Diagnostic utility of cardiac biomarkers in discriminating Takotsubo cardiomyopathy from acute myocardial infarction.

Background: Takotsubo cardiomyopathy (TC) mimics acute myocardial infarction (AMI). We postulated that ventricular dysfunction in TC in the absence of significant myocardial necrosis would produce higher B-type natriuretic peptide (BNP)/troponin T (TnT) and BNP/creatine kinase MB fraction (CKMB) ratios than in AMI.Methods and Results: We studied 58 consecutive TC (age 65.8 +/- 12.9) and 97 AMI patients (age 59.8 +/-13.4). The ratios of BNP/TnT and BNP/CKMB were calculated with the use of first simultaneously drawn laboratory values. Receiver operating characteristic curves were used to distinguish TC from AMI with 95% specificity based on cardiac biomarker ratios. Median BNP/TnT and BNP/CKMB ratios were, respectively,1,292 [interquartile range 443.4-2,657.9] and 28.44 [13.7-94.8] in the TC group and 226.9[69.91-426.32] and 3.63 [1.07-10.02] in the AMI group (P <.001). TC can be distinguished from AMI with 95% specificity with the use of BNP/TnT ratio ≥1,272 (sensitivity 52%) and BNP/CKMB ratio ≥29.9 (sensitivity 50%).Conclusions: The value of BNP is significantly higher in TC than in AMI. Early BNP/TnT and BNP/CKMB ratios help to differentiate TC from AMI with greater accuracy than BNP alone.

Diagnostic utility of cardiac biomarkers in discriminating Takotsubo cardiomyopathy from acute myocardial infarction.

BACKGROUND: Takotsubo cardiomyopathy (TC) mimics acute myocardial infarction (AMI). We postulated that ventricular dysfunction in TC in the absence of significant myocardial necrosis would produce higher B-type natriuretic peptide (BNP)/troponin T (TnT) and BNP/creatine kinase MB fraction (CKMB) ratios than in AMI. METHODS AND RESULTS: We studied 58 consecutive TC (age 65.8 ± 82.9) and 97 AMI patients (age 59.8 ± 83.4). The ratios of BNP/TnT and BNP/CKMB were calculated with the use of first simultaneously drawn laboratory values. Receiver operating characteristic curves were used to distinguish TC from AMI with 95% specificity based on cardiac biomarker ratios. Median BNP/TnT and BNP/CKMB ratios were, respectively, 1,292 [interquartile range 443.4-2,657.9] and 28.44 [13.7-94.8] in the TC group and 226.9 [69.91-426.32] and 3.63 [1.07-10.02] in the AMI group (P < .001). TC can be distinguished from AMI with 95% specificity with the use of BNP/TnT ratio ≥ 1,272 (sensitivity 52%) and BNP/CKMB ratio ≥ 29.9 (sensitivity 50%). CONCLUSIONS: The value of BNP is significantly higher in TC than in AMI. Early BNP/TnT and BNP/CKMB ratios help to differentiate TC from AMI with greater accuracy than BNP alone.

Multicentric Castleman's Disease, Associated with Idiopathic Thrombocytopenic Purpura.

The most common cause of a neck mass in young adults is hyperplastic lymphadenopathy consequent to infection and inflammation. Castleman's disease (CD), an unusual benign lymphoproliferative disorder, infrequently causes neck masses. It occurs in unicentric (UCD) and multicentric (MCD) forms and is associated with human immunodeficiency virus (HIV), human herpes virus 8 (HHV-8), and Kaposi's sarcoma. We present the third known association between MCD and previous immune thrombocytopenia in the absence of HIV and HHV-8 infection and review its association with other autoimmune disorders and attendant implications for pathogenesis. Finally, we summarize the current approach to therapy.

Anatomic twist to a straightforward ablation.

