Relationship Between Hyperglycemia and Heart Transplant Rejection.

PURPOSE: Hyperglycemia increases risks of kidney and liver transplant rejection. To determine whether perioperative and subsequent glycemic control was associated with increased risk of heart transplant rejection over the year after transplantation, we performed a retrospective analysis of glycemic control and rejection rates in heart transplantation patients. METHODS: Perioperative glucose levels were analyzed in 157 patients undergoing transplantation at Northwestern Memorial Hospital from June 2005 to December 2012 and compared in patients with and without rejection found on routine follow-up biopsy specimens. RESULTS: Grade ≤1R rejection on biopsy was observed in 116 patients and grade ≥2R rejection (grade requiring increased anti-rejection treatment) in 41 patients. Although no significant differences in the preoperative fasting or inpatient mean glucose levels were found, the mean glucose levels from discharge to 1 year trended higher in those with grade ≥2R compared to grade ≤1R (128.8 ± 40.9 versus 142.2 ± 46.6 mg/dL, P = .084). In a multivariable logistic regression model, neither the lowest nor highest quartile of glucose levels had significantly different odds ratios (ORs) for the development of ≥2R compared to the middle 50% glucose levels. Older age (OR 0.96, P = .020) and higher body mass index levels (OR 0.86, P = .004) were significantly associated with lower odds of developing grade ≥2R. CONCLUSIONS: Although the glucose trend regarding rejection was not statistically significant, we cannot exclude the possibility that much higher glucose levels would influence rejection rates.

Acromegaly: an endocrine society clinical practice guideline

OBJECTIVE: The aim was to formulate clinical practice guidelines for acromegaly. PARTICIPANTS: The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), five experts in the field, and a methodologist. The authors received no corporate funding or remuneration. This guideline is cosponsored by the European Society of Endocrinology. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society and the European Society of Endocrinology reviewed drafts of the guidelines. CONCLUSIONS: Using an evidence-based approach, this acromegaly guideline addresses important clinical issues regarding the evaluation and management of acromegaly, including the appropriate biochemical assessment, a therapeutic algorithm, including use of medical monotherapy or combination therapy, and management during pregnancy.(AU)

Macimorelin (AEZS-130)-stimulated growth hormone (GH) test: validation of a novel oral stimulation test for the diagnosis of adult GH deficiency.

CONTEXT: In the absence of panhypopituitarism and low serum IGF-I levels, the diagnosis of adult GH deficiency (AGHD) requires confirmation with a GH stimulation test. Macimorelin is a novel, orally active ghrelin mimetic that stimulates GH secretion. OBJECTIVE: The objective of the study was to determine the diagnostic efficacy and safety of macimorelin in AGHD. DESIGN: This was a multicenter open-label study comparing the diagnostic accuracy of oral macimorelin with that of arginine+GHRH in AGHD patients and healthy, matched controls. After 43 AGHD patients and 10 controls were tested, the GHRH analog Geref Diagnostic [GHRH(1-29)NH2] became unavailable in the United States. The study was completed by testing 10 additional AGHD patients and 38 controls with macimorelin alone. MAIN OUTCOME MEASURE: Peak GH area under the receiver operating characteristic curve after macimorelin was measured. RESULTS: Fifty AGHD subjects and 48 controls were evaluated. Peak GH levels in AGHD patients and controls after macimorelin were 2.36 ± 5.69 and 17.71 ± 19.11 ng/mL, respectively (P < .0001). With macimorelin, the receiver operating characteristic analysis yielded an optimal GH cut point of 2.7 ng/mL, with 82% sensitivity, 92% specificity, and 13% misclassification rate. For subjects receiving both tests, macimorelin showed discrimination comparable with arginine+GHRH (area under the receiver operating characteristic curve 0.99 vs 0.94, respectively, P = .29). Obesity (body mass index > 30 kg/m(2)) was present in 58% of subjects, and peak GH levels were inversely associated with body mass index in controls (r = -0.37, P = .01). Using the separate cut points of 6.8 ng/mL for nonobese and 2.7 for obese subjects reduced the misclassification rate to 11%. Only 1 drug-related serious adverse event, an asymptomatic QT interval prolongation on the electrocardiogram, was reported. CONCLUSION: Oral macimorelin is safe, convenient, and effective in diagnosing AGHD with accuracy comparable with the arginine+GHRH test.

Growth hormone treatment in adults with growth hormone deficiency: the transition.

The approval of GH treatment of adults with GH deficiency (GHD) raises issues regarding continuation of GH treatment in the GH-deficient child following achievement of near adult height. The transition period begins in late puberty and ends with full adult maturation and includes hormonal and many lifestyle changes. Children treated with GH should be retested near the time of reaching adult height to determine if they have persistence of GHD. Although most children with organic causes of GHD will again be found to have GHD on retesting, most of those with idiopathic GHD will not. Retesting usually involves measurement of IGF-I and stimulation with insulin-induced hypoglycemia or arginine-GHRH, but important questions remain about adjustment of established cut-offs for age and body mass index. Most studies have shown the benefit of GH treatment in young adults with GHD in body composition, especially the achievement of peak bone mass. It is important for pediatric endocrinologists to discuss the potential need for continued treatment beyond achievement of adult height at the time of initiation of GH treatment, especially in those children with organic causes of GHD.

Disorders of prolactin secretion.

Prolactinomas are a common cause of reproductive/sexual dysfunction. Once other causes of hyperprolactinemia have been excluded with a careful history and physical examination, routine chemistries, and an assay for TSH, MR imaging, or CT will delineate the size and extent of the tumor. Medical therapy is the initial treatment of choice. When infertility is the primary indication for treatment, bromocriptine use has an extensive safety record and is preferred. For other indications, cabergoline seems to be more efficacious and better tolerated. Transsphenoidal surgery remains an option, especially for patients with microadenomas, when medical therapy is ineffective.

Endocrine problems in the chronically critically ill patient.

The endocrine adaptations to critical illness are varied. In the diabetic patient, counterregulatory hormones predispose to insulin resistance and hyperglycemia, a derangement accentuated by the use of glucocorticoids and enteral or parenteral nutrition. Thyroid abnormalities include the euthyroid sick syndrome, which may manifest as a low T3, low T4, low TSH, or all three. Illness in patients with pre-existing hypothyroidism or hyperthyroidism may precipitate myxedema coma or thyroid storm, respectively. The most important issue related to calcium is that of acute hypercalcemia, which, in the intensive care unit, usually is caused by malignancy and dehydration. Hyponatremia, a frequently encountered electrolyte disturbance, is evaluated best and treated according to volume status.

Growth hormone therapy for hypopituitary adults: time for re-appraisal.

The advent of the production of large quantities of recombinant growth hormone (GH) has made it possible to have sufficient material to assess its efficacy in adult growth hormone deficiency (GHD). Although some studies have shown that patients who are severely deficient benefit from GH therapy, the spectrum of GHD is broad, and the degree of deficiency at times is very difficult to define. In some cases, benefit is not easily quantified, and some studies have claimed benefits that, although statistically significant, are either not clinically important or are so marginal as to be questionable in terms of cost, difficulty of administration and potential risks. The purpose here is to identify the current problems in the diagnosis of GHD, to discuss the rationale for GH therapy and to assess the potential effects of GHD as well as the benefits of GH therapy in GHD adults. We will include a commentary as to which effects appear more robust than others and which are likely to result in the greatest patient benefit. Finally, some attention will be paid to long-term safety issues that should be monitored to ensure that this medication is safe even for the patients with the greatest need.

Medical treatment of prolactinomas.

Prolactinomas are a common cause of reproductive and sexual dysfunction. Once other causes of hyperprolactinemia have been excluded with a careful history, physical examination, routine chemistries, and a TSH, MR imaging or computerized tomography will delineate the size and extent of the tumor. Medical therapy is the initial treatment of choice. When infertility is the primary indication for treatment, bromocriptine use has an extensive safety experience and is preferred. For other indications, however, cabergoline appears to be more efficacious and better tolerated. Transsphenoidal surgery remains an option, especially for patients with microadenomas, when medical therapy is ineffective.

