Characterization of Calcium Homeostasis in Lithium-Treated Patients Reveals Both Hypercalcaemia and Hypocalcaemia.

INTRODUCTION: Prevalence studies demonstrate that a significant proportion of lithium-treated patients develop hypercalcaemia (3-30%). Lithium-associated hyperparathyroidism (LHPT) is poorly defined, and calcium homeostasis may be affected in a more complicated fashion than purely by elevated PTH secretion. The current study aims to examine in detail calcium homeostasis principally with regard to lithium duration. METHODS: Medical records of 297 lithium-treated patients (193 women, 104 men; median age 58 years) were examined, and information on gender, age, lithium treatment duration and calcium homeostasis was obtained. The median treatment duration with lithium was 16 (1.5-45) years. RESULTS: A total of 8504 calcium values were retrieved. Before initiation of lithium treatment, serum calcium was on average 2.33 mmol/l (2.02-2.60). During the treatment period, 178 patients (60%) remained normocalcaemic, 102 (34%) developed hypercalcaemia or were strongly suspected of LHPT, 17 (6%) had 3 or more intermittent episodes of hypocalcaemia. Forty-one per cent of patients with suspected or confirmed LHPT had low (<4 mmol) 24-h urine calcium levels. The success rate after 33 parathyroidectomies was 35%, hyperplasia being diagnosed in 75% of extirpated glands. CONCLUSIONS: The prevalence of hypercalcaemia during lithium treatment is very high. In addition, hypocalcaemic episodes appear to occur frequently, possibly reflecting a more complicated parathyroid dysfunction than previously known. Long-term surgical results are unsatisfactory. LHPT biochemical profile is different from that of primary hyperparathyroidism and is in some ways similar to familial hypocalciuric hypercalcaemia.

Lithium-Associated Hypercalcemia: Pathophysiology, Prevalence, Management.

BACKGROUND: Lithium-associated hypercalcemia (LAH) is an ill-defined endocrinopathy. The aim of the present study was to determine the prevalence of hypercalcemia in a cohort of bipolar patients (BP) with and without concomitant lithium treatment and to study surgical outcomes for lithium-associated hyperparathyroidism. METHODS: Retrospective data, including laboratory results, surgical outcomes and medications, were collected from 313 BP treated with lithium from two psychiatric outpatient units in central Sweden. In addition, data were collected from 148 BP without lithium and a randomly selected control population of 102 individuals. Logistic regression was used to compare odds of hypercalcemia in these respective populations. RESULTS: The prevalence of lithium-associated hypercalcemia was 26%. Mild hypercalcemia was detected in 87 out of 563 study participants. The odds of hypercalcemia were significantly higher in BP with lithium treatment compared with BP unexposed to lithium (adjusted OR 13.45; 95% CI 3.09, 58.55; p = 0.001). No significant difference was detected between BP without lithium and control population (adjusted OR 2.40; 95% CI 0.38, 15.41; p = 0.355). Seven BP with lithium underwent surgery where an average of two parathyroid glands was removed. Parathyroid hyperplasia was present in four patients (57%) at the initial operation. One patient had persistent disease after the initial operation, and six patients had recurrent disease at follow-up time which was on average 10 years. CONCLUSION: The high prevalence of LAH justifies the regular monitoring of calcium homeostasis, particularly in high-risk groups. If surgery is necessary, bilateral neck exploration should be considered in patients on chronic lithium treatment. Prospective studies are needed.

The prevalence of lithium-associated hyperparathyroidism in a large Swedish population attending psychiatric outpatient units.

OBJECTIVE: This retrospective study determined the prevalence of lithium-associated hyperparathyroidism (LHPT) in 2 geographically defined, equivalent populations in Sweden, with no other selection bias. METHODS: The medical journals of all patients receiving lithium treatment were examined specifically regarding their biochemistry: calcium, parathyroid hormone (PTH), creatinine, and vitamin D. The condition LHPT was defined biochemically. All patient data were noted, and the prevalence of the condition could thereby be calculated. RESULTS: A total of 423 patients were included (251 women and 172 men; 3:2), treated over a mean of 13.5 years (range, 1-46 years), aged 19 to 92. 77 patients (18%) were identified with LHTP whose median serum calcium was 2.55 mmol/L and PTH was 99 ng/L. A further 21% showed tendencies toward hypercalcemia. Forty-three percent had vitamin D insufficiency. Five patients (approximately 1%) had undergone parathyroidectomy. CONCLUSION: The prevalence of LHPT is high and often goes undetected. Vitamin D insufficiency is common as is polypharmacy. Surgery, for unclear reasons, has not been performed extensively, possibly because of limited knowledge of the underlying pathophysiology or surgery's significance. We present standard recommendations on patient management and suggest continual, specific follow-up including the monitoring of calcium, PTH, and vitamin D at least annually. Surgery should be considered with intention to improve psychiatric well-being and provide multiorgan protection.

Incidence and risk factors for injuries to the recurrent laryngeal nerve during neck surgery in the moderate-volume setting.

PURPOSE: Total lobectomy is currently recommended also in benign thyroid disease in order to reduce the risk of goitre recurrence, an approach claimed not to increase post-operative morbidity. The aim of the study was to analyse risk factors for recurrent laryngeal nerve (RLN) palsy during neck surgery, with particular interest in complications after total lobectomy and subtotal resection, respectively. METHODS: All consecutive patients operated for thyroid and parathyroid diseases at one institution between 1984 and 2011 were prospectively recorded, and 1,322 patients were included. Patients with permanent post-operative RLN palsy were re-examined in 2011. RESULTS: The risk of permanent RLN palsy after parathyroid surgery was 0.3 %. Patients operated for thyroid cancer had a 5.9 % risk of permanent nerve injury, higher than that of patients with benign thyroid disease (1.4 %; P = 0.029). Independent risk factors for RLN paralysis after benign thyroid surgery were intrathoracic goitre (odds ratio (OR), 3.57; 95 % confidence interval, 1.70-7.48), ipsilateral redo-surgery (OR, 3.64; 1.00-13.28) and total lobectomy (OR, 2.41; 1.05-5.55). At long-time follow-up (median, 10 years), 7 of 12 patients with permanent RLN palsy still suffered moderate or severe symptoms. CONCLUSIONS: RLN paralysis is an infrequent complication after neck surgery, but with major negative impact on patients' well-being when permanent. Hemithyroidectomy/total thyroidectomy is increasingly preferred over subtotal resection in multinodular goitre. This is supported by an increased risk of RLN injury during redo-surgery for recurrency but should be carefully weighed against individual risk factors for nerve palsy, including surgical experience and volume.

Health-related quality of life in family members of patients with an advanced cancer diagnosis: a one-year prospective study.

BACKGROUND: Receiving a cancer diagnosis affects family members as well as the person diagnosed. Family members often provide support for the sick person in daily life out of duty and love, and may not always think of their own vulnerability to illness. To individualise support for them, family members who are most at risk for becoming ill must be identified.The aim of this study was to investigate health-related quality of life (HRQOL) in family members of patients with advanced lung or gastrointestinal cancer 3 to 15 months after diagnosis. METHODS: Data on mental and physical dimensions of HRQOL were collected from family members of these patients in this prospective quantitative study. Five assessments using the Short Form 36 Health Survey (SF-36) and EuroQol (EQ-5D) were conducted during a 1-year period starting 3 months after diagnosis. Thirty-six family members completed the study, i.e. participated in all five data collections. RESULTS: No statistically significant changes in physical or mental HRQOL within the study group appeared over the 1-year follow-up. Compared with norm-based scores, family members had significantly poorer mental HRQOL scores throughout the year as measured by the SF-36. Family members also scored statistically significantly worse on the EQ-5D VAS in all five assessments compared to the norm-based score. Findings showed that older family members and partners were at higher risk for decreased physical HRQOL throughout the 1-year period, and younger family members were at higher risk for poorer mental HRQOL. CONCLUSIONS: It is well known that ill health is associated with poor HRQOL. By identifying family members with poor HRQOL, those at risk of ill health can be identified and supported. Future large-scale research that verifies our findings is needed before making recommendations for individualised support and creating interventions best tailored to family members at risk for illness.

Alternating from subtotal thyroid resection to total thyroidectomy in the treatment of Graves' disease prevents recurrences but increases the frequency of permanent hypoparathyroidism.

PURPOSE: This study aims to compare the results of three different surgical techniques in the treatment of Graves' disease. METHODS: All patients operated on due to Graves' disease at a single institution between 1985 and 2009 were followed up for a median time of 152 months. The same endocrine surgeon operated altogether 265 patients; 111 with bilateral subtotal thyroid resection, 65 with lobectomy + unilateral subtotal resection (Dunhill's operation) and 99 with total thyroidectomy. RESULTS: Recurrence of thyreotoxicosis was seen in 11 (9.9%) patients operated on with bilateral thyroid resection, in two (3.1%) of those operated on with Dunhill's method and in none treated with total thyroidectomy. Permanent hypoparathyroidism was observed in 6% of the patients with total thyroidectomy, in 0.9% of those operated with bilateral subtotal resection and in none of the patients with Dunhill's procedure (p < 0.001). The frequency of permanent paresis of one recurrent laryngeal nerve was 2%, 0% and 1.5%, respectively, in the three different groups. At follow-up, thyroxine supplementation therapy was given to 81 (73%) of the patients treated with bilateral subtotal resection, to 58 (89%) of those treated with Dunhill's operation and to all of those treated with total thyroidectomy. CONCLUSIONS: It is concluded that surgical treatment of Graves' disease with Dunhill's procedure, leaving a remnant of 1-2 g, seems to minimize the risks of both recurrences and permanent hypoparathyroidism.

Cocaine- and amphetamine-regulated transcript in neuroendocrine tumors.

BACKGROUND/AIMS: Cocaine- and amphetamine-regulated transcript (CART) is an anorexigenic regulatory peptide highly expressed in the brain's appetite control centers, but also in peripheral neurons and in endocrine cells in the adrenal medulla, thyroid, pancreatic islets, and in the gastrointestinal tract. Plasma levels of CART were recently shown to be elevated in patients with neuroendocrine tumors (NETs), but the cellular sources of CART in NETs have remained unknown. The aim of the study was to establish whether CART is expressed in various types of NETs and, if so, to examine the frequency, distribution and phenotype of CART-expressing cells. METHODS: Tumor specimens from 133 NETs originating in the stomach, ileum, rectum, pancreas and thyroid were examined with immunohistochemistry and in situ hybridization. The expression of CART was quantified and the CART-expressing cells were phenotyped by double staining for established markers and hormones. RESULTS: CART-expressing tumor cells were found in the majority of the examined NETs. The expression pattern of CART was highly heterogeneous not only between tumors, but also within individual tumors. In 14% of the NETs, CART was found in a major population of the tumor cells. CONCLUSION: CART is produced in the majority of NETs, regardless of tumor origin. This likely explains the elevated levels of circulating CART in certain NETs patients, as recently described. CART could therefore prove to be a useful tool in the diagnostics of NETs not only in blood samples, but also in histopathological specimens.

First report on metastasizing small bowel carcinoids in first-degree relatives in three generations.

BACKGROUND/AIMS: There is an established association between the multiple endocrine neoplasia type 1 (MEN 1) syndrome and foregut carcinoids. Some registry studies also indicate that offspring to carcinoid patients run an increased risk of developing a carcinoid tumor themselves. However, there are only scattered reports of gastrointestinal carcinoids in two generations. The aim of this study was to describe the clinical characteristics as well as the histopathological, immunohistochemical (IHC) and genetic data of metastasizing ileal carcinoids in three consecutive first-degree relatives. METHODS: The histopathological and IHC analyses were performed on newly cut sections of the tumor specimens and included growth pattern, proliferation index (Ki-67) as well as expression of established neuroendocrine markers and recently introduced cocaine-amphetamine-regulated transcript (CART). The genetic analyses were focused on establishing whether a connection with the MEN 1 syndrome existed in this family, by means of mutation screening using polymerase chain reaction, multiple ligation-dependent probe amplification, and genotyping using fluorescent-labeled microsatellite markers. RESULTS: Histopathology and IHC revealed that the tumors were virtually identical, with only minor differences in proliferation index and expression of CART. Genetic analyses indicated that the inheritance of the small bowel carcinoids in the family was not linked to the MEN1 gene. CONCLUSION: Metastasizing small bowel carcinoids have been found in first-degree relatives in three consecutive generations. All three tumors were very similar when characterized by histopathology and IHC. Based on clinical findings and genetic analyses, it seems unlikely, although not completely excluded, that inheritance was linked to the MEN 1 syndrome.