Atrioventricular (AV) junction ablation for treatment of refractory atrial fibrillation is a well defined, standardized procedure and the simplest of commonly performed radiofrequency ablations in the field of cardiac electrophysiology. We report successful AV junction ablation using an inferior approach in a case of inferior vena cava interruption. Inability during the procedure to initially pass the ablation catheter into the right ventricle, combined with low amplitude electrograms, led to suspicion of an anatomic abnormality. This was determined to be a heterotaxy syndrome with inferior vena cava interruption and azygos continuation, draining in turn into the superior vena cava. Advancing Schwartz right 0 (SRO) sheath through the venous abnormality into the right atrium allowed adequate catheter stability to successfully induce complete AV block with radiofrequency energy.

Paradoxical severe decrease in high-density lipoprotein cholesterol due to rosiglitazone-fenofibrate interaction.

OBJECTIVE: To determine whether the marked decrease in high-density lipoprotein cholesterol (HDL-C) occasionally associated with combination fibrate-thiazolidinedione therapy results from interaction between the 2 drugs or is solely the result of fibrate administration, a previously recognized cause. METHODS: We prospectively followed the clinical course of 2 patients receiving fenofibrate and rosiglitazone and reviewed the relevant literature, searching PubMed for reports describing striking reductions in HDL-C associated with fibrate administration alone and in conjunction with rosiglitazone and statins. Additional references were obtained from the bibliography of each identified article. RESULTS: Each of the 2 patients demonstrated a Drug Interaction Probability Score score of 9, indicating a highly probable likelihood of interaction. Critical review of all reported cases of concurrent fenofibrate-rosiglitazone-associated decreases in HDL-C failed to show conclusive evidence that the HDL-C decrease could be due to an interaction between the 2 drugs as opposed to either drug being given alone. CONCLUSIONS: In at least some patients who experience marked HDL-C decrease when given a combination of fenofibrate and rosiglitazone, this severe adverse effect is the result of a drug interaction between the 2 pharmaceutical agents and is not reproduced by the administration of either drug singly.

Exenatide-induced acute pancreatitis.

OBJECTIVE: To report acute pancreatitis in a patient with non-insulin-dependent diabetes mellitus (NIDDM) receiving exenatide and critically review previous reports. METHODS: We describe clinical and laboratory data of a woman with probable exenatide-induced pancreatitis and apply the same criteria to previously published cases. RESULTS: A 64-year-old, nonalcoholic woman with NIDDM presented with a 1-month history of epigastric pain beginning 2 days after starting exenatide. Serum lipase concentration was 2700 U/L (reference range, 114-320 U/L), and serum amylase concentration was 131 U/L (reference range, 30-110 U/L). Liver function test results, lipid profile, and serum creatinine concentration were normal. Abdominal computed tomography (CT) showed changes consistent with pancreatitis, and the gallbladder was absent. Exenatide was discontinued. Conservative therapy resulted in rapid resolution of symptoms, normal lipase concentration (151 U/L), and normal findings from CT of the pancreas 90 days later. The US Food and Drug Administration has reported 36 cases of presumed pancreatitis associated with exenatide. However, none of the selection criteria were specified, two-thirds of the patients did not have CT, and 90% had at least 1 other risk factor for acute pancreatitis. A single published case report of exenatide-induced pancreatitis contains no description of the pancreas on abdominal CT, does not mention alcohol use, and does not report normal lipase values. CONCLUSIONS: This is the most thoroughly documented example of probable exenatide-induced pancreatitis. In any diabetic patient with acute pancreatitis, exenatide must be ruled out as the cause and its use discontinued.

Venous thromboembolism in lymphoma: how effectively are we treating patients?

INTRODUCTION: Patients with solid tumors and venous thromboembolic episodes (VTE) have a high risk of recurrence and bleeding during oral anticoagulant treatment. However, we are unaware of studies expressly evaluating such risks in patients with lymphoma. Therefore, we conducted a retrospective study to determine the frequency of such complications during treatment of lymphoma patients who develop VTE. METHODS: Charts of patients with histologically proven non-Hodgkin lymphoma and Hodgkin lymphoma were retrospectively reviewed and patients with their first acute symptomatic VTE episode were identified (49 non-Hodgkin lymphoma, 8 Hodgkin lymphoma). Recurrence of VTE episodes and major and minor bleeding during treatment with warfarin or low molecular weight heparin (LMWH) were recorded. RESULTS: All 57 patients were initially treated with high-dose-adjusted intravenous heparin or body-weight-adjusted LMWH. Forty-six patients were started on oral warfarin and 11 patients continued LMWH. Recurrent VTE episodes occurred in 14 of 46 patients on warfarin therapy, whereas major bleeding was documented in 6 of 46 patients, and minor bleeding in 9 of 46 patients. Recurrent VTE episodes occurred in 1 of 11 patients treated with LMWH, whereas major bleeding occurred in 0 of 11 and minor bleeding in 3 of 11 patients. CONCLUSIONS: Lymphoma patients treated with warfarin experienced a 30.4% rate of recurrent thrombosis and 13% major bleeding. During this treatment most (65%), but not all, bleeding and thrombotic complications occurred with an international normalized ratio within the therapeutic range. The percentage of serious complications (recurrent VTE and major bleeding) during warfarin use was 44.5%, and the death rate was 6.5%, compared with 9% and 0%, respectively, during use of LMWH.

Aromatase inhibitor-related musculoskeletal symptoms: is preventing osteoporosis the key to eliminating these symptoms?

BACKGROUND: Aromatase inhibitors (AIs) are an effective treatment for postmenopausal women with hormone receptor-positive breast cancer. However, patients receiving AIs report a higher incidence of musculoskeletal symptoms and bone fractures; the mechanism and risk factors for this correlation are not well studied. The aim of this study was to correlate these musculoskeletal symptoms and bone fractures in patients receiving AIs with bone mineral density (BMD), previous tamoxifen use, and administration of calcium/bisphosphonate (Ca/Bis). PATIENTS AND METHODS: We reviewed charts of 856 patients with hormone receptor-positive nonmetastatic breast cancer seen at our institution between January 1999 and October 2007. A total of 316 patients met the inclusion criteria of treatment with one of the AIs for > or = 3 months and availability of a dualenergy X-ray absorptiometry (DEXA) during this treatment. Arthralgia, generalized bone pain and/or myalgia, bone fracture after beginning AIs, any tamoxifen treatment, and Ca/Bis therapy were recorded. RESULTS: Our study demonstrates a significant association between symptoms and DEXA-BMD results (P < .001). Similarly, the group receiving tamoxifen before AIs had fewer patients with arthralgia or generalized bone pain/myalgia or bone fracture (P < .001). Furthermore, the group receiving AIs plus Ca/Bis had more patients without musculoskeletal symptoms and had fewer fractures. Finally, the group receiving steroidal AIs compared with nonsteroidal AIs had more patients with arthralgia or generalized bone pain and/or myalgia, and bone fractures (P < .001). CONCLUSION: Patients on AIs who develop osteoporosis are at increased risk of musculoskeletal symptoms and bone fracture. Comedication with Ca/Bis reduces the likelihood for osteoporosis and musculoskeletal symptoms. Patients who received tamoxifen before AIs were less likely to develop AI-related musculoskeletal symptoms. We recommend that patients on AIs should be offered Ca/Bis to reduce the incidence of musculoskeletal symptoms and fracture, especially if patients are receiving steroidal AI and/or did not receive tamoxifen before AIs.

Venous thromboembolism in patients with monoclonal gammopathy of undetermined significance.

Monoclonal gammopathy of undetermined significance (MGUS) is defined by the presence of a serum M-protein at a concentration of 3 g/dL or less, with less than 10% plasma cells in the bone marrow, and the absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the plasma cell proliferative process. The annual risk of MGUS progressing to a symptomatic plasma cell proliferation or other related malignancy is approximately 1%. The association between malignancy and venous thromboembolism (VTE) is well recognized. In this retrospective study of MGUS patients, VTE was seen in 8% (9/112) of patients, a rate that is 22.8-fold higher than that in the general population (P is less than .001). Although many studies have identified VTE as a marker for subsequent malignancy, we did not find a significant difference in the incidence of VTE as a function of the risk factor group.

The utility of 18-F-fluorodeoxyglucose positron emission tomography in evaluation of bone marrow involvement by non-Hodgkin lymphoma.