Management of prolactinomas during pregnancy.

Infertility is a common problem for women presenting with hyperprolactinemia, and lowering of prolactin (PRL) levels to normal or near normal is often necessary to permit ovulation. Dopamine agonists are effective in a majority of women, with cabergoline somewhat more effective than bromocriptine. Bromocriptine use by the mother appears to be safe for the developing fetus when its use is discontinued four to six weeks after conception. For women with microadenomas, the subsequent risk of adenoma growth during pregnancy appears to be 1% after discontinuing the drug, and symptomatic follow-up each trimester appears to be reasonable in such patients. For women with macroadenomas, bromocriptine may be discontinued after diagnosis of pregnancy (23% risk of tumor enlargement) or continued throughout pregnancy with monthly visual field testing. Alternatively, prepregnancy debulking of the tumor may be undertaken with appropriate follow-up (2.8% risk of tumor enlargement). Although data are less extensive on cabergoline, preliminary evidence does not suggest any increase in adverse fetal outcomes. As such, therapeutic abortion is not warranted if pregnancy occurs during cabergoline treatment. The drug appears reasonably safe for continued use. Further accrual of safety data will clarify that issue.

Octreotide as primary therapy for acromegaly.

The effects of octreotide (up to 5 yr) as primary treatment in 26 patients with acromegaly were compared with those in 81 patients with acromegaly who received octreotide as secondary or adjunctive therapy after previous surgery and/or pituitary radiation. These patients were part of a multicenter study that took place between 1989-1995. The study was divided into 3 phases beginning with a 1-month placebo-controlled treatment period followed by a 1-month washout period. In the second phase, patients were randomized to treatment with either 100 or 250 micrograms octreotide, sc, every 8 h for 6 months. Octreotide was then discontinued for 1 month and reinitiated at the lower dose for a total mean treatment duration of 39 months. The dose was titrated by each investigator to improve each patient's individual response, which included improvement in symptoms and signs of acromegaly as well as reduction of GH and insulin-like growth factor I (IGF-I) into the normal range. In the second phase of the study, in which patients were randomized to either 100 or 250 micrograms octreotide, three times daily, mean integrated GH and IGF-I concentrations after 3 and 6 months were equivalent in the primary and secondary treatment groups. During long term open label treatment, mean GH fell from 32.7 +/- 5.2 to 6.0 +/- 1.7 micrograms/L 2 h after octreotide injection in the primary therapy group and remained suppressed for a mean period of 24 months (range, 3-60 months). The mean final daily dose was 777 micrograms. In the patients receiving secondary treatment, mean GH fell from 30.2 +/- 7.6 to 5.6 +/- 1.1 micrograms/L after 3 months and remained suppressed for the remainder of the study (average dose, 635 micrograms daily). Mean IGF-I concentrations fell from 5.2 +/- 0.5 x 10(3) U/L (primary treatment group) and 4.7 +/- 0.4 x 10(3) U/L (secondary treatment group) to a mean of 2.2 +/- 0.3 x 10(3) U/L in both groups after 3 months of open label treatment and remained suppressed. IGF-I was reduced into the normal range during at least half of the study visits in 68% of the primary treatment group and in 62% of the secondary treatment group. Patients whose GH levels fell to at least 2 SD below the baseline mean GH were considered responders. There was no significant difference in the percentage of responders in the primary and secondary treatment groups (70% vs. 61%), nor was there a statistical difference in the mean GH concentrations between the groups. Symptoms of headache, increased perspiration, fatigue, and joint pain were reported at baseline by 46%, 73%, 69%, and 85%, respectively, of patients in the primary therapy group and improved during 3 yr of octreotide treatment in 50-100%. Similarly, these acromegaly-related symptoms were reported by 62%, 58%, 78%, and 60% of patients in the secondary therapy group, and improvement was noted in 62-88%. Pituitary magnetic resonance imaging scans were available in 13 of 26 patients in the primary treatment group before and after 6 months of octreotide treatment. Tumor shrinkage was observed in 6 of 13 patients, with reduction in tumor volume greater than 25% in only 3. Of 6 patients with documented tumor shrinkage, IGF-I was reduced into the normal range in 4 patients. Of the 7 remaining patients in whom tumor shrinkage was less than 10%, IGF-I was reduced into the normal range in 4 patients. Of the 7 remaining patients in whom tumor shrinkage was less than 10%, IGF-I was reduced into the normal range in 5 patients. The degree of tumor shrinkage did not correlate with the percent reduction in IGF-I or GH. In summary, octreotide was equally effective in 26 previously untreated acromegalic patients (primary treatment group) and 81 patients previously treated with either surgery or pituitary radiation (secondary treatment group). These observations call into question the current practice of surgical resection of all newly diagnosed GH-secreting pituitary adenomas regardless of the likelihood of cure. (AB

Pituitary diseases in pregnancy.

Pituitary adenomas are the most common pituitary disorder affecting pregnancy, and prolactinomas are the most common of the hormone-secreting pituitary adenomas. Hyperprolactinemia must be corrected to allow ovulation and fertility. Bromocriptine has been shown to be safe for use during early gestation. There is less than a 2% risk of microprolactinoma enlargement during pregnancy but a greater than 15% risk of symptomatic enlargement of a macroprolactinoma. Treatment options for patients with macroadenomas include stopping bromocriptine when pregnancy is diagnosed and reinstituting with tumor enlargement, continuous bromocriptine throughout pregnancy, and prepregnancy tumor debulking by surgery. The diagnosis of acromegaly may be difficult to make during pregnancy and relies, in part, on the persistence of the normal pulsatile secretion of growth hormone and loss of this secretory characteristic with a tumor. The growth hormone oversecretion may exacerbate tendencies to gestational diabetes, fluid retention, and hypertension. Treatment for acromegaly and other tumors generally may be deferred until after delivery. There are rare reports of enlargement of clinically nonfunctioning and growth hormone secreting tumors during pregnancy, and surveillance is needed. Tumors may need to be differentiated from lymphocytic hypophysitis. Patients with chronic hypopituitarism usually will need treatment with gonadotropins or pulsatile GnRH to become pregnant and may need increased steroid coverage during labor and delivery. Hypopituitarism developing during pregnancy is usually caused by lymphocytic hypophysitis and usually also will require steroid replacement therapy. Hypopituitarism arising postpartum may be caused by either lymphocytic hypophysitis or Sheehan's syndrome, and the latter may present as an acute or chronic syndrome. Borderline diabetes insipidus may manifest during pregnancy because of increased vasopressin degradation caused by markedly increased levels of placental vasopressinase. Treatment with desmopressin usually is satisfactory. Patients presenting with either anterior or posterior pituitary insufficiency in the peripartum period should always be evaluated for function of the other portion of the pituitary.

The relationship between glucose control and the development of diabetic nephropathy in type I diabetes.

Diabetic nephropathy is a major cause of morbidity and mortality in patients with diabetes and occurs in about one-third of such patients. The course of nephropathy has become better defined, with patients initially developing microalbuminuria (albumin excretion rates [AER] between 20 and 200 micrograms/min), then overt nephropathy (AER > or = 200 micrograms/min) and finally a decline in GFR eventuating in end-stage renal disease (ESRD). Although metabolic control has long been hypothesized as a contributor to the development of nephropathy, it is only in recent years that this hypothesis has been proven. A number of observational studies have shown correlations between glycemic control and the development of various levels of albuminuria and also declines in GFR. Several small, prospective, randomized, interventional studies and the Diabetes Control and Complications Trial (DCCT) have now definitely proven that improved metabolic control that achieves near-normoglycemia can significantly decrease the development and progression of early nephropathy as well as other long-term complications of diabetes, including retinopathy and neuropathy. It is now conceivable that the achievement of near-normoglycemia plus the addition of angiotensin-converting enzyme inhibitors if microalbuminuria develops may greatly decrease the numbers of patients eventually requiring renal replacement therapy.

Approach to the incidentally discovered pituitary mass.

