Subclinical Pulmonary Involvement in Active IBD Responds to Biologic Therapy.

OBJECTIVE: Increased mortality from respiratory diseases was observed in epidemiological studies of patients with ulcerative colitis [UC] as a potentially underestimated extraintestinal manifestation. We therefore investigated the presence of pulmonary manifestations of inflammatory bowel disease [IBD] and the potential effect of tumour necrosis factor alpha [TNF-α] inhibitors on pulmonary function tests [PFT] in a prospective, longitudinal study. METHODS: In all, 92 consecutive patients with IBD (49 Crohn´s disease [CD], 43 UC) and 20 healthy controls were recruited. Fifty patients with IBD were in remission, and 42 had active disease with 22 of these being examined before and 6 weeks after initiating anti-TNF therapy. Pulmonary function tests [PFT] were evaluated using the Medical Research Council [MRC] dyspnoea index and a standardized body plethysmography. IBD activity was assessed using Harvey-Bradshaw index for CD and partial Mayo score for UC. Data are presented as mean ± standard error of the mean [SEM]. RESULTS: Patients with active IBD showed significant reduction of PFT. Forced expiration [Tiffeneau index] values [FEV1%] were significantly reduced in IBD patients with active disease [78.8 ± 1.1] compared with remission [86.1 ± 0.9; p = 0.0002] and with controls [87.3 ± 1.3; p = 0.001]. Treatment with anti-TNF induced a significant relief in obstruction [p = 0.003 for FEV1% in comparison with baseline levels]. The level of pulmonary obstruction significantly correlated with clinical inflammation scores [HBI or Mayo]. CONCLUSIONS: PATIENTS: with active IBD present with significant obstructive abnormalities in their PFTs. Obstruction is related to inflammatory activity, with anti-TNF improving PFTs. Pulmonary obstruction and possibly chronic bronchopulmonary inflammation is an overlooked problem in active IBD that is probably obscured by intestinal symptoms.

Secretin-stimulated amylase release into blood is impaired in type 1 diabetes mellitus.

BACKGROUND: Prior studies have provided data indicating the existence of close interaction between pancreatic endocrine and exocrine function, but few clinical studies have explored this relationship in depth. We compared pancreatic exocrine function non-endoscopically in individuals with type 1 diabetes mellitus, type 2 diabetes mellitus, and normal glucose tolerant controls, to assess the importance of local insulin production to pancreatic exocrine function. METHODS: The plasma amylase response to intravenous secretin challenge was measured in men with type 1 diabetes mellitus (n = 5), type 2 diabetes mellitus (n = 5), and normal controls (n = 3). Patients were characterized by their urinary excretion of c-peptide and albumin over 24 hours. Autonomic neuropathy was non-invasively assessed by measuring RR variation (with deep respiration on EKG). RESULTS: Post-secretin amylase responses were generally absent with low baseline levels in the patients with type 1 diabetes mellitus. Patients with type 2 diabetes mellitus and controls showed similar twofold increases over baseline after secretin administration. When normal glucose tolerant and type 2 diabetic patients were pooled and compared against type 1 diabetes mellitus, the differences were statistically significant (p < 0.03). Total amylase response correlated positively, but weakly, with 24 h urinary C-peptide excretion (r = 0.507; p < 0.112), but not with glycemic control, duration of diabetes, or indices of autonomic neuropathy. CONCLUSIONS: Patients with type 1 diabetes mellitus, but not type 2 diabetes mellitus, have reduced pancreatic exocrine function, supporting the concept of a local paracrine effect of insulin on pancreatic acinar cells. Further studies are needed to determine the clinical impact of this deficiency, and whether such patients with type 1 diabetes mellitus would benefit from therapy with pancreatic enzyme supplementation.

Fast T1- and T2-weighted pulmonary MR-imaging in patients with bronchial carcinoma.

PURPOSE: A prospective study to evaluate the diagnostic potential and limitations of three fast MRI sequences in patients with bronchial carcinoma based on the comparison with spiral CT. MATERIAL AND METHODS: Three fast chest MRI sequences from 20 patients with central or peripheral bronchial carcinoma were evaluated by two observers for relation of tumour to adjacent structures, lymph node enlargement, additional pulmonary lesions and artefacts. The information from MR-imaging was compared with the results from spiral CT. MRI comprised a T1-3D-GRE breath-hold examination ("VIBE", TR/TE 4.5/1.9 ms, flip-angle 12 degrees , matrix 502 x 512, 2.5 mm coronal slices), a breath-hold, T2-HASTE sequence (TR/TE 2000/43 ms, matrix 192 x 256, 10 mm coronal slices) and a respiration-triggered T2-TSE sequence (TR/TE 3000-6000/120 ms, matrix 270 x 512, 6 mm transverse slices). The FOV was adapted individually (380-480 mm). RESULTS: The presence of the primary bronchial carcinoma and infiltration of thoracic structures by tumour tissue could be demonstrated by all sequences. VIBE sequence was more suitable for detecting small pulmonary nodules than the other MRI examinations, but compared to CT still 20% of these lesions were missed. Contrary to VIBE and T2-weighted TSE scans, HASTE sequence was limited in imaging mediastinal lymph nodes due to missing relevant findings in 2/20 patients. HASTE images significantly provided the lowest rate of artefacts in imaging lung parenchyma (P < 0.001 in peripheral parenchyma), but spatial resolution was limited in this sequence. Concerning the differentiation between tumour and adjacent atelectasis (n = 8), T2-weighted TSE imaging was superior to CT and VIBE in all cases and to HASTE sequence in 4/8 patients. CONCLUSION: The combination of VIBE and HASTE sequence allows for an adaequate imaging of thoracic processes in patients with bronchial carcinoma, limited only in visualizing small pulmonary nodules. To obtain more detail resolution and to differentiate tumour tissue from adjacent atelectasis, T2-TSE examination may be added in selected cases.

Safety and efficacy of metformin in a restricted formulary.

OBJECTIVE: To assess the efficacy and safety of metformin (MET) in the Veterans' Administration Northern California Health Care System during the period from June 1995 through April 1996 when its use required approval by Endocrinology. STUDY DESIGN: A retrospective review of patient charts and computerized pharmacy and laboratory records. Patients served as their own historical controls. PATIENTS AND METHODS: Patients receiving MET (n = 251) were identified from the pharmacy database. On-line laboratory data, including the intermediate outcome variable HbA1c, were retrieved by computer for the interval 4 months prior to the initial prescription to May 1996. Clinical data including weight and blood pressure were obtained from chart review. RESULTS: Of 228 patients whose charts were available for review, 29 reported side effects, and 12 discontinued use due to these side effects. No patients were identified with lactic acidosis. Both baseline and treatment data on HbA1c were available on 164 patients. Mean HbA1c (%) data (unpaired), expressed as mean +/- SE, were as follows: between 4 months pretreatment and 1 month pretreatment, 9.41 +/- 0.19 (n = 103 tests); between 1 month pretreatment and baseline, 9.41 +/- 0.19 (n = 110 tests); 3 months of treatment, 8.79 +/- 0.16 (n = 157 tests, P < 0.05); 6 months of treatment, 8.30 +/- 0.17 (n = 79 tests, P < 0.0001); 9 months of treatment, 8.72 +/- 0.24 (n = 70 tests, P < 0.05), compared to pretreatment values. Similar analysis of unpaired weight and blood pressure data in 152 patients did not reveal any reduction in these clinical parameters over this treatment period. Serum lipids were unchanged on treatment (by paired analysis), but the number of tests was limited. CONCLUSION: In this setting, MET provided sustained beneficial effects on glycemic control and was well tolerated. Any effects on weight, blood pressure, and serum lipids were not demonstrable in this analysis. We conclude that MET can substantially improve outcome of diabetes care.

Postmarketing analysis of lovastatin use in the VA Northern California System of Clinics: a retrospective, computer-based study.

Prevention of coronary heart disease is a major public health goal. The efficacy of lovastatin in lowering serum cholesterol has been proven in research studies, but its efficacy in practice is unclear. To evaluate our practice patterns and outcome in the Veterans Administration Northern California System of Clinics, we reviewed computer-based records of 203 unselected patients issued lovastatin; 193 (95%) were men, and the average patient age was 66 +/- 9 years. The average daily dose of lovastatin was 24 +/- 10 mg, and average duration of therapy was 22 +/- 11 months. Only 72 patients (35%) were instructed on the prescription to take their medication with the evening meal, and only 59 patients (29%) had seen a dietitian during the observed (1 to 3 years) treatment period. Nevertheless, among the 124 patients with pretreatment lipid data, total serum cholesterol decreased by 18% from 271 +/- 45 to 221 +/- 41 mg/dL (P < 0.001), and low density lipoprotein (LDL)-cholesterol decreased by 23% from 185 +/- 43 to 143 +/- 37 (P < 0.001) mg/dL. High density lipoprotein-cholesterol and triglycerides were unchanged. Of the 168 patients with LDL-cholesterol data during the treatment period, only 74 (44%) achieved an LDL-cholesterol level of less than 130 mg/dL, the minimum goal for a population of older males with a high incidence of other cardiac risk factors. Safety surveillance with liver function testing was performed at least once in 192 patients (95%), but with creatine phosphokinase (CPK) testing in only 123 patients (61%) during the survey period. Enzyme elevations were minor, but occurred at least intermittently in approximately one quarter of patients. Only 5.7% of patients on lovastatin manifested an increase in transaminases on therapy. Due to incomplete baseline data, it is unclear how many patients had elevated CPK as a result of lovastatin. We conclude that: (1) lovastatin is effective in lowering total and LDL-cholesterol in practice, but is often used in dosage insufficient to lower LDL-cholesterol to goal levels; (2) patients are not being adequately educated on dosing schedules; (3) toxicity may be underestimated by infrequent and inconsistent surveillance; and (4) nonpharmacologic therapy is underutilized.

