirradiation patients.

Genetic studies of a family with hereditary hyperparathyroidism-jaw tumour syndrome.

BACKGROUND AND OBJECTIVES: Familial hyperparathyroidism may occur as familial isolated hyperparathyroidism (FIHP) or as part of an inherited syndrome, in particular multiple endocrine neoplasia types 1 and 2A (MEN1, MEN2A) and hyperparathyroidism-jaw tumour (HPT-JT) syndrome. The localization of the genes responsible for these syndromes has enabled genetic screening of families with primary hyperparathyroidism (PHPT) to be carried out. This has important clinical implications in terms of individual follow-up and management. We previously reported a large FIHP family with an increased risk of parathyroid cancer and excluded its linkage to MEN1, MEN2 and PTH genes. Here we re-analysed this family and performed genetic linkage to the HPT-JT locus in chromosome 1q21-q32. Loss of heterozygosity studies of 1q21-q32, 11q13 and X chromosome were also performed. PATIENTS AND DESIGN: We studied 19 family members, aged 6-63 years. High molecular weight DNA was isolated from peripheral blood samples from 17 family members. For the two deceased individuals, DNA was extracted from normal paraffin embedded tissues. MEASUREMENTS: All individuals (except two deceased patients) had serum corrected calcium, inorganic phosphate, intact PTH, prolactin and various pancreatic hormones, measured on fasting blood samples. Twenty microsatellite markers were examined for the 1q21-q32 region, the locus for the HPT-JT gene. Genetic polymorphisms were determined by polymerase chain reaction amplification of genomic DNA and genetic linkage analysis was performed. Loss of heterozygosity studies were performed using paraffin-embedded parathyroid tissues from four affected members. RESULTS: Seven of the eight affected family members included in this study had biochemical evidence of PHPT and surgically proven parathyroid tumours. Indication of linkage of the disease to the HPT-JT locus was demonstrated with a maximum lod score of 2.32 by two-points linkage analysis. Linkage data were supported by multi-point analysis which gave a maximum lod score of 2.7. Meiotic recombinations detected in one affected individual narrowed the region to 26 cM. As a result of the genetic findings, we re-screened the living family members by orthopantomograph and renal ultrasound, and identified two jaw lesions in two gene carriers. One affected family member demonstrated polycystic kidney disease, thus establishing the association between the two conditions. A reduced penetrance of HPT in females was evident, in agreement with our previous study. No allelic deletion was detected in any tumour at 1q21-q32, 11q13 or X chromosome. CONCLUSIONS: This study illustrates the usefulness and importance of genetic studies in familial isolated hyperparathyroidism families. Our clinical and genetic findings indicate that this previously reported familial isolated hyperparathyroidism family has hyperparathyroidism-jaw tumour syndrome.

Structural and functional changes in skeletal muscle in anorexia nervosa.

Protein-energy malnutrition in anorexia nervosa is an under-recognised cause of muscle dysfunction. To characterise the skeletal myopathy that occurs in patients with severe anorexia nervosa, muscle function and structure were comprehensively examined in eight young adult female patients with severe (40%) self-induced weight loss. All of the patients showed impaired muscle function on strength and exercise measurement. The maximum voluntary contraction force for the patient group was significantly less than predicted values. Electromyography revealed myopathy in five of the patients, four of whom also had electro-physiological evidence of neuropathy. However, muscle biopsy specimens consistently showed myopathic changes with severe type 2 fibre atrophy but with no evidence of neuropathic changes. Ultrastructurally, there was separation and segmental loss of myofibrils and most biopsy samples contained abundant glycogen granules; we have previously reported that one of the most consistent biochemical abnormalities in these patients is impaired ischaemic lactate responses to forearm exercise. The result of severe protein-energy malnutrition on the musculo-skeletal system is a metabolic myopathy. Although the patients admitted to a variety of abnormal dieting behaviours, such as over-exercising and self-induced vomiting, no association was found between any of these and quantitative histological changes in the muscle biopsy samples. It is recommended that myopathy in anorexia nervosa be treated by instituting an appropriate refeeding programme.

Differential loss of heterozygosity in familial, sporadic, and uremic hyperparathyroidism.

Various genetic loci harboring oncogenes, tumor suppressor genes, and genes for calcium receptors have been implicated in the development of parathyroid tumors. We have carried out loss of heterozygosity (LOH) studies in chromosomes 1p, 1q, 3q, 6q, 11q, 13q, 15q, and X in a total of 89 benign parathyroid tumors. Of these, 28 were sporadic parathyroid adenomas from patients with no family history of the disease, 41 were secondary parathyroid tumors, 5 were from patients with a history of previous irradiation to the neck, 12 were from patients with a family history of hyperparathyroidism, and 3 were parathyroid tumors related to multiple endocrine neoplasia type 1 (MEN1). In addition, we determined the chromosomal localization of a second putative calcium-sensing receptor, CaS, for inclusion in the LOH studies. Based on analysis of somatic cell hybrids and fluorescent in situ hybridization to metaphase chromsomes, the gene for CaS was mapped to chromosomal region 2q21-q22. The following results were obtained from the LOH studies: (1) out of the 24 tumors that showed LOH, only 4 had more than one chromosomal region involved, (2) in the tumors from uremic patients, LOH of chromosome 3q was detected in a subset of the tumors, (3) LOH of the MEN1 region at 11q13 was the most common abnormality found in both MEN1-related and sporadic parathyroid tumours but was not a feature of the other forms of parathyroid tumors, (4) LOH in 1p and 6q was not as frequent as previously reported, and (5) tumor suppressor genes in 1q and X might have played a role, particularly on the X chromosome, in the case of familial parathyroid adenomas. We therefore conclude that the tumorigenesis of familial, sporadic, and uremic hyperparathyroidism involves different genetic triggers in a non-progressive pattern.

Continuing clinically severe vitamin D deficiency in Asians in the UK (Leicester).

Deprivational vitamin D deficiency began to be noted in immigrant Asians in the early 1960s. Although there have been suggestions that the level of this problem may be declining, we describe a number of clinical cases seen over a consecutive 3 1/2 year period. Musculoskeletal symptoms were the commonest though there were a variety of medical presentations requiring hospital referral. Most of the cases were Hindu vegetarians. There is likely to be significant underdiagnosis of this condition. In spite of the extensive medical, social and political attention this condition has received, our study shows that vitamin D deficiency continues to persist in certain Asians in a clinically florid fashion. An effective preventative policy is long overdue.

Use of dynamic tests of muscle function and histomorphometry of quadriceps muscle biopsies in the investigation of patients with chronic alcohol misuse and chronic fatigue syndrome.

Ischaemic lactate/ammonia tests, serum carnosinase and creatine kinase assays and percutaneous needle muscle biopsies were performed on 10 patients with chronic fatigue syndrome (CFS), and 10 with chronic alcohol misuse complaining of muscular symptoms. Basal serum lactate levels were significantly elevated in the alcohol misusers compared to the CFS patients, but all were within the reference range. Lactate profiles after ischaemic forearm exercise did not differ significantly for the two patient groups. In one patient previously diagnosed as having CFS, myoadenylate deaminase deficiency was identified on the basis of a flat ammonia response to ischaemia and absent muscle adenosine monophosphate deaminase activity. In addition, two further patients in the CFS group were subsequently shown to have other disorders: one had polymyositis and one had myopathy with mild type II fibre atrophy of unknown cause. Histomorphometric examination of muscle needle biopsy in the alcohol misusers showed features of chronic alcohol-induced skeletal myopathy in six patients and polymyositis in one patient. Type II fibre atrophy factors were significantly elevated in the alcohol group but were within the reference range in CFS patients. Dynamic tests of muscle function and muscle histology are valuable tools in excluding alternative pathology in CFS, whereas muscle histomorphometry is of the greatest value in the diagnosis of chronic alcoholic myopathy.

Carboxyterminal propeptide of type I procollagen in osteomalacia.

Carboxyterminal propeptide of type I procollagen (PICP) was measured in sera from 25 patients with osteomalacia due to privational vitamin D deficiency. The mean value of serum PICP was significantly raised in patients with osteomalacia compared with 40 normal subjects (mean +/- SD, 161 +/- 82 ng/ml and 113 +/- 31 ng/ml, respectively; P = 0.01). The raised serum PICP reflected the accelerated bone turnover in this condition as did the elevated serum total alkaline phosphatase (ALP), but the variation in values of serum PICP noted in individual patients may reflect the different stages of osteomalacia. The normalization of serum PICP and ALP, indicating a healing process of the bone disorder, needed longer time of vitamin D and calcium therapy. In contrast, adjusted serum calcium and inorganic phosphate (IP) responded and normalized rapidly. Serum PICP and total ALP appeared to behave differently in the disease and in its response to vitamin D therapy suggesting that these two markers may represent different functions of osteoblasts in osteomalacia.

Familial isolated hyperparathyroidism: a distinct genetic entity with an increased risk of parathyroid cancer.

Familial isolated hyperparathyroidism (FIHP) is a rare heritable disorder characterized by hypercalcemia, inappropriately high PTH levels, and isolated parathyroid tumors with no evidence of hyperfunction of any other endocrine tissues. To establish whether FIHP exists as a distinct disease entity or represents a variant of any of the known multiple endocrine neoplasia (MEN) syndromes, we tested 19 members of a large, well characterized family with FIHP in which the disease is transmitted through 4 generations in an autosomal dominant fashion. Fourteen DNA markers at 10 polymorphic loci closely linked to the MEN1 locus on the long arm of chromosome 11 and 5 markers close to the MEN2A gene on chromosome 10 were tested using Southern blot analysis and polymerase chain reaction-based techniques. Additionally, two polymorphic markers (Mir1 and Mir2) within the prepro-PTH gene on the short arm of chromosome 11 were analyzed using denaturant gradient gel electrophoresis. Linkage was clearly excluded between FIHP and the MEN1 and MEN2A loci as well as to the PTH gene. Comparison of constitutional and tumor genotypes showed that constitutional heterozygosity was retained for markers in the MEN1 and MEN2A regions as well as to the PTH gene in 4 tumors from 3 affected members. In 1 individual, a parathyroid carcinoma was found after recurrence of hypercalcemia. We, therefore, propose that autosomal dominant FIHP can occur as a genetically and clinically distinct entity with an increased risk of malignant transformation of parathyroid tumors.

The relationship between muscle fibre atrophy factor, plasma carnosinase activities and muscle RNA and protein composition in chronic alcoholic myopathy.

The relationship between chronic ethanol consumption and muscle biopsy morphometry (i.e. atrophy factor), plasma analytes, including carnosinase activities and tissue composition was investigated. In approximately half of chronic alcohol misusers there was Type II-fibre atrophy, which was correlated with reductions in muscle protein and serum carnosinase activities. The protein composition was also correlated with RNA composition. These results directly implicate defects in protein and RNA turnover as characteristics of chronic alcoholic myopathy and re-affirms the routine diagnostic use of fibre-type morphometry to identify these patients.