Differentiated thyroid cancer in a Swedish county--long-term results and quality of life.

BACKGROUND: There is still no complete agreement about the proper treatment of differentiated thyroid cancer (DTC). MATERIAL AND METHODS: All patients (n=130) with DTC in a defined population, treated with surgery between 1985 and 1999, were carefully followed up (median 13.1 years). Fifty three were operated with subtotal and 77 with total thyroidectomy. Twenty seven percent of the patients in the subtotal group and 56% of those in the total thyroidectomy group had postoperative radioiodine ablation. Thirty nine patients had papillary cancers incidentally detected during surgery for benign disorders (median size 7 (1-30) mm). Living patients answered the Swedish version of the SF-36 health survey. RESULTS: Eleven of 106 patients considered tumour-free after primary surgery developed recurrences during follow-up. Fifteen patients (12%) died from DTC but only one within stage I-II (1.2%). No patient below 50 years of age at diagnosis died from DTC. Only three of 29 patients with isolated loco-regional spreading of their disease at the time of diagnosis have died from thyroid cancer. There was no statistically significant difference in the 10 year cancer-specific survival rate between those operated with subtotal or total thyroidectomy--irrespective of stage. Survival rate was significantly better for papillary than for follicular cancer. Mental and physical quality of life among patients treated for DTC were similar to the healthy Swedish population. CONCLUSIONS: Patients with DTC stage I-II (according to TNM) or low-risk (according to AMES) have an excellent prognosis. Treatment as well as follow-up should not be exaggerated.

Epidemiology of small bowel carcinoids in a defined population.

BACKGROUND: This retrospective study describes the epidemiology of small bowel carcinoids in a geographically defined population, with no other selection bias. METHODS: All patients (n = 145) resident in Jönköping County when diagnosed with carcinoid in the jejunum or ileum from 1960 to 2005 were included. Medical records were reviewed in detail, and tumor specimens were histopathologically and immunohistochemically reexamined when required (n = 44). RESULTS: The annual age-adjusted incidence of small bowel carcinoids was 1.12 (95% confidence interval 0.95-1.31) per 100,000 persons. Median age at diagnosis was 69 years. The predominating presenting symptom was uncharacteristic abdominal pain (50%), whereas a smaller number suffered from typical flushes (13%). Surprisingly, 14% presented with overt gastrointestinal hemorrhage. Most of the patients diagnosed based on their symptoms had metastases at diagnosis (44% regional, 40% distant). Metastasized tumors by definition belong to World Health Organization (WHO) histopathologic group 2; and when reexamined, most (83%) of the localized tumors were also found to belong to WHO group 2. CONCLUSIONS: In comparison to previous reports, a higher age-adjusted incidence of small bowel carcinoids was observed, and the patients were clearly older at the time of diagnosis. Even with metastatic disease, the presenting symptoms were usually uncharacteristic, and the carcinoid syndrome was infrequently seen.

Prospective evaluation of symptom responses to successful operation for mild-moderate primary hyperparathyroidism.

BACKGROUND: Parathyroidectomy is claimed to strongly improve the hypercalcemic symptoms in patients with primary hyperparathyroidism (HPT). The object of this study was to register the patients own experience of symptom changes in response to successful parathyroid surgery. METHODS: Material one. 44 HPT patients filled in a questionnaire consisting of 8 visual analogue scales referring to "typical" hypercalcemic symptoms before as well as 2 and 12 months after neck surgery. Their results were compared with those obtained from an age- and sex-matched group of patients undergoing surgery for non-toxic thyroid disease. Material two. 25 elderly women with mild-moderate HPT were followed more closely up to 3 years after neck surgery with the same type of questionnaire. RESULTS: HPT patients expressed significantly more of fatigue, muscular weakness, impaired memory, thirst and polyuria than patients with non-toxic thyroid disorders. These differences were eliminated 2 months after surgery. The pattern of response to parathyroidectomy was similar for most symptoms: an impressive improvement after 2 months and then a gradual return towards the preoperative value. However, the response was still significant for fatigue, weakness, thirst, polyuria and inactivity after 1 year. The effect of normalization of serum calcium on symptom scoring varied considerably between different individuals and also between different symptoms in the same individual. The elderly women responded in a similar biphasic way but their improvements were less pronounced. CONCLUSIONS: HPT patients experience significant improvements of most "hypercalcemic" symtoms after successful parathyroidectomy, but the effects are transient and vary considerably between different individuals.

Anastrozole can cause severe hypercalcaemia mimicking primary hyperparathyroidism.

A 65-year-old woman on anastrozole treatment because of a recurrent breast cancer developed hypercalcaemia and increased parathyroid hormone (PTH) levels 2½ years after start of the treatment. A diagnosis of hyperparathyroidism was suspected and the patient underwent neck surgery, but only normal parathyroid glands were found. Postoperatively, the hypercalcaemia as well as the PTH level continued to rise, and 9 months after exploration of the parathyroids her calcium level was extremely high (adjusted serum calcium = 3.39 mmol/l). Anastrozole was then withheld, and within 2 weeks the severe hypercalcaemic state turned into hypocalcaemia. A month later, anastrozole treatment was started again, and after 6 weeks her calcium and PTH values had returned to extremely high levels. After withdrawal of anastrozole, calcium and PTH concentrations again fell toward normal values. The urinary excretion of calcium was very low during anastrozole treatment and high after cessation of the drug. The mechanism(s) by which anastrozole can cause hypercalcaemia are unknown. However, it might be hypothesised that anastrozole, directly or indirectly, interferes with the calcium-sensing receptors known to be present on the cell surface of both parathyroid and renal tubular cells.

A Conservative Approach Is Reasonable in Patients with Non-Toxic Goitre: Results from an Observational Study during 30 Years.

BACKGROUND: There is a lack of consensus in Europe regarding the management of patients with benign goitre. The object of this study was to find out the long-term results of recommending to patients with clinically and cytologically benign non-toxic goitres not to be operated. METHODS: 980 patients were initially referred for surgical evaluation due to non-toxic goitre, 508 of whom underwent directly thyroidectomy. The remaining 473 patients (median age 56 years) were not operated and followed prospectively for a median period of 145 months. RESULTS: During follow-up, 38% of the 473 patients were re-referred to the surgeon for a new evaluation due to different complaints, mainly growth of the goitre and/or worsening of local symptoms. 102 of the 473 patients (22%) had surgery and 27 (5.7%) developed thyrotoxicosis. 14 patients (3%) were diagnosed with thyroid carcinoma, 4 (0.46%) of whom (all elderly women) died of the disease. CONCLUSIONS: In patients with non-toxic goitre in whom surgery is not deemed necessary at initial evaluation, a conservative approach is reasonable. There is, however, a small risk for the development of aggressive carcinomas, and a fourth of the patients are operated at a median follow-up of 12 years.

Overrepresentation of HLA-DQ2 in small intestinal neuroendocrine tumor patients.

PURPOSE: To investigate whether celiac disease risk haplotypes HLA-DQ2 and DQ8 also increase the risk for developing small intestinal neuroendocrine tumor (SI-NET). METHODS: Thirty-five patients with serotonin-producing jejunal and ileal SI-NET were examined with HLA-DQ genotyping and serology for IgA anti-tissue transglutaminase (tTG) antibodies. RESULTS: Twenty-one patients (60 %) carried HLA-DQ2 or DQ8, twice the frequency of the general population (P < 0.001). In particular DQ2 was overrepresented (P = 0.013). Gender, age, disease stage, histopathological grade, or multifocality of primary tumor did not differ between patients with DQ2 or DQ8 and patients with other HLA-DQ haplotypes. No patient in the study was diagnosed with celiac disease (latent or symptomatic) as anti-tTG antibodies were negative in all 35. CONCLUSION: HLA-DQ haplotypes associated with celiac disease are overrepresented also in patients with SI-NET, in particular HLA-DQ2.