Incidental pituitary adenomas are being found commonly with our improved neuroradiologic imaging procedures. Screening for hormone oversecretion by these tumors appears to be warranted. For patients with macroadenomas, patients should also be screened for hypopituitarism. In the absence of visual-field abnormalities or hypothalamic/stalk compression, it may be appropriate to observe such patients carefully with repeated MRI scans. A limited amount of data suggest that significant tumor enlargement will occur in < 5% of patients with microadenomas [8,11]. However, all macroadenomas must start out as microadenomas, and so periodic follow-up is indicated to assess for this possibility. Macroadenomas, by their very existence at the time of detection, have already indicated a propensity for growth. Over the limited period of follow-up in the two series reported, significant growth occurred in just over one quarter of the patients with macroadenomas [8,11]. Hemorrhage into such tumors is uncommon, but anticoagulation may predispose to this complication. When there is no evidence of visual-field deficits, an attempt at medical therapy with a dopamine agonist or octreotide is reasonable, realizing that only about 10% of such patients will respond with a decrease in tumor size. Surgery is indicated if there is evidence of tumor enlargement, especially when such growth is accompanied by compression of the optic chiasm, cavernous sinus invasion, or the development of pituitary hormone deficiencies.

Pituitary incidentalomas.

Incidental pituitary masses are commonly found during CT and MR imaging performed for a variety of reasons. Screening for hormone oversecretion by these tumors seems to be warranted. Patients with lesions greater than 1 cm should be screened for hypopituitarism. In the absence of visual field abnormalities or hypothalamic/stalk compression, it may be appropriate to observe such patients carefully with repeated MR imaging scans. A limited amount of data suggest that significant tumor enlargement occurs in less than 5% of patients with lesions smaller than 1 cm in diameter. However, all macroadenomas must start out as microadenomas, and thus periodic follow-up is indicated to assess for this possibility. Lesions larger than 1 cm in diameter by their very existence at the time of detection have already indicated a propensity for growth. Significant tumor growth occurs in just over one-quarter of such patients. Hemorrhage into such tumors is uncommon, but anticoagulation may predispose to this complication. When there is no evidence of visual field deficits, an attempt at medical therapy with a dopamine agonist or octreotide is reasonable, realizing that only 10% of such patients will respond with a decrease in tumor size. Alternatively, careful periodic observation without intervention may determine that the lesion is not growing. Surgery is indicated with evidence of tumor enlargement, especially when such growth is accompanied by compression of the optic chiasm, cavernous sinus invasion, or the development of pituitary hormone deficiencies.

Effect of pregnancy on renal function in patients with moderate-to-severe diabetic renal insufficiency.

OBJECTIVE: Previous studies of patients with diabetic nephropathy and mild renal impairment have suggested no determination in renal function as a result of pregnancy. The objective of this study was to determine whether pregnancy may permanently worsen renal function in women with diabetic nephropathy and moderate-to-severe renal insufficiency. RESEARCH DESIGN AND METHODS: Eleven patients were identified with diabetic nephropathy and moderate-to-severe renal dysfunction (creatinine [Cr] > or = 124 mumol/l [1.4 mg/dl]) at pregnancy onset by retrospective chart review. Alterations in glomerular filtration rate were estimated by using linear regression of the reciprocal of Cr over time. An equal number of nonpregnant premenopausal type 1 diabetic women with similar degrees of renal dysfunction served as a comparison group for nonpregnant rate of decline of renal function and potential contributing factors. RESULTS: Mean serum Cr rose from 159 mumol/l (1.8 mg/dl) prepregnancy to 221 mumol/l (2.5 mg/dl) in the third trimester. Renal function was stable in 27%, showed transient worsening in pregnancy in 27%, and demonstrated a permanent decline in 45%. Proteinuria increased in pregnancy in 79%. Exacerbation of hypertension or preeclampsia occurred in 73%. Seven patients progressed to dialysis 6-57 months postpartum, with 71% (five of seven) of these cases attributed to acceleration of disease during the pregnancy. Student's tests and repeated-measures analysis of variance support a pregnancy-induced acceleration in the rate of decline of renal function. CONCLUSIONS: In this series, patients with diabetic nephropathy and moderate-to-severe renal insufficiency were found to have a > 40% chance of accelerated progression of their disease as a result of pregnancy.