Cardiovascular and Cerebrovascular Events After Parathyroidectomy in Patients on Renal Replacement Therapy.

BACKGROUND: A majority of patients with end-stage renal disease suffer from secondary hyperparathyroidism, which is associated with osteoporosis and cardiovascular disease. Parathyroidectomy (PTX) is often necessary despite medical treatment. However, the effect of PTX on cardio- and cerebrovascular events (CVE) remains unclear. Data on the effect of PTX from population-based studies are scarce. Some studies have shown decreased incidence of CVE after PTX. The aim of this study was to evaluate the effect of PTX on risk of CVE in patients on renal replacement therapy. METHODS: We performed a nested case-control study within the Swedish Renal Registry (SRR) by matching PTX patients on dialysis or with functioning renal allograft with up to five non-PTX controls for age, sex and underlying renal disease. To calculate time to CVE, i.e., myocardial infarct, stroke and transient ischemic attack, control patients were assigned the calendar date (d) of the PTX of the case patient. Crude and adjusted proportional hazards regressions with random effect (frailty) were used to calculate hazard ratios for CVE. RESULTS: The study cohort included 20,056 patients in the SRR between 1991 and 2009. Among these, 579 patients had undergone PTX, 423 during dialysis and 156 during time with functioning renal allograft. These patients were matched with 1234 dialysis and 736 transplanted non-PTX patients. The adjusted hazard ratio (HR) with 95% confidence interval (CI) of CVE after PTX was 1.24 (1.03-1.49) for dialysis patients compared with non-PTX patients. Corresponding results for patients with renal allograft at d were HR (95% CI) 0.53 (0.34-0.84). CONCLUSIONS: PTX patients on dialysis at d had a higher risk of CVE than patients without PTX. Patients with renal allograft at d on the other had a lower risk after PTX than patients without PTX.

High Ki-67 index in fine needle aspiration cytology of follicular thyroid tumors is associated with increased risk of carcinoma.

PURPOSE: Preoperative distinction of follicular thyroid carcinoma (FTC) from follicular thyroid adenoma (FTA) is a diagnostic challenge. Our aim was to investigate whether the Ki-67 proliferation index in fine needle aspiration material can contribute to the diagnosis of FTC. METHODS: We analyzed retrospectively cytological Ki-67 index determined in routine clinical setting and clinical data for 61 patients with FTC, 158 patients with FTA and 15 patients with follicular tumor of uncertain malignant potential (FT-UMP) surgically treated and diagnosed by histopathology at Karolinska University Hospital 2006-2017 (Cohort A). A previously published cohort of 109 patients with follicular tumors was re-analyzed as well (Cohort B). RESULTS: In Cohort A, patients with FTC had a higher Ki-67 index (p < 0.001), larger tumor size (p < 0.001) and higher age at diagnosis (p = 0.036) compared to patients with FTA or FT-UMP. Hürthle cell differentiation, present in 50 FTA, 20 FTC and 8 FT-UMP, was associated with higher Ki-67 index (p = 0.009). Multivariate analysis of Cohort A identified a high Ki-67 index (odds ratio [OR]: 1.215, p < 0.001) and large tumor size (OR: 1.038, p < 0.001) as independent predictors of FTC. Results remained consistent after exclusion of Hürthle cell tumors and in pooled analysis of Cohort A + B. The area under curve of the Ki-67 index for predicting FTC was 0.722 and a cut-off for Ki-67 index at above 5% resulted in a specificity at 93% and sensitivity at 31%. Subgroup analysis of FTCs in Cohort A showed an association of higher Ki-67 index to extrathyroidal extension (p = 0.001) as well as widely invasive subtype (p = 0.019) based on the WHO 2017 classification. CONCLUSIONS: Pre-operative Ki-67 index may add diagnostic information for a subset of patients with follicular thyroid tumors.

The effect of parathyroidectomy on patient survival in secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism is a common condition in patients with end-stage renal disease and is associated with osteoporosis and cardiovascular disease. Despite improved medical treatment, parathyroidectomy (PTX) is still necessary for many patients on renal replacement therapy. The aim of this study was to evaluate the effect of PTX on patient survival. METHODS: A nested index-referent study was performed within the Swedish Renal Registry (SRR). Patients on maintenance dialysis and transplantation at the time of PTX were analysed separately. The PTX patients in each of these strata were matched for age, sex and underlying renal diseases with up to five referent patients who had not undergone PTX. To calculate survival time and hazard ratios, indexes and referents were assigned the calendar date (d) of the PTX of the index patient. The risk of death after PTX was calculated using crude and adjusted Cox proportional hazards regressions. RESULTS: There were 20 056 patients in the SRR between 1991 and 2009. Of these, 579 (423 on dialysis and 156 with a renal transplant at d) incident patients with PTX were matched with 1234/892 non-PTX patients. The adjusted relative risk of death was a hazard ratio (HR) of 0.80 [95% confidence interval (CI) 0.65-0.99] for dialysis patients at d who had undergone PTX compared with matched patients who had not. Corresponding results for the patients with a renal allograft at d were an HR of 1.10 (95% CI 0.71-1.70). CONCLUSIONS: PTX was associated with improved survival in patients on maintenance dialysis but not in patients with renal allograft.

Temporal trends and risk factors for parathyroidectomy in the Swedish dialysis and transplant population - a nationwide, population-based study 1991 - 2009.

BACKGROUND: Many patients on renal replacement therapy (RRT) require parathyroidectomy (PTX). Trends and current rates of PTX on a national level are not known. Furthermore, it is not completely clear which factors influence rates of PTX. Thus, our aim was to investigate the incidence, regional distribution and factors associated with PTX as well as possible temporal changes, in the Swedish RRT population. METHODS: From the Swedish Renal Registry we extracted data on 20 015 patients on RRT between 1991 and 2009. In these, 679 incident PTX (3.4%) were identified by linkage with the National Inpatient Registry, and the Scandinavian Quality Registry for Thyroid Parathyroid and Adrenal Surgery. Poisson models were used to estimate rates per calendar year, adjusted for risk factors such as gender, age, time with renal transplant, and underlying cause of renal disease. RESULTS: The PTX rate was 8.8/1 000 person-years. There was a significant increase 2001-2004 after which the rate fell, as compared with year 2000. Female gender, non-diabetic cause of renal disease and age between 40-55 were all associated with an increased frequency of PTX. CONCLUSION: The rise in PTX rates after year 2000 might reflect increasing awareness of the potential benefits of PTX. The introduction of calcimimetics and paricalcitol might explain the decreased rate after 2005.

Results of surgery for sporadic primary hyperparathyroidism in patients with preoperatively negative sestamibi scintigraphy and ultrasound.

PURPOSE: The purpose of this study is to investigate the results of first-time surgery for sporadic primary hyperparathyroidism (pHPT) in patients with preoperatively negative sestamibi scintigraphy and ultrasound. METHODS: Data were gathered prospectively in a multicenter database for quality control in parathyroid surgery. Between 2004 and 2008, 3,158 patients underwent first-time surgery for sporadic pHPT. A total of 984 patients were subjected to preoperative localization with ultrasound and sestamibi scintigraphy, and in 173 patients, both investigations were negative. Intraoperative findings and early outcome are reported. RESULTS: One hundred and fifty-five of 173 patients underwent bilateral neck exploration. The median weight of excised parathyroid tissue was 350 mg. In 23 patients (13.3%), the exploration was negative. A total of 112 patients (64.7%) had a histological diagnosis of parathyroid adenoma and 38 patients (22%) had multiglandular disease. Six weeks after operation, 164 patients were available for analysis, and 30 patients (18%) had persistent pHPT. The risk for persistent pHPT increased for patients with few intraoperatively identified (p = 0.001) and excised (p = 0.024) parathyroid glands. Patients operated with intraoperative parathyroid hormone (iOPTH) had lower risk for persistent pHPT 7/79 (9%) compared with 23/85 patients (27%) operated without iOPTH (p = 0.003). CONCLUSIONS: Negative localization with sestamibi and ultrasound in pHPT infers a highly selected patient population with small parathyroid adenomas, an alarmingly high rate of negative exploration, and an increased risk for persistent disease. The use of iOPTH influences cure rate favorably.

Impact of modern techniques on short-term outcome after surgery for primary hyperparathyroidism: a multicenter study comprising 2,708 patients.

PURPOSE: Preoperative localization procedures and the use of intraoperative parathyroidism (iOPTH) have led to a shift of paradigm from bilateral neck exploration to focused parathyroidectomy in primary hyperparathyroidism (pHPT). However, only a small number of randomized trials from specialized centers have been published. The main purpose of the study was to analyze the impact of localization procedures and iOPTH on short-term outcome after pHPT surgery in a multi-institutional setting. METHODS: An audit for quality assurance in pHPT surgery was performed in 23 Scandinavian departments in 2004-2008. Data were gathered prospectively in a database. Two thousand seven hundred and eight patients were registered and 78% were females. The median serum calcium level was 2.79 mmol/l. RESULTS: Localization procedures were performed in 1,831 patients (68%), (sestamibi in 54% and ultrasound in 41%) and iOPTH in 792 operations (29%). Bilateral exploration was performed in 61%, focused parathyroidectomy in 17%, and unilateral exploration in 22%. Histology showed parathyroid adenoma in 82%, with the median weight of 0.6 g. The alleviation of hypercalcemia at the first follow-up was 93% (94% for primary operation). In the multivariate logistic regression analysis, iOPTH increased cure rate (OR 1.70, 95% CI 1.14-2.53, p = 0.0092). The risk for postoperative medically treated hypocalcemia decreased with the use of localization procedures (OR 0.56, 95% CI 0.43-0.78, p = 0.0004) and iOPTH (OR 0.56, 95% CI 0.39-0.90, p = 0.0015). CONCLUSIONS: Localization procedures and iOPTH decreased the risk for hypocalcemia after pHPT surgery. Additionally, iOPTH influenced short-term cure rate favorably.