Microalbuminuria in a normotensive insulin-treated diabetic population.

Thirty-five insulin-treated diabetics without overt proteinuria or hypertension, and taking no antihypertensive medications were screened at three clinical centers for the presence of microalbuminuria. In addition to the presence of albuminuria, patients were evaluated for duration and type of diabetes, retinopathy, blood pressure, and degree of diabetic control. In these patients, it was possible to examine the degree of microalbuminuria as a function of systolic and diastolic blood pressures, age and sex of the patient, site of recruitment, duration of diabetes, and glycemic control. On multivariate statistical analysis, systolic blood pressure was the only factor that contributed to microalbuminuria. An additional 37 patients had urinary albumin excretion measured, although biochemical and clinical characteristics were incompletely determined. Blood pressures were documented to be normal in 23 of these individuals, while the other fourteen were normal by history. The range of urinary albumin excretion was comparable in the patients with complete data bases and those without. Overall, 22.2% of the normotensive insulin-treated patients screened had microalbuminuria, 5.5% had gross albuminuria, while 72.2% had normal urinary albumin excretion. We agree with previous reports that microalbuminuria is relatively uncommon in the normotensive diabetic population, but further conclude that even in the context of "normal" blood pressure, systolic blood pressure should be carefully observed in diabetic patients. It is possible that these individuals should be considered for more aggressive monitoring programs, e.g., ambulatory blood pressure recording.

Estradiol stimulates cortisol production by adrenal cells in estrogen-dependent primary adrenocortical nodular dysplasia.

Adrenal glands from a patient with ACTH-independent Cushing's syndrome, whose symptoms worsened during pregnancy and oral contraceptive use, were cultured in different concentrations of estradiol. Estradiol stimulated cortisol secretion in a dose-response manner in the absence of ACTH. Since immunoglobulins G from this patient did not stimulate corticosterone production in a mouse adrenal bioassay, an adrenal-stimulating immunoglobulin is unlikely to be the cause of adrenal hyperfunction in this case. This is the first description of estradiol stimulation of cortisol production by cultured adrenal cells in ACTH-independent Cushing's syndrome.

Anomalous serum thyroxin measurements with the Abbott TDx procedure.

We describe a patient whose serum gave consistently low results for thyroxin as measured with the Abbott TDx but normal results by radioimmunoassay. Further clinical and laboratory studies did not support the low TDx results. Anti-thyroxin antibodies did not explain the discordant results, and we found no evidence of heterophilic antibodies in the patient's serum. We were unable to identify the cause of the problem.

Diabetic nephropathy: hemodynamic basis and implications for disease management.

New evidence shows that systemic and intrarenal hemodynamic abnormalities are major factors in the initiation and progression of diabetic nephropathy. Genetic predisposition to elevated systemic blood pressure may contribute to its development. Glomerular vasodilation and hyperfiltration, mediated in part by prostaglandins, may play a role in glomerular damage early in the course of diabetes, but clinical studies are limited. The development of more sensitive assays for albuminuria now allows early diagnosis of incipient nephropathy in the "microalbuminuria" phase. Treatment during this phase with antihypertensive agents, including angiotensin-converting enzyme inhibitors, or with dietary protein restriction, can decrease the degree of albuminuria, but data on their long-term effects on disease progression are limited. In hypertensive patients with established clinical diabetic nephropathy characterized by proteinuria in excess of 0.3 to 0.5 g/d, antihypertensive therapy has a major impact on delaying renal failure. Modalities that lower both systemic and intraglomerular pressure may be more beneficial in preserving renal function than those that primarily lower systemic pressure. Any therapeutic intervention should be monitored meticulously to establish its efficacy and safety in the individual patient. Therapy specifically directed against hemodynamic abnormalities throughout the course of diabetic renal disease may significantly delay and decrease the negative impact of this diabetic complication on survival and quality of life.

University of California, Davis, conference: Mild hypertension.

Prevalence of "higher than normal" blood pressures in a community is inversely related to the magnitude of the elevation; the milder grades of elevation are far more prevalent. A multifactorially inherited tendency to develop hypertension is modulated by multiple environmental influences. Autonomic nervous and behavioral factors plausibly appear to contribute to the initiating mechanisms of hypertension; the associated hemodynamic changes and the resulting cardiovascular structural changes interact to perpetuate the process. The complex interaction of hypertension and atherosclerosis is further complicated by direct as well as secondary effects of antihypertensive drugs on atherogenesis. Attributable cardiovascular risk is generally proportional to the degree of hypertension across the entire range of elevated blood pressure; this kind of relationship holds also for normal versus subnormal blood pressure values. Pharmacologic lowering of blood pressure, however, does not confer proportional benefit. Thus, such lowering of blood pressure to normotensive levels does not reduce the risk level to that in the normotensive population. Therapeutic outcome is influenced by the interaction of blood pressure lowering, type of antihypertensive agents used, existing risk factors, and target organ damage. Benefits of lowering blood pressure in established mild hypertension (diastolic blood pressure greater than 95 mm Hg) are confirmed. Drug treatment of patients with lower diastolic blood pressure or with isolated elevations of systolic blood pressures continues to be controversial as does the choice of initial therapeutic agent(s). The large-scale experience of clinical trials encompassing the long-term risks and benefits of the drug treatment of mild hypertension is limited to the use of diuretics and adrenergic beta blockers. A variety of new and promising therapeutic agents for use as alternate choices for initial therapy needs to undergo comparative evaluation.

Primary hyperaldosteronism.

Primary hyperaldosteronism is a challenging diagnosis because of its low incidence and variable pathophysiology. Serum potassium, properly done, is the routine screening test, but is not without its limitations. Confirmation of the diagnosis requires demonstration of abnormally high and nonsuppressible values for aldosterone in plasma and urine and low plasma renin activity. Sophisticated biochemical profiling and localization procedures often are required to identify those subtypes that will benefit from surgical management, including aldosterone-producing adenomas, primary adrenal hyperplasia, unilateral hyperplasia, and aldosterone-producing renin responsive adenomas. Glucocorticoid-suppressible hyperaldosteronism and isolated aldosterone-producing adrenal carcinoma are rare additional subtypes to be identified. Differentiation among these subtypes is a developing process that can be expected to continue to improve with new techniques and new understanding of underlying pathophysiology.

Age and the endocrine system.

The pattern of age-induced changes in each endocrine system is unique. Both hormone levels and target organ responsivity are altered in the aging endocrine-cardiovascular system. Serum levels of vasopressor hormones both increase (norepinephrine) and decrease (renin, aldosterone). Target organ responses to beta-adrenergic stimulation in the heart and probably also in vascular smooth muscle decrease due to postreceptor changes. These effects contribute to the clinical problems of hypertension and orthostatic hypotension which characterize the elderly. Aging produces mild carbohydrate intolerance and a minimal increase in fasting serum glucose in healthy, nonobese individuals, primarily due to decreasing postreceptor responsiveness to insulin. Aging decreases the metabolism of thyroxine, including its conversion to triiodothyronine, but clinically significant alterations of thyroid hormone levels do not occur. Changes in the end-organ response to thyroid hormones, however, significantly alter the clinical presentation of thyroid diseases. Aging shifts the serum vasopressin-serum osmolality relationship toward higher serum vasopressin levels probably due to altered baroreceptor input, probably contributing to the tendency toward hyponatremia in the elderly. Aging slows the metabolism of cortisol, but glucocorticoid levels in the human are essentially unaltered by age. However, recent data indicate that delta-5 adrenal steroids decrease markedly in both men and women. Nodules in the anterior pituitary, the thyroid, and the adrenal increase in frequency with aging. Finally, the reproductive system is primarily altered by endocrine cell death, by unknown mechanisms, resulting in decreased estrogen and testosterone levels in women and men. This most obvious age-related endocrine change turns out to be incompletely understood and is not representative of most age-related endocrine changes. Despite characterization of these many age-related alterations in endocrine systems, therapeutic issues often remain unexplored, and more data are needed in many areas.

The effects of alcohol on the endocrine system.

Male hypogonadism is the best documented endocrine effect of chronic alcoholism. A reversible clinical syndrome resembling Cushing's syndrome has also recently been described in some chronic alcoholics. The pituitary-thyroid axis is relatively resistant to the effects of ethanol, although mild abnormalities in various thyroid tests are frequently noted in the presence of alcoholic liver disease.

The effects of alcohol on blood pressure and electrolytes.

The interaction between alcohol abuse, changes in blood pressure, and electrolyte abnormalities is complex. Some effects of alcohol are seen only with acute ingestion, some during withdrawal, and some only in chronic drinkers. Careful attention to the interactions between the metabolism of various electrolytes can prevent unnecessary morbidity and mortality in alcoholic patients.