PURPOSE: In non-Hodgkin lymphomas (NHLs), the bone marrow (BM) involvement is a sign of extensive disease and the iliac crest BM biopsy (BMB) is the established method for the detection of BM infiltration. However, iliac crest BMB is associated with a high rate of false negative results. We assess the ability of 18-F-fluorodeoxyglucose positron emission tomography (F-FDG PET) scan to ascertain the presence of BM involvement in NHL. METHODS: After reviewing charts of histologically proven NHLs, 97 patients were eligible for our study. All patients were examined by whole-body F-FDG PET scan for initial staging, and all had unilateral posterior iliac crest BMB. BM involvement was established after the result of unilateral posterior iliac crest BMB and image-guided BMB after positive F-FDG PET scan in selected patients. RESULTS: Our data demonstrate an overall sensitivity of 79% for the F-FDG PET scan detecting BM involvement in all patients and specificity of 91%. Further analysis revealed no significant difference in the ability of the F-FDG PET scan to detect BM involvement between the indolent-NHL and the aggressive/highly aggressive-NHL groups (sensitivity P = 0.23, specificity P = 0.64). CONCLUSION: F-FDG PET scan shows potential to detect BM involvement in NHL. In particular, image-guided repeat BMB should be considered in patients with negative initial iliac crest BMB, whose F-FDG PET scan demonstrates BM involvement in a different site.

Sclerosing epithelioid fibrosarcoma of the pituitary.

Primary pituitary sarcoma in the absence of previous radiation therapy is very rare, only eight cases having been reported. We present the first reported case of sclerosing epithelioid fibrosarcoma of the pituitary, a 56-year-old woman presenting with diplopia and panhypopituitarism. Magnetic resonance imaging showed a 1.2 x 0.4 x 0.5-cm sellar mass invading the right cavernous sinus. Despite surgery and radiation therapy, our patient developed intracranial metastases and died 2 years after the initial diagnosis. Sclerosing epithelioid fibrosarcoma is an infrequently occurring, distinct variant of soft tissue fibrosarcoma. Its immunophenotype includes vimentin and occasionally CD-34, B cell lymphoma-2, S-100 protein, or keratin expression. Although initially thought to be a low-grade lesion, sclerosing epithelioid fibrosarcomas may also behave in a high-grade manner.

Renal tubular acidosis type 2 with Fanconi's syndrome, osteomalacia, osteoporosis, and secondary hyperaldosteronism in an adult consequent to vitamin D and calcium deficiency: effect of vitamin D and calcium citrate therapy.

OBJECTIVE: To describe a unique example of renal tubular acidosis type 2 (RTA 2) in conjunction with Fanconi's syndrome and osteomalacia consequent to vitamin D and calcium deficiency in an adult without underlying gastrointestinal disease. METHODS: We review the clinical, hormonal, histomorphometric, and micro-computed tomographic findings and the response to therapy with vitamin D and calcium in our patient. RESULTS: On admission, a 33-year-old African American woman had the following laboratory findings: serum ionized calcium 3.8 mg/dL (0.95 mmol/L), venous pH 7.26, bicarbonate 20 mEq/L, chloride 111 mEq/L, alkaline phosphatase 1,192 U/L (20.26 microkat/L) (normal, 40 to 136 U/L), 25-hydroxyvitamin D <5 ng/mL (<12 nmol/L) (normal, 10 to 60 ng/mL), parathyroid hormone 1,620 pg/mL (165.2 pmol/L) (normal, 10 to 60 pg/mL), aldosterone 68.4 ng/dL (1,894.7 pmol/L) (normal, 4.5 to 35.4 ng/dL), supine plasma renin activity 19.8 ng/mL per hour (5.35 ng/L per second) (normal, 0.5 to 1.8 ng/mL per hour), and aminoaciduria. A lumbar spine bone density T-score was -4.6, and a femoral neck T-score was -4.9. An undecalcified tetracycline-labeled bone biopsy specimen showed severe osteomalacia, severe osteoporosis, and peritrabecular fibrosis. A small intestinal biopsy revealed normal findings. Results of an ammonium chloride loading test and a bicarbonate infusion test were consistent with RTA 2. After 24 months of vitamin D and calcium therapy, results of serum and urine chemistry studies and bicarbonate infusion normalized. The lumbar spine T-score improved to -2.0, and the femoral neck T-score improved to -2.7. Bone biopsy specimens demonstrated resolution of the osteomalacia. CONCLUSION: Nutritional vitamin D and calcium deficiency may cause RTA 2, Fanconi's syndrome, and osteomalacia in adults as well as in children.

Simvastatin-amiodarone interaction resulting in rhabdomyolysis, azotemia, and possible hepatotoxicity.

OBJECTIVE: To describe the fifth reported instance, as of February 15, 2006, of a severe interaction between simvastatin and amiodarone and hypothesize inhibition of CYP3A4 as the major mechanism. CASE SUMMARY: A 72-year-old white man (178 cm, 77.2 kg) with diabetes mellitus, hyperlipidemia, hypertension, and mild azotemia was hospitalized on September 21, 2004, with thigh weakness, achiness, and dark urine for 7 days. Coronary artery bypass had been performed on July 7, 2004. Amiodarone 200 mg/day was started on July 10, and simvastatin 80 mg/day was initiated on August 13. Laboratory testing on the present admission included creatine kinase (CK) 19,620 U/L (reference range 60-224), blood urea nitrogen 50 mg/dL, creatinine 2.6 mg/dL, aspartate aminotransferase (AST) 912 U/L (30-60), alanine aminotransferase (ALT) 748 U/L (30-60), urine myoglobin 71,100 microg/L (<50), and serum myoglobin 13,877 microg/L (<110). Simvastatin and amiodarone were discontinued, and the patient was hydrated with forced alkaline diuresis. Thirteen days later, his CK was 323 U/L, creatinine 1.7 mg/dL, ALT 145 U/L, and AST 37 U/L. DISCUSSION: Simvastatin is metabolized primarily by CYP3A4, and amiodarone is a recognized inhibitor of this enzyme. This may, therefore, account for the presumed drug interaction. CONCLUSIONS: An objective causal assessment suggests that rhabdomyolysis, renal failure, and possibly hepatotoxicity were probably related to an amiodarone-simvastatin interaction.

Hypocalcemia, hypovitaminosis d osteopathy, osteopenia, and secondary hyperparathyroidism 32 years after jejunoileal bypass.

OBJECTIVE: To detail, for the first time, the results of bone histomorphometry, micro-computed tomography, and the calcium-vitamin D-parathyroid hormone (PTH) axis in a unique patient 32 years after undergoing a jejunoileal bypass (JIB) procedure for obesity. METHODS: A case report is presented, serial results of serum chemistry studies before and after treatment are outlined, and histomorphometric data on a bone biopsy specimen are summarized. RESULTS: In a 65-year-old woman with chronic lymphedema who had undergone JIB >3 decades earlier, baseline serum studies showed the following: total calcium, 6.2 mg/dL (normal, 8.5 to 10.5); ionized calcium, 0.87 mmol/L (normal, 1.15 to 1.35); creatinine, 1.3 mg/dL (normal, 0.6 to 1.0); albumin, 2.0 g/dL (normal, 3.0 to 5.0); magnesium, 1.0 mg/dL (normal, 1.5 to 2.1); phosphorus, 3.1 mg/dL (normal, 2.5 to 4.5); potassium, 3.1 mEq/L (normal, 3.5 to 5.0); alkaline phosphatase, 204 U/L (normal, 50 to 136); PTH, 311 pg/mL (normal, 10 to 60); 25-hydroxyvitamin D, <7 ng/mL (normal, 10 to 60); and 1,25-dihydroxyvitamin D, 37 pg/mL (normal, 25.1 to 66.1). Histomorphometry of an undecalcified iliac crest bone biopsy specimen demonstrated increased osteoid surface of 59.4% (Z-score = 5.6), increased mineralization lag time of 90.1 days (Z-score = 2.96), decreased adjusted apposition rate of 0.05 mm3/mm2/yr (Z-score = -2.45), but increased volume-based bone formation rate of 0.715 mm3/mm3/yr (Z-score = 2.0). Tetracycline labeling was diffuse and smudged, and the osteoblast-osteoid interface was decreased, indicating a mineralization defect. Increased cortical porosity, but no evidence of significant marrow fibrosis, was noted, whereas cancellous bone volume was decreased to 15.2% (Z-score = -0.92). Micro-computed tomography of bone biopsy specimens confirmed both increased cortical porosity and decreased cancellous bone volume. Vitamin D and calcium therapy resulted in near-normal or low-normal levels of 25-hydroxyvitamin D and calcium and improvement in PTH and alkaline phosphatase levels during a 9-month period. CONCLUSION: Significant hypovitaminosis D osteopathy, osteopenia, and hypocalcemia attributable to vitamin D deficiency may remain a problem in patients with unreversed JIB operations after more than 3 decades. Clinicians should be aware of this important clinical problem.