Scandinavian Quality Register for Thyroid and Parathyroid Surgery: audit of surgery for primary hyperparathyroidism.

BACKGROUND AND AIM: Scandinavian Quality Register for Thyroid and Parathyroid Surgery is an on-line web-based database with the aim to improve the quality of thyroid and parathyroid surgery. Preliminary data from surgery for primary hyperparathyroidism are reported here. MATERIALS AND METHODS: Fifteen departments registered 806 operations, with 639 women (79.7%) and 167 men. The median age of the patients was 62 years. RESULTS: Approximately 95.4% of the patients had sporadic disease and first time operation was performed in 93.8% of the patients. Localization examinations were performed in 524 patients (65%); sestamibi scintigraphy in 413 patients, with a true positive adenoma localization in 64.4% and ultrasound in 293 patients with adenoma localization in 61.1%. Bilateral neck exploration was performed in 66.8%, unilateral exploration in 16.1%, and focused minimal invasive surgery in 17.1%. In 301 patients planned for limited parathyroid exploration, conversion to bilateral neck surgery occurred in 11%. The cure rate, based on short follow-up, was 91.9%. Postoperative hypocalcemia occurred in 11.4% of the patients, and was associated with reoperation, concomitant thyroid operation, and the weight of excised parathyroid tissue. CONCLUSION: Localization examinations are performed in 2/3 of the patients, but limited neck exploration was performed in only approximately 1/3 of the operations. The cure rate was lower and postoperative hypocalcemia was more frequent than expected.

Human sterol 12a-hydroxylase (CYP8B1) is mainly expressed in hepatocytes in a homogenous pattern.

The liver is the only organ where the complete synthesis of bile acids takes place. The present study was undertaken to investigate whether regional differences exist within the individual human hepatic lobuli regarding the pattern of expression of sterol 12alpha-hydroxylase (CYP8B1), a key enzyme in bile acid synthesis. A specific anti-human CYP8B1 peptide antiserum was developed and used for Western blotting and hepatic immunostaining of livers from various patients. CYP8B1 in human liver was expressed in the cytoplasm of hepatocytes with an even nonzonal distribution within the liver lobulus. Pericentral expression was confirmed for CYP2E1. A weak staining was noted in cholangiocytes and Kupffer cells. Previous studies on hepatic CYP27A1 and CYP7A1 in rats have shown a zonal expression, primarily in the pericentral region. Our studies indicate a different pattern for CYP8B1 expression in human liver, which was even rather than zonal.

Regulation of hepatic low-density lipoprotein receptor, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and cholesterol 7alpha-hydroxylase mRNAs in human liver.

To characterize the coordinate regulation of cholesterol metabolism in human liver, we simultaneously quantified mRNA levels of cholesterol 7alpha-hydroxylase (CYP7A1), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), and low- density lipoprotein receptors (LDLRs) in liver biopsies from 76 patients undergoing cholecystectomy. The three transcript levels were not different between untreated gallstone and gallstone-free patients and not significantly altered by 10-d exclusion of dietary cholesterol. Treatment with chenodeoxycholic acid suppressed CYP7A1 and to a lesser extent HMGR mRNA levels. Cholestyramine treatment increased CYP7A1, but also HMGR and LDLR mRNA, and statins only increased HMGR mRNA. Resin + statin treatment increased all mRNA species. In untreated patients, the mRNA levels of HMGR and LDLR were more strongly correlated (r = +0.60) than those of CYP7A1 and HMGR (r = +0.49) or CYP7A1 and LDLR (r = +0.21). In the treated patients, in whom bile acid synthesis was suppressed or stimulated, mRNA levels of CYP7A1 and HMGR (r = +0.84) as well as CYP7A1 and LDLR (r = +0.62) were more strongly correlated than those of HMGR and LDLR (r = +0.59). The coordinate control of HMGR and LDLR mRNA levels reflects their common regulation by shared transcriptional activation. In contrast, following changes in bile acid flux through the liver, CYP7A1 gene expression becomes a strong modulator of hepatic cholesterol metabolism.