Effect of 2 years of cortisol normalization on the impaired bone mass and turnover in adolescent and adult patients with Cushing's disease: a prospective study

BACKGROUND: Osteoporosis is a frequent, severe and often underestimated consequence of long-term hypercortisolism, often presenting as bone fracture. OBJECTIVE: This prospective study was designed to evaluate whether the abnormalities of bone mass and turnover can be similarly reversed in adolescent and adult patients with Cushing's disease, after correction of hypercortisolism. PATIENTS AND METHODS: Bone mineral density (BMD) at lumbar spine, serum osteocalcin (OC) and urinary cross-linked N-telopeptides of type I collagen (Ntx) levels were measured at diagnosis and 2 years after cure of Cushing's disease (CD) in six patients with childhood-onset and nine with adulthood-onset disease. Fifteen age-, sex- and body mass index (BMI)-matched healthy subjects served as controls. RESULTS: At diagnosis, BMD Z scores at lumbar spine and OC levels were lower (2.3 +/- 0.1 vs.-0.2 +/- 0.01; P < 0.01 and 1.6 +/- 0.1 vs. 9.6 +/- 1.2; P < 0.01 respectively) while urinary Ntx levels were significantly higher (139.9 +/- 6.1 vs. 82.0 +/- 1.6; P < 0.01) in CD patients than in controls. Among CD patients, similar values of Z scores (-2.4 +/- 0.3 vs.-2.2 +/- 0.1, P = 0.4) and OC levels (1.7 +/- 0.2 vs. 1.6 +/- 0.2, P = 0.6) were observed in adolescent and adults patients, whereas urinary Ntx levels were significantly higher (159.7 +/- 7.9 vs. 125.9 +/- 3.3, P < 0.001) in the former than in the latter group. Two years after remission from hypercortisolism, OC levels (P < 0.001) and lumbar BMD Z scores (-2.2 +/- 0.3, P < 0.05; and -1.9 +/- 0.2; P < 0.01, respectively) increased significantly, while urinary Ntx levels reduced significantly (P < 0.001) in both adolescent and adult patients. However, biochemical markers and Z scores of BMD remained significantly suppressed compared to controls. CONCLUSIONS: Bone impairment in childhood- and adulthood-onset Cushing's disease patients can be partly, but not completely, reversed 2 years after normalization of cortisol levels. Longer recovery times or additive therapeutic approaches are necessary to maximize peak bone mass in children and restore bone mass in adults with Cushing's disease.     

Decreased bone area, bone mineral content, formative markers, and increased bone resorptive markers in endogenous Cushing's syndrome.

It is well established that chronic excess of glucocorticoids has negative effects on bone and collagen turnover, and that secondary osteoporosis is a known clinical complication of endogenous Cushing's syndrome (CS). The aim of the present study was to evaluate bone dimension and bone mineral content in relation to biochemical markers of bone and collagen turnover, in a consecutive series of 23 patients with endogenous CS (18 with pituitary adenoma and 5 with adrenal tumor; 17 women, 6 men; mean age 39.7+/-2.8 (S.E. M.) and 44.3+/-3.1 years respectively), compared with 23 age-, sex- and body mass index-matched healthy controls. Bone mineral densities were uniformly reduced in the different regions analyzed: lumbar spine (16.1%, P<0.001), femoral neck (15.2%, P<0.001), total body (11.5%, P<0.001), and the subregions of arms (8.4%, P<0.05), legs (10.1%, P<0.05) and trunk (15.8%, P<0.001). Similar results were observed for bone mineral content, although these were less prominent. The calculated area was significantly decreased in trunk (13.8%, P<0.01) and total body (11.6%, P<0.05). Serum levels of osteocalcin were significantly decreased (28%, P<0.03) in patients with CS. No significant differences were observed for the formative markers carboxyterminal propeptide of type I procollagen and aminoterminal propeptide of type I procollagen. Markers of bone resorption, serum Crosslaps and carboxyterminal cross-linked telopeptide of type I collagen were increased in patients compared with controls, although only significantly for Crosslaps (P<0.02). No correlations between formative and resorptive markers were found in the patients, but in controls, the formative markers were positively correlated with resorptive markers. In conclusion, bone dimension and bone mineral content of the entire skeleton are found to be decreased in endogenous CS. As judged by biochemical markers of bone remodeling, this is caused by decreased bone formation and an increased bone resorption.     