Adrenal insufficiency attributable to adrenal hemorrhage: long-term follow-up with reference to glucocorticoid and mineralocorticoid function and replacement.

OBJECTIVE: To describe the long-term follow-up of acute adrenal insufficiency attributable to bilateral adrenal hemorrhage. METHODS: We performed a retrospective review of medical records of four patients who underwent follow-up for 6(1/2) to 19 years. RESULTS: Despite published reports of more than 500 patients with bilateral massive adrenal hemorrhage through 2001, no long-term data assessing the continuing requirements for glucocorticoid and mineralocorticoid replacement are available. After follow-up of four patients with acute bilateral adrenal hemorrhage and glucocorticoid insufficiency for 6(1/2) to 19 years, we document the absence of need for long-term mineralocorticoid replacement on the basis of no occurrence of postural hypotension, normal electrolytes, normal baseline or cosyntropin-stimulated serum aldosterone levels, and generally, though not invariably, normal plasma renin activity levels. We further document the improvement in either or both baseline and cosyntropin-stimulated serum cortisol levels in three of the four patients and the ability of one patient to function normally without cortisol replacement for 4 years. Adrenal histologic findings in this last-mentioned patient revealed previously undescribed changes consistent with regeneration and myelolipoma. Finally, we confirm bilateral atrophic adrenal glands by computed tomography 5(1/2) to 11(1/2) years after bilateral adrenal hemorrhage in three of the four patients. CONCLUSION: Long-term follow-up of patients with acute adrenal insufficiency attributable to adrenal hemorrhage demonstrates, for the first time, absence of need for prolonged mineralocorticoid replacement and some improvement in endogenous glucocorticoid function in at least some of these patients.

Resolution of Cushing's disease followed by secondary adrenal insufficiency after anticoagulant-associated pituitary hemorrhage: report of a case and review of the literature.

OBJECTIVE: To describe the 12th well-documented case of spontaneous resolution of pituitary Cushing's disease due to pituitary hemorrhage and to review data on the previous 11 such patients described in the literature. METHODS: We present the longitudinal clinical, endocrinologic, and radiographic data in a 41-year-old woman with Cushing's disease before and after pituitary hemorrhage and summarize similar data in 11 previous reports of patients who convincingly appear to demonstrate the same syndrome. RESULTS: A 41-year-old woman with classic features of Cushing's disease had an overnight dexamethasone suppressed serum cortisol level of 23 mg/dL. Five months later, symptomatic pituitary hemorrhage developed in conjunction with characteristic pituitary magnetic resonance imaging findings and a serum cortisol value of 2.2 mg/dL. During the ensuing 8 months, she lost her Cushing's habitus, demonstrated improvement in her secondary adrenal insufficiency, and developed an empty right sella turcica, which remained unchanged on 1-year follow-up magnetic resonance imaging of the pituitary. An overnight metyrapone test 3 months later yielded normal results. CONCLUSION: Spontaneous remission in pituitary Cushing's disease, with or without later recurrence, has now been well documented in 12 patients. These findings (1) compel a reassessment of whether previously described patients experiencing spontaneous remission in association with medical therapy may have actually sustained asymptomatic pituitary hemorrhage and (2) raise the question of whether, in selected patents with microadenomas, medical treatment of Cushing's disease should be considered more often.