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J Clin Endocrinol Metab

Hepatitis C-associated osteosclerosis: late onset after blood transfusion in an elderly woman.

Shaker JL. Reinus WR. Whyte MP.
Department of Medicine, St. Luke's Medical Center, Milwaukee, Wisconsin 53215, USA. jshaker@execpc.com
A 69-yr-old woman with hepatitis C virus (HCV) infection from blood transfusion 14 yr earlier was evaluated in 1997 for increasing appendicular skeletal pain. Diffusely elevated radioisotope uptake on bone scanning had appeared during the past 15 months. Radiographs spanning 1978-1997 showed remarkable restoration of bone mass and a skeleton like that of a young woman. Bone mineral densities of the femoral neck and lumbar spine were above the mean peak bone mass of young women (T scores, +1.8 and +1.3, respectively) and 160% and 147% of mean values for age-matched female controls (Z-score, +3.7 and +3.6, respectively). Biochemical markers of skeletal remodeling were substantially increased. Bone marrow biopsy showed normal lamellar bone. Serum alkaline phosphatase activity assays suggested that accelerated skeletal turnover began 6-12 months before symptoms. HC-associated osteosclerosis has been reported in nine individuals 27-73 yr of age, most with a history of i.v. drug abuse. Our patient demonstrates that parenteral exposure to blood rather than illicit drugs is the feature common to all affected subjects. Furthermore, we document that there can be a long latency between HCV infection and the development of skeletal abnormalities. We also find that bone mass can be restored by this disorder in a postmenopausal woman. Routine radiographs, however, may not show overt osteosclerosis in the elderly. The precise pathogenesis of this disorder is unknown. Understanding and control of the mechanism of HC-associated osteosclerosis could potentially lead to correction of low bone mass from osteoporosis with good quality skeletal tissue.

Pheochromocytoma in von Hippel-Lindau disease: clinical presentation and mutation analysis in a large, multigenerational kindred.

Atuk NO. Stolle C. Owen JA Jr. Carpenter JT. Vance ML.
Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
The clinical presentation and characterization of the mutation in members of a large kindred with von Hippel-Lindau disease (VHLD) and pheochromocytoma were examined. Twenty-five proven cases of VHLD occurring in four generations of a large kindred have been followed since 1964, and pheochromocytoma has occurred in 17. Symptoms of pheochromocytoma developed at an early age, on average at 12.5 +/- 1.3 yr, and definitive diagnosis and treatment of pheochromocytoma occurred at 19.9 +/- 2.6 yr. Significantly higher urine catecholamine concentrations were observed in younger patients than in older ones. Mutation analysis was performed in 14 family members, and a new mutation in the VHLD gene was identified in 11; this mutation is a G to T change at nucleotide 658 that results in the substitution of a serine for an alanine residue at position 149 of the polypeptide chain. Seven of the 11 patients with the mutation have VHLD; four, all 10 yr old or less, are asymptomatic and have no evidence of disease, but are at high risk for developing VHLD. These children are being followed closely for clinical and biochemical manifestations. The characterization of this new mutation has permitted identification of family members who are likely to develop VHLD.

Comparison of the impact of transdermal versus oral estrogens on biliary markers of gallstone formation in postmenopausal women.

Uhler ML. Marks JW. Voigt BJ. Judd HL.
Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
This prospective, randomized, double blind, parallel study was undertaken to elucidate further the potential mechanisms through which estrogens could promote the formation of cholesterol gallstones and to compare the impact of nonoral (transdermal) and oral estrogens on serum, hepatic, and biliary markers of estrogen action. Ninety-seven postmenopausal women were randomized to receive either transdermal estradiol (E2; 0.1 mg every 3.5 days; n = 48) or oral conjugated equine estrogens (1.25 mg every day; n = 49) for 8 weeks. Blood samples were drawn, and bile samples were obtained by cholecystokinin-stimulated duodenal drainage before and after 8 weeks of estrogen administration. The main outcome measures included serum FSH, LH, E2, estrone, estrone sulfate, sex hormone-binding globulin, lipid profiles, biliary cholesterol saturation index, cholesterol nucleation time, presence of cholesterol crystals in bile, as well as biliary arachidonate, PGE2, and mucous glycoproteins. Estrogens administered by both routes increased circulating estrogens and resulted in similar suppression of both gonadotropins. Sex hormone-binding globulin was clearly increased, and the changes in serum lipids were more pronounced with oral conjugated equine estrogens than with transdermal E2. The biliary cholesterol saturation index was significantly increased compared to the baseline values with both transdermal E2 (1.08 +/- 0.04 vs. 1.00 +/- 0.03; mean change, 8%) and oral conjugated equine estrogens (1.04 +/- 0.03 vs. 0.99 +/- 0.03; mean change, 6%); however, there was no difference between the treatments. The number of patients with cholesterol crystals detected in bile was similar after both estrogen regimens. Transdermal and oral estrogens decreased nucleation time in vitro, increased arachidonate and PGE2 levels, and minimally raised total glycoprotein concentrations. In conclusion, transdermal and oral estrogens exerted comparable nonhepatic effects, as evidenced by similar reductions of gonadotropin levels, but oral therapy exhibited substantially greater actions on hepatic markers of estrogen action. Both transdermal E2 and oral conjugated equine estrogens significantly elevated the biliary cholesterol saturation index and reduced the nucleation time. These results suggest that estrogens at the doses studied could promote gallstone formation by alteration of biliary lipids and cholesterol nucleation time that have been incriminated in this process.

Localized aberrant expression of cytochrome P450 aromatase in primary and metastatic malignant tumors of human liver.

Harada N. Ota H. Yoshimura N. Katsuyama T. Takagi Y.
Division of Molecular Genetics, Fujita Health University, Aichi, Japan. nharada@fujita-hu.ac.jp
The present study was designed to demonstrate localized aberrant expression of aromatase in primary and metastatic malignant liver tumors. Immunocytochemistry revealed the presence of locally increased aromatase protein in regions around tumors in all specimens from seven primary and seven metastatic liver tumors. This observation was further confirmed by Western blotting analysis and assay of aromatase activity in tumorous, proximal, and distal regions. Western blots showed most intensely immunoreactive bands at the position corresponding to aromatase in proximal tissues where aromatase activities also were higher (2.75 +/- 1.59 pmol/mg.h) than in tumors (0.137 +/- 0.115 pmol/mg.h) and distal tissues (1.90 +/- 1.47 pmol/mg.h), in spite of a gradient decline of NADPH-cytochrome P-450 reductase activity from the distal regions to the tumors. RT-PCR analysis indicated that the aberrant increase in aromatase protein and enzyme activity in the regions proximal to tumors is caused by locally elevated aromatase messenger RNA.

The ret/ptc1 oncogene is activated in familial adenomatous polyposis-associated thyroid papillary carcinomas.

Year 1998
Cetta F. Chiappetta G. Melillo RM. Petracci M. Montalto G. Santoro M. Fusco A.
Istituto di Clinica Chirurgica, Universita di Siena, Nuovo Policlinico, Italy.
Familial adenomatous polyposis (FAP) is caused by germ-line mutations of the apc gene, and it is associated with an increased risk of developing papillary thyroid carcinomas. We have previously reported that a significant fraction of sporadic human papillary thyroid carcinomas is characterized by gene rearrangements affecting the ret protooncogene. These rearrangements generate chimeric transforming oncogenes designated ret/ptc. By a combined immunohistochemical and RT-PCR approach, we analyzed, for ret/ptc oncogene activation, papillary thyroid carcinomas occurred in two FAP kindreds, both showing typical apc gene mutations. Kindred 1 had seven members affected by FAP, and among these, three patients showed papillary thyroid carcinomas. Kindred 2 had two patients, mother and daughter, affected by colonic polyposis; the 20-yr-old daughter showed also a papillary carcinoma. Here we report that ret/ptc1 oncogene was activated in two of the three papillary carcinomas of FAP kindred 1 and in the papillary carcinoma of FAP kindred 2. These findings document that loss of function of apc coexists with gain of function of ret in some papillary thyroid carcinomas, suggesting that ret/ptc1 oncogene activation could be a progression step in the development of FAP-associated thyroid tumors.

Neonatal hyperinsulinemic hypoglycemia: heterogeneity of the syndrome and keys for differential diagnosis.

Year 1998
Sempoux C. Guiot Y. Lefevre A. Nihoul-Fekete C. Jaubert F. Saudubray JM. Rahier J.
Department of Pathology, University Hospital St. Luc, Brussels, Belgium.
The two major forms of infantile persistent hyperinsulinemic hypoglycemia require different treatments, but are difficult to differentiate during surgery. Indeed, one is characterized by focal adenomatous hyperplasia often macroscopically invisible, whereas the other consists of a diffuse, but discreet, beta-cell abnormality. We evaluated, in a large series of persistent hyperinsulinemic hypoglycemia, the reliability of two criteria in differentiating these two forms: the mean beta-cell nuclear radius (MNR) and the beta-cell nuclear crowding, i.e. the number of nuclei per 1000 micron 2 beta-cell (BCNC). The values of the largest MNR and of BCNC in cases bearing a focal lesion (respectively, 3.27 microns +/- 0.25 and 14.62 +/- 1.78) were significantly different from those in the diffuse pathology (4.25 microns +/- 0.43 and 10.00 +/- 1.55). Setting the threshold value of MNR at 3.70 microns and that of BCNC at 12.00 enabled correct classification of 90.9% of the diffuse and 100% of the focal forms. beta-Cell nuclear analysis can thus contribute to a subclassification of the syndrome, not allowed by clinical or biological data. If performed during surgery it could help in determining the extent of pancreatectomy necessary to cure the patient, as the diffuse form, with abnormal nuclei in the whole pancreas, requires subtotal to near-total pancreatectomy, whereas the focal form, devoid of abnormal insular beta-cell nuclei, can be cured by partial pancreatectomy.

The pathophysiology of circulating corticotropin-releasing hormone-binding protein levels in the human.

Year 1998
Trainer PJ. Woods RJ. Korbonits M. Popovic V. Stewart PM. Lowry PJ. Grossman AB.
Department of Endocrinology, St. Bartholomew's Hospital, West Smithfield, London, United Kingdom. p.j.trainer@mds.qmw.ac.uk
To establish the factors that modulate circulating CRH-binding protein (CRH-BP) levels, we measured plasma CRH-BP in patients with a variety of endocrine and systemic disorders. CRH-BP was measured by RIA. Young women have higher plasma levels of CRH-BP than young men [females (n = 18), mean +/- SEM, 145 +/- 7; males (n = 20), 99 +/- 6 ng/mL; P < 0.0001], but levels do not fall with the menopause or vary during the menstrual cycle and are unaffected by estrogen replacement therapy. Levels were lower in patients with liver disease than in healthy men (26 +/- 3 vs. 99 +/- 6; P < 0.0001) and were elevated in chronic renal failure compared to those in healthy women (211 +/- 11.2 vs. 145 +/- 7; P < 0.01). Levels were unaffected by fasting in men or women (male fasted, 97 +/- 11; male fed, 97 +/- 8; female fasted, 136 +/- 9; female fed, 152 +/- 10). Dexamethasone treatment lowered CRH-BP in all subjects (129 +/- 8 vs. 111 +/- 9; P < 0.003). Similarly, CRH-BP levels were lower in patients with Cushing's syndrome (all female) than in healthy female controls (median, 82; range, 53-106; vs. median, 142; range, 101-190; P < 0.0001). In Cushing's patients, an i.v. bolus of 100 micrograms human CRH further lowered plasma CRH-BP at 15 min (81 +/- 5 vs. 50 +/- 4; P < 0.0003). Plasma levels of CRH-BP are higher in women than men, but this is unrelated to circulating estrogen levels. The low levels in liver disease and the high levels in renal failure support its hepatic origin and the kidneys as the route of clearance from plasma. The ability of glucocorticoids and exogenous CRH to lower plasma CRH-BP levels and of CRH-BP to modulate the bioactivity of circulating CRH suggest that the protein may be an important regulator of circulating CRH or related ligands.

Molecular basis of severe gynecomastia associated with aromatase expression in a fibrolamellar hepatocellular carcinoma.

Year 1998
Agarwal VR. Takayama K. Van Wyk JJ. Sasano H. Simpson ER. Bulun SE.
Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas 75235-9051, USA.
This report represents the first study in the literature linking development of severe gynecomastia, in a 17 1/2-yr-old boy, to high levels of aromatase expression in a large fibrolamellar hepatocellular carcinoma, which gave rise to extremely elevated serum levels of estrone (1200 pg/mL) and estradiol-17 beta (312 pg/mL) that suppressed FSH and LH (1.3 and 2.8 IU/L, respectively), and consequently testosterone (1.53 ng/mL). After removal of a 1.5-kg hepatocellular carcinoma, gynecomastia partially regressed, and essentially, normal hormone levels were restored (estradiol-17 beta, < 50 pg/mL; estrone, 74 pg/mL; testosterone, 6.85 ng/mL; and FSH/LH, 6.3/3.7 mIU/mL). Conversion of C19 steroids to estrogens occurs in a number of human tissues and is catalyzed by aromatase P450 (P450arom), the product of the CYP19 gene in a number of human tissues. Tissue-specific promoters are used to regulate P450arom gene transcription in adult human tissues, e.g. promoters I.4 and I.3 in adipose fibroblasts, and promoter II in the gonads. Human fetal liver uses promoter I.4 to express markedly high levels of P450arom, whereas hepatic P450arom expression normally becomes undetectable in postnatal life. Using immunohistochemistry, diffuse intracytoplasmic aromatase expression was detected in the liver cancer cells from this severely feminized boy. Northern analysis indicated the presence of P450arom transcripts in total RNA from the hepatocellular cancer but not in the adjacent liver nor in disease-free adult liver samples. Promoter use for aromatase expression was determined by a specific RT-PCR method. Promoters I.3 and II were used for P450arom gene expression in the hepatocellular cancer tissue. Because aromatase is not expressed in the disease-free adult liver, the presence of extremely high levels of aromatase expression in this fibrolamellar hepatocellular carcinoma tissue is intriguing, particularly because there is preferential use of the proximally located P450arom promoters I.3 and II by the tumor, instead of the much more distally located fetal liver-type promoter I.4.

Источник: https://gastroportal.ru/science-articles-of-world-periodical-eng/j-clin-endocrinol-metab.html
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