Recovery of bone mass and normalization of bone turnover in long-term survivors of allogeneic bone marrow transplantation

Osteoporotic fractures are potential long-term complications of bone marrow transplantation (BMT). We previously reported that bone mineral density (BMD) of patients undergoing allogeneic BMT decreased by 6% to 9% during the first 6 months after BMT and that bone turnover rate was still increased 1 year after BMT. BMT patients do not need lifelong immunosuppressive treatment, which should offer favorable circumstances for the recovery of BMD. Thus, 27 (14 women, 13 men) of 29 long-term survivors of our previous study were invited to a follow-up study at a median of 75 months after BMT. From 12 months after BMT the BMD of the lumbar spine had increased by 2.4% (P = 0.002). The respective changes in femoral sites were +4.1% in the femoral neck (P = 0.087), 4.0% in the trochanter (P = 0.095), +4.7% in Ward's triangle (P = 0.072) and +1.4% in the total hip (P = 0.23). The markers of bone formation, serum osteocalcin and type I procollagen aminoterminal propeptide (PINP) had returned to control levels, but out of the markers of bone resorption the mean level of serum type I carboxyterminal telopeptide (ICTP) was 41% higher (P = 0.0001) and that of urinary type I collagen N-terminal telopeptide/creatinine (NTx) 41% lower (P = 0.0002) in patients than in controls. The mean serum 25-hydroxyvitamin D [25(OH)D] was 33% lower in patients (P = 0.0002), most of whom had hypovitaminosis D [serum 25(OH)D < or = 37 nmol/l]. Except for two, males had serum testosterone level lower than before BMT and four men had hypogonadism. In conclusion, in long-term survivors of allogeneic BMT BMD recovers and bone turnover state normalizes as compared to the situation 1 year after BMT. More attention should be paid to the vitamin D status of all recipients and to possible hypogonadism of male patients.     

Bone mineral density at diagnosis and following successful treatment of pediatric Cushing's disease

Bone mineral density (BMD) is frequently reduced in children and adolescents with Cushing's disease (CD), but there is little follow-up data after cure. BMD was determined by dual energy X-ray absorptiometry (DEXA) in two groups of patients with CD. Group 1 comprised 8 patients, 5 males and 3 females, aged 12.4 yr (8.2-16.8), assessed at diagnosis. Group 2 comprised 11 subjects, 6 males and 5 females, diagnosed at age 13.3 yr (6.4-17.4), cured by transsphenoidal surgery (TSS) (no.=7) or TSS + pituitary irradiation (no.=4). They had measurement of BMD, at mean age of 18.3 yr (11.1-28.5), i.e. 4.5 yr (0.8-11.4) after cure. Four patients, mean age 20.2 yr (17.6-22.4), had repeated DEXA'scans, 1-4 times, for up to 5.8 yr. After cure, GH deficiency was present in 9 patients and treated with hGH in 8. In Group 1, patients' L2-L4 volumetric (v)BMD Z-score was variable with a mean of -1.04 (-3.21-0.11). L2-L4 vBMD Z-score values correlated negatively with midnight cortisol (p < 0.05). In Group 2, mean L2-L4 vBMD was -0.38 (-1.0-0.13); and in 7/11, mean femoral neck (FN) areal (a)BMD Z-score was 0.14 (-1.62-2.46). FN aBMD Z-score was higher than L2-L4 aBMD Z-score (p < 0.05). In patients with repeated scans, mean change in L2-L4 vBMD Z-score was 0.20 (-0.15-0.45), and mean change in FN aBMD Z-score 0.03 (-0.53-0.38). These findings show variability of BMD at diagnosis and near normal BMD after cure of pediatric CD, suggesting that with appropriate replacement of pituitary hormone deficiency normal peak bone mass is achievable.     

A prospective study of psychiatric and psychological aspects of Cushing's syndrome

OBJECTIVE Cushing's syndrome is associated with psychiatric and psychological disturbances. The aim of this study was to ascertain the extent of mental illness in patients before and after treatment for Cushing's syndrome. DESIGN AND PATIENTS Patients with Cushing's syndrome were identified for a prospective study. Control patients were selected with pituitary adenomas secreting GH or PRL. The aim was to reassess patients after Cushing's syndrome had been treated. MEASUREMENTS Psychiatric symptoms were measured and classified using the Present State Examination (PSE), and analysed on the Catego Programme. The Hamilton Rating Scale (HRS) was used to measure depression. The Crown-Crisp Experiential Index was used to measure common psychoneurotic symptoms (anxiety, phobia, obsession, somatic, depression and hysteria scales). The Eysenck Personality Inventory was used to assess extroversion and neuroticism. Cortisol, ACTH, and other hormones were measured by conventional methods. Parametric and non-parametric tests were used where appropriate. RESULTS Catego analysis of psychiatric ratings showed only 8 patients of 43 with active Cushing's syndrome (19%) were normal. Psychiatric diagnoses were obtained as follows: neurotic depression in 20 (46%), possible neurotic depression in 1 (2%), reactive depression in 6 (14%), and non-specific neurotic symptoms in 8 (19%). Additional Catego ratings of suspected other psychoses were made for 3 patients who were also depressed. None of these 43 patients with active Cushing's syndrome had ratings of schizophrenia or mania, obsessional neurosis or pathological anxiety. In the control group 13 (87%) were normal, 1 patient with acromegaly had an anxiety state and one patient with a prolactinoma had neurotic depression. It was possible to reassess the Present State Examination after treatment in 25 patients, when cortisol levels had been substantially reduced (to normal in 88%), the percentage rated as psychiatrically normal increased from 19 to 68 (χ²=11.7, 1 d.f., P<0.01). Hamilton Rating Scale scores for depression showed significant improvements after treatment for Cushing's syndrome (mean decrease from 9.2 to 2.4, n=36, P<0.001). Crown-Crisp experiential index data showed significant improvements in anxiety, somatic symptoms, and depression (n=25, P<0.05). Eysenck Personality Inventory assessments showed a significant improvement in neuroticism score (n=26 P=0.016), but no significant change in extroversion (P=0.5) or lie score (P=0.6). CONCLUSIONS Most patients with Cushing's syndrome had significant psychiatric pathology, usually depressive illness. As cortisol levels were returned to normal there were significant improvements in scores for depression and anxiety. Management of patients with Cushing's syndrome should include careful assessment of psychological and psychiatric illness.     

Loss of body cell mass in Cushing's syndrome: effect of treatment

Cushing's syndrome (CS) is associated with low fat-free mass, but it is unclear whether hypercortisolism causes a loss of whole body protein. Body composition was studied prospectively in 15 patients with untreated CS (n = 14 pituitary adenoma; n = 1 adrenal adenoma), in 15 nonobese healthy controls, and in 15 weight-matched obese controls by 3 different methods: total body potassium counting (TBP), bioelectrical impedance analysis (BIA), and anthropometry. In 6 patients, body composition was studied before and within 6 months after pituitary surgery. In CS patients and weight-matched controls, body weight and total body fat were significantly higher than in nonobese controls. In CS patients, TBP was 18.4% lower than predicted, whereas in weight-matched controls TBP was 7.1% higher than predicted. As compared with nonobese and weight-matched controls, in CS patients TBP indicated a significant loss of body cell mass (BCM) of -20.2 and -21.1%, respectively. A significantly reduced arm muscle area of -21.3% compared with weight-matched controls also indicated a loss of whole body protein. In CS, however, BIA overestimated BCM when compared with TBP by +18% and agreement between BIA and TBP in the individual patient was poor (limits of agreement plus minus 27.6%), indicating the invalidity of standard BIA equations in this population. Measurements performed before and 6 months after successful pituitary surgery demonstrated a significant loss of body weight (-11%) and body fat (-33%), but BCM and muscle mass remained on a constant low level. In conclusion, this study shows that, in patients with CS, a significantly reduced BCM indicates a true protein loss. The second interesting finding is that in the early recovery after successful treatment of hypercortisolism patients lose body fat without gaining BCM or muscle mass.     

Interleukin-1 receptor antagonist is associated with fat distribution in endogenous Cushing's syndrome: a longitudinal study

The weight gain and visceral obesity associated with Cushing's syndrome (CS) has been linked to elevated plasma leptin levels, although the mechanism behind a central leptin resistance in these patients is unknown. Several studies describe interactions among the hypothalamic-pituitary-adrenal axis, leptin, and the IL-1 system. To investigate these interactions, we have evaluated changes in regional fat distribution, by DEXA, and the role of circulating cortisol, leptin, IL-1beta, and IL-1 receptor antagonist (IL-1Ra), in relation to these changes, in 27 (19 DEXA; 27 serum measurements) patients with CS, before and after surgical treatment (mean follow-up, 31 months; range, 5-80), and compared them with measurements of age-, sex-, and body mass index-matched healthy controls (also obtained longitudinally). We found that surgical treatment caused a decrease in all fat parameters, without changing lean body mass, and these changes were significantly larger than the so-called natural changes occurring in control subjects. These changes in CS patients were paralleled by decreases in cortisol, leptin, and IL-1Ra, whereas IL-1beta increased. Stepwise linear regression showed that serum IL-1Ra was strongly associated with regional fat distribution, and especially truncal fat mass, both at baseline and during treatment. In conclusion, the present study shows that treatment significantly changes body composition in CS patients by decreasing fat mass, especially in the truncal region, without major effects on lean body mass. We also show that circulating IL-1Ra is strongly associated with these changes, signifying a relationship among the hypothalamic-pituitary-adrenal axis, IL-1 system, and regional fat distribution in these patients.     

Pediatric Cushing's syndrome: clinical features, diagnosis, and treatment

Cushing's syndrome (CS) results from prolonged exposure to supraphysiological levels of circulating glucocorticoids, endogenously or exogenously derived. Although rare in childhood, CS remains a difficult condition to diagnose and treat. A multidisciplinary approach and close collaboration with adult colleagues is adopted at most large centres that manage pediatric CS patients. Although pediatric protocols are derived from adult data, significant differences exist between adult and childhood CS. Furthermore, long term outcome parameters including final height, bone mineral density, reproductive function, body composition and psychological health pose challenges for pediatric care. This article will aim to provide an overall view of pediatric CS highlighting some of the differences between adult and pediatric CS.     

Hypercoagulability in Cushing's syndrome: prevalence,pathogenesis and treatment

Cushing's syndrome is not only accompanied by an increased prevalence of cardiovascular disease but also by a hypercoagulable state that is reflected by an increased incidence of venous thromboembolism. Overall, patients with CS have been reported to have a more than 10‐fold increased risk of developing venous thromboembolism. Moreover, the incidence of postoperative thrombosis has been shown to be comparable to the risk after major orthopaedic surgery. Hypercoagulability in CS is due to both increased production of procoagulant factors with activation of the coagulation cascade and an impaired fibrinolytic capacity, resulting in a shortened activated partial thromboplastin time and an increased clot lysis time respectively. Although these abnormalities seem to improve 1 year following successful surgery, they do not yet normalize. Therefore, sustained biochemical remission might be required to fully resolve the hypercoagulable state in CS. Considering the risk of venous thromboembolism in uncontrolled CS there may be a rationale to give patients with active CS thromboprophylaxis. So far this seems warranted following surgical interventions. However, further studies are needed to determine the optimal dosage and duration of thromboprophylaxis.     

Factors predicting successful outcome following neostigmine therapy in acute colonic pseudo-obstruction: a prospective study

AIM: To evaluate predictors of neostigmine response in patients with acute colonic pseudo-obstruction. METHODS: Twenty-seven patients with acute colonic pseudo-obstruction were enrolled in the study. All patients had received initial conservative management such as nil orally, nasogastric suction, rectal tube placement and correction of electrolyte imbalance for the first 24 h. Those who did not resolve with conservative management received 2 mg neostigmine intravenously. The same dose was repeated after 24 h in patients who did not response to the first dose (initial non-responders), or in those patients who relapsed after an initial response (initial responders). All non-responders to neostigmine underwent colonoscopic decompression followed by 2 mg neostigmine infusion for 30 min. A sustained response was defined as the resolution of symptoms and colonic dilatation on a plain radiograph. RESULTS: The study enrolled 27 patients; 18 were male (67%), and the median age was 60 years (range 18-78 years). Eight (30%) patients had spontaneous resolution. Initial response with neostigmine was observed in 16 (84%) patients, of which 10 (63%) had a sustained response. Nine patients (three initial non-responders and six initial responders) had received a second dose of neostigmine. A sustained response was seen only in five initial responders. Four patients who did not respond to neostigmine underwent colonoscopic decompression followed by neostigmine infusion and had a sustained response. Neostigmine responders were more likely to be postoperative patients (11 of 15 (73%) vs one of four (25%), P = 0.07), less likely to have electrolyte imbalance and to be on antimotility agents (three of 15 (20%) vs four of four (100%), P = 0.009 and two of 15 (13%) vs four of four (100%), P = 0.003). CONCLUSIONS: Electrolyte imbalance and usage of anti-motility agents are factors associated with a poor response, while postoperative patients showing good response to neostigmine therapy.     

Assessment of GH reserve before and after successful treatment of adult patients with Cushing's syndrome

OBJECTIVE: Several studies have demonstrated impaired GH secretion in patients with active Cushing's syndrome (CS). It has been suggested that persistence of GH deficiency, despite treatment of cortisol excess, may delay the recovery of these patients and therefore temporary treatment with GH may have some benefit. However, the time course of restoration of GH secretion after successful treatment of CS has only been investigated in a limited number of mostly paediatric reports. The aim of the present study was the evaluation of GH reserve in adult patients with CS before and after correction of cortisol excess. DESIGN AND PATIENTS: Sixteen patients (12 females, four males) with CS aged 44.7 +/- 5.05 years were recruited. These included seven patients with Cushing's disease, four patients with ectopic ACTH secretion and five patients with adrenal adenoma. All patients were evaluated before any therapeutic intervention. Twelve patients were successfully treated following appropriate surgery and these were further studied. The combined pyridostigmine/GHRH test was used to assess GH reserve in these patients. In a proportion of cases an insulin tolerance test (ITT) was also used. RESULTS: Before any therapeutic intervention, an impaired GH response to PD/GHRH was noted in all patients. Restoration of GH response at 6 months was observed in six patients (50%); at 12 months in two; at 18 months in one patient. Two of the patients with no restoration of GH response at 12 months did not accept further investigation. Only one patient did not achieve an adequate GH response even when tested 30 months following cure of CS. Restoration of GH reserve was more commonly observed in those patients in whom there was recovery of the HPA axis. There was a good correlation between peak GH levels to PD + GHRH and ITT. No statistically significant difference was revealed in IGF-I levels between pre- and post-treatment evaluation. CONCLUSIONS: Adult patients with active Cushing's syndrome demonstrate a profound suppression of stimulated GH secretion. In the majority of these patients the disruption of GH secretion is normalized within a year after successful treatment of endogenous cortisol excess.     

Adjuvant sclerotherapy after ligation for the treatment of esophageal varices: a prospective, randomized long-term study

BACKGROUND: To assess the efficacy of adjuvant sclerotherapy after banding for the treatment of esophageal varices, a randomized trial was carried out of endoscopic variceal ligation (EVL) alone with sequential sclerotherapy versus sequential ligation-sclerotherapy (SLS) after banding with respect to variceal eradication, associated complications, and recurrence of varices. METHODS: One hundred patients qualified for this study. Fourteen patients were not included for the following reasons: 6 chose not to participate, 4 had fundal varices, and 4 had some form of cancer. Of the remaining 86 patients in the study, 42 underwent EVL alone and the other 44 SLS. Variceal ligation was begun in the region of the gastroesophageal junction, with subsequent ligatures applied cephalad 3 to 5 cm; ligation was repeated every 2 weeks until variceal obliteration. For SLS, ligation was also begun in the region of the gastroesophageal junction and repeated until varices were reduced to F1 size. Subsequently, these patients underwent sclerotherapy with between 6 and 8 mL of sodium tetradecyl sulfate (free hand technique). RESULTS: No significant differences were found between EVL alone and SLS with regard to variceal eradication, development of associated complications, and recurrent bleeding during a follow-up of 2 years. The probability of variceal recurrence requiring further treatment after 1 year was 14% for the SLS group and 26% for EVL group patients. Another year later, the probability of variceal recurrence was 24% and 45%, respectively, for the SLS and EVL groups. CONCLUSIONS: Because a significantly lower rate of variceal recurrence was found for SLS patients, sequential sclerotherapy followed by ligation to eradicate those varices too small to easily band may be a better procedure.     

Pulmonary function after autologous bone marrow transplantation in children: a long-term prospective study

We performed serial pulmonary function tests (PFTs) consisting of spirometry and diffusing capacity in 26 children after BMT. The median follow-up was 10 years. The influence of total body irradiation (TBI) on long-term pulmonary function was of particular interest. In the 20 children who had received TBI, after an initial decrease the PFTs showed recovery, but the mean lung volumes were still significantly decreased 5 years after BMT at 10% below baseline. The proportions of children with restrictive impairment 5 and 10 years after BMT were 20 and 21%, respectively. Only one child was diagnosed with obstructive impairment. The proportions of children with isolated diffusing impairment at 5 and 10 years were 7/20 (35%) and 7/13 (54%), respectively. Six children had received chemotherapy only and showed isolated diffusing impairment as the only long-term sequela in 4/5 and 1/3 at 5 and 10 years. Our main finding was that there was little change in PFTs 1-10 years after BMT. TBI was associated with persistently decreased lung volumes in a proportion of patients, whereas chemotherapy also might have been of importance for the development of impaired gas exchange.     

Renal function after autologous bone marrow transplantation in children: a long-term prospective study

We measured glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and the concentrating capacity of the kidneys in children after autologous BMT. Twenty-six patients had received TBI in their conditioning regimen and 14 patients had received chemotherapy only. Median follow-up was 10 years. Mean GFR before BMT was close to normal in both groups. Mean GFR decreased from 124 [CI 114,134] ml/min/1.73 m(2) before BMT to 99 [CI 82,115] ml/min/1.73 m(2) 6 months after BMT in the + TBI group (P < 0.001). There was no significant change in the -TBI group. Mean ERPF before BMT was high: 1110 [95% CI 830,1390] ml/min/1.73 m(2) in the + TBI group and 910 [CI 570,1250] ml/min/1.73 m(2) in the - TBI group. Six months after BMT, there was a tendency to a decrease in ERPF in the +TBI group, to 760 [CI 580,940] ml/min/1.73 m(2) (P = 0.064). After this initial decrease, GFR and ERPF remained essentially unchanged in both groups. The mean concentrating capacity of the kidneys was normal before and after BMT. In seven patients chronic renal impairment developed after BMT (GFR <70 ml/min/1.73 m(2)). All had received TBI. They had also received more nephrotoxic antibiotics than the other patients. We conclude that TBI was the principal cause of deterioration of renal function after BMT, possibly by limiting compensatory hyperperfusion and resulting in a fall in GFR. Antibiotic treatment may have contributed.     

Famciclovir treatment of hepatitis B infection following liver transplantation: a long-term, multi-centre study

Abstract: Famciclovir is a novel guanosine nucleoside analogue with activity against herpes viruses and hepatitis B virus (HBV). Several preliminary reports have described efficacy of famciclovir in patients with recurrent hepatitis B after orthotopic liver transplantation (OLT). This report describes the largest study to date of long‐term famciclovir treatment in patients with de novo or recurrent hepatitis B post‐OLT. One hundred thirty patients with detectable serum HBV DNA after OLT received oral famciclovir 500 mg tid on a compassionate‐use basis. Safety analyses included all treated patients; efficacy was assessed in all patients and a subgroup of 73 patients with complete baseline HBV DNA and alanine aminotransferase (ALT) data who had received ≥6 months of treatment. Efficacy parameters included serum levels of HBV DNA, ALT, and anti‐HBe or anti‐HBs seroconversion rates. Of the 70 patients treated for ≥6 months who could be evaluated for response/non‐response to famciclovir, 52 (74%) were responders, defined as patients who experienced a 70% decrease or more in HBV DNA levels from baseline, or who became HBV DNA‐negative, for at least two consecutive visits. In famciclovir responders, HBV DNA levels decreased by a median of 91% after 12 weeks of treatment, 95% after 6 months and >99% after 18 months of treatment. Marked differentiation between responders and non‐responders could be made soon after the onset of treatment. Among anti‐HBe positive patients with evidence of HBV replication, 12/13 were responders. Patients with high baseline ALT levels experienced more rapid suppression of HBV DNA during therapy with famciclovir. Famciclovir therapy was safe and well tolerated; serious adverse events were reported infrequently. Famciclovir treatment may be beneficial in patients with hepatitis B infection post‐OLT.     

Cushing's syndrome due to ectopic adrenocorticotropic hormone production by a non-metastatic gastrinoma after long-term conservative treatment of Zollinger-Ellison syndrome

This report concerns a case of a Cushing's syndrome 10 years after first diagnosis of a Zollinger-Ellison syndrome within the same patient. In a 69-year-old female patient symptoms of hypergastrinaemia have been successfully treated with a proton pump inhibitor. Cushing's syndrome was the result of ectopic adrenocorticotropic hormone production by a large cystic gastrin-producing tumour of the pancreatic tail. After resection by subtotal pancreatectomy serum adrenocorticotropic hormone, cortisol, gastrin levels and secretin infusion test returned to normal. In contrast to all other previously published cases of ectopic adrenocorticotropic hormone syndrome associated with Zollinger-Ellison syndrome, this tumour had not metastasized into the liver and did not show local invasive growth.     

Raised serum levels of interleukin-8 and interleukin-18 in relation to bone metabolism in endogenous Cushing's syndrome

OBJECTIVE: It is well known that patients with endogenous Cushing's syndrome (CS) have decreased bone mass and enhanced risk for osteoporotic fractures, secondary to decreased bone formation and increased bone resorption. Immunological mediators, such as cytokines, have recently been shown to influence bone metabolism, and in the present study we examined serum levels of several cytokines, with known or potential effects on bone homeostasis, in 33 consecutive recruited untreated CS patients and 33 age-, sex- and body mass index-matched healthy controls. METHODS: Cytokine levels were measured by enzyme immunoassay and bone mass by dual-energy X-ray absorptiometry. RESULTS: Our main findings were (i) interleukin (IL)-8 and IL-18 levels were significantly increased in CS patients compared with controls. (ii) Levels of both IL-8 and IL-18 were positively correlated to serum cortisol. (iii) For serum levels of the 'classical' resorptive cytokines, i.e. IL-6 and tumor necrosis factor alpha, no significant differences were found between CS patients and controls. (iv) Raised IL-18 levels were correlated with decreased osteocalcin levels in CS patients. CONCLUSIONS: Our results demonstrated that CS patients have markedly elevated levels of the proinflammatory cytokines IL-8 and IL-18 in spite of high levels of the immunosuppressive hormone cortisol. These cytokines may be involved in the pathogenesis of disturbed bone homeostasis in CS.