A clinical prediction score using age at diagnosis and saline infusion test parameters can predict aldosterone-producing adenoma from idiopathic adrenal hyperplasia.

PURPOSE: Accurate subtyping of the primary aldosteronism into aldosterone-producing adenoma (APA) and idiopathic adrenal hyperplasia (IAH) is important to direct for specific treatment modalities. The objective of the study was to compare the clinical and biochemical parameters of APA and IAH patients to derive a Clinical Prediction Score reliably predicting APA from IAH. METHODS: This was a retrospective multi-centre study recruiting 38 APA patients and 42 IAH patients from four major hospitals in Hong Kong using database from Surgical Outcomes Monitoring and Improvement Programme and Clinical Data Analysis and Reporting System. Their clinical and biochemical parameters were evaluated. RESULTS: Patients in APA group were younger than IAH group (mean age 48.6 ± 9.2 vs. 57.1 ± 7.3 years old, p < 0.001), had more suppressed renin before saline infusion in saline infusion test (SIT) (median 0.19 [IQR 0.15-0.37] vs. 0.39 [IQR 0.19-0.69] ng/mL/h, p = 0.01), and higher aldosterone level after saline infusion in SIT (median 674 [IQR 498-1000] vs. 327 [IQR 242-483] pmol/L, p < 0.001). A clinical prediction score using three parameters was devised, comprising age at diagnosis < 50 years, PRA before saline infusion in SIT ≤ 0.26 ng/mL/h, and aldosterone level after saline infusion in SIT ≥ 424 pmol/L. A score of 2 would predict APA with a sensitivity of 84.2% and specificity of 88.1%, and a score of 3 would predict APA with a sensitivity of 31.6% and specificity of 100%. CONCLUSIONS: Clinical Prediction Score based on the combination of age at diagnosis, PRA, and aldosterone level in the saline infusion tests could reliably predict APA from IAH.

Genetics of Apparently Sporadic Pheochromocytoma and Paraganglioma in a Chinese Population.

Identification of germline mutation in patients with apparently sporadic pheochromocytomas and paragangliomas is crucial. Clinical indicators, which include young age, bilateral or multifocal, extra-adrenal, malignant, or recurrent tumors, predict the likelihood of harboring germline mutation in Caucasian subjects. However, data on the prevalence of germline mutation, as well as the applicability of these clinical indicators in Chinese, are lacking. We conducted a cross-sectional study at a single endocrine tertiary referral center in Hong Kong. Subjects with pheochromocytomas and paragangliomas were evaluated for the presence of germline mutations involving 10 susceptibility genes, which included NF1, RET, VHL, SDHA, SDHB, SDHC, SDHD, TMEM 127, MAX, and FH genes. Clinical indicators were assessed for their association with the presence of germline mutations. Germline mutations, 2 being novel, were found in 24.4% of the 41 Chinese subjects recruited and 11.4% among those with apparently sporadic presentation. The increasing number of the afore-mentioned clinical indicators significantly correlated with the likelihood of harboring germline mutation in one of the 10 susceptibility genes. (r=0.757, p=0.026). The presence of 2 or more clinical indicators should prompt genetic testing for germline mutations in Chinese subjects. In conclusion, our study confirmed that a significant proportion of Chinese subjects with apparently sporadic pheochromocytoma and paraganglioma harbored germline mutations and these clinical indicators identified from Caucasians series were also applicable in Chinese subjects. This information will be of clinical relevance in the design of appropriate genetic screening strategies in Chinese populations.

A middle-aged man with increasing body fat.

A 51-year-old man was referred for evaluation of gradual increase in body fat over bilateral arms, chest and abdomen for 6 months. He was a non-smoker and he drank at least four bottles of beer daily since the age of 18. There was no significant past medical history or any family history of obesity or endocrine diseases. Physical examination showed localized large bulk of fat over the neck, both arms and mammary regions, abdomen, and back (Figs and ). The lower limbs and buttock were relatively spared. There was telangiectasia over the face and chest wall, but no palmar erythema nor finger clubbing. The liver span was normal, and the spleen tip was palpated 2 cm below the costal margin. Examination of the cardiovascular, respiratory and neurological system was normal. [Figure: see text] [Figure: see text] Blood tests showed thrombocytopenia (platelet 140 × 10(9) L(-1) [normal: 170-380 × 10(9) L(-1) ]) and liver function derangement (bilirubin 27 µmol L(-1) , ALP 298 U L(-1) , ALT 127 U L(-1) , AST 165 U L(-1) , GGT 1353 U L(-1) , albumin 33 g L(-1) and globulin 42 g L(-1) ). His clotting profile and renal functions were normal. His hepatitis B surface antigen was positive, but his HBV DNA was <60 copies per mL. Fasting glucose was 5.0 mmol L(-1) . HbA1c was 5.6%. His lipid profile was satisfactory with total cholesterol of 2.9 mmol L(-1) , triglycerides 1.0 mmol L(-1) , HDL-C 1.37 mmol L(-1) and LDL-C 1.1 mmol L(-1) . Ultrasound of the abdomen showed normal-sized liver with coarsened liver parenchymal echogenicity. The spleen was enlarged to 14 cm. This middle-aged man suffered from multiple symmetric lipomatosis and alcoholic liver disease. Dual-energy X-ray showed 1746 gm (40.1%), 1498 gm (32.8%) and 8322 gm (26.8%) fat over the left arm, right arm and trunk, respectively. The legs were unaffected with 1703 gm (19.4%) and 1627 gm (17.7%) fat over the left and right sides, respectively. The patient was advised to stop drinking and he declined surgical treatment.

Impact of serum amyloid A on cellular cholesterol efflux to serum in type 2 diabetes mellitus.

OBJECTIVE: Serum amyloid A (SAA) is an acute phase response protein and has apolipoprotein properties. Since type 2 diabetes is associated with chronic subclinical inflammation, the objective of this study is to investigate the changes in SAA level in type 2 diabetic patients and to evaluate the relationship between SAA and the capacity of serum to induce cellular cholesterol efflux via the two known cholesterol transporters, scavenger receptor class B type I (SR-BI) and ATP-binding cassette transporter G1 (ABCG1). METHODS: 264 patients with type 2 diabetes mellitus (42% with normoalbuminuria, 30% microalbuminuria, and 28% proteinuria) and 275 non-diabetic controls were recruited. SAA was measured by ELISA. SR-BI and ABCG1-mediated cholesterol efflux to serum were determined by measuring the transfer of [(3)H]cholesterol from Fu5AH rat hepatoma cells expressing SR-BI and from human ABCG1-transfected CHO-K1 cells to the medium containing the tested serum respectively. RESULTS: SAA was significantly increased in diabetic patients with incipient or overt nephropathy. Both SR-BI and ABCG1-mediated cholesterol efflux to serum were significantly impaired in all three groups of diabetic patients (p < 0.01). SAA inversely correlated with SR-BI-mediated cholesterol efflux (r = -0.36, p < 0.01) but did not correlate with ABCG1-mediated cholesterol efflux. Stepwise linear regression analysis showed that HDL, the presence or absence of diabetes, and log(SAA) were significant independent determinants of SR-BI-mediated cholesterol efflux to serum. CONCLUSION: SAA was increased in type 2 diabetic patients with incipient or overt nephropathy, and SAA was associated with impairment of SR-BI-mediated cholesterol efflux to serum.

Effect of insulin on the soluble receptor for advanced glycation end products (RAGE).

AIMS: The receptor for advanced glycation end products (RAGE) plays an important role in the pathogenesis of diabetic complications. RAGE transcript splicing generates a number of isoforms, including a full-length membrane-bound receptor and a soluble isoform, endogenous secretory RAGE (esRAGE). Soluble forms of the receptor (sRAGE) can also be formed by ectodomain shedding of the membrane-associated receptor. We have evaluated serum levels of sRAGE and esRAGE in Chinese patients with Type 1 diabetes and investigated the effect of insulin on the generation of esRAGE and sRAGE in vitro. METHODS: Serum sRAGE and esRAGE were measured by ELISA. The in vitro effect of insulin was investigated by incubating THP-1 macrophages with insulin and RAGE isoforms in cell lysate and conditioned media determined. RESULTS: In patients with diabetes, both serum esRAGE and sRAGE were significantly higher than in age-matched healthy subjects without diabetes. In vitro, insulin increased esRAGE and total RAGE isoform expression in cell lysate on a western blot, and reverse transcription-polymerase chain reaction showed an increase in esRAGE and full-length RAGE mRNA. This was accompanied by an increase in esRAGE and sRAGE in cell conditioned media. Pretreatment of THP-1 cells with a general metalloproteinase inhibitor GM6001 significantly reduced the production of sRAGE, suggesting that insulin also increased the cleavage of full-length cell surface RAGE to form sRAGE. CONCLUSIONS: Chinese patients with Type 1 diabetes have higher serum levels of esRAGE and sRAGE. In vitro, insulin not only increases both full-length RAGE and esRAGE expression, but can also stimulate the shedding of sRAGE from the membrane-bound receptor.

Effects of treatment with Sandostatin LAR on small dense LDL and remnant-like lipoproteins in patients with acromegaly.

OBJECTIVE: Acromegalic patients have been shown to have an increase in the concentrations of small dense low-density lipoprotein (LDL) and remnant-like lipoprotein particles (RLP). These lipoproteins are atherogenic and may contribute to the cardiovascular risk of these patients. The aim of this study was to determine whether treatment of acromegaly using Sandostatin LAR could lower these atherogenic lipoproteins. METHODS: Fourteen patients with active acromegaly were recruited and Sandostatin LAR, a long-acting somatostatin analogue, was given every 4 weeks by intramuscular injection for 6 months. Fasting lipids, lipoproteins, lipolytic enzymes were determined at baseline, 12 and 24 weeks after treatment. Small dense LDL was measured using density gradient ultracentrifugation and RLP-cholesterol (RLP-C) by an immunoseparation assay. RESULTS: There was already a marked reduction in GH and IGF-1 by week 8 and, in all subjects, IGF-1 levels within their respective age-specific normal range were achieved. At week 12, plasma triglyceride significantly decreased (P < 0.01) and both HDL2 (P < 0.01) and HDL3 (P < 0.01) subfractions increased. A reduction was seen in small dense LDL concentration (P < 0.05) and RLP-C (P < 0.05). Lipoprotein lipase (LPL) activity increased (P < 0.01) and the magnitude of the increase in LPL activity correlated with the increase in HDL at 3 months (r = 0.55, P < 0.05) but not with the changes in plasma triglyceride, small dense LDL or RLP-C. The improvement in plasma lipids and lipoproteins persisted until the end of the study. CONCLUSION: Sandostatin LAR is effective in the treatment of acromegaly and is associated with favourable changes in plasma lipids and a reduction in small dense LDL and RLP-C.

Multiple endocrine neoplasia type 1 (MEN1): genetic and clinical analysis in the Southern Chinese.

OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is characterized by a triad of neoplasia affecting the parathyroid glands, enteropancreatic endocrine tissue and the anterior pituitary gland. DESIGN: In order to define the prevalence of MEN1 germ-line mutations in Southern Chinese patients with MEN1 syndrome, we performed direct sequencing of the entire open reading frame of the MEN1 gene for 12 index patients and their first-degree relatives. RESULTS: Six patients had familial MEN1 syndrome and six had apparently sporadic disease. Nine different germ-line mutations at the MEN1 gene were identified, including three novel mutations [248-249delTT in exon 2, K559X(AAG --> TAG) in exon 10 and IVS 2nt + 2(G --> T) in intron 2]. All patients with familial MEN1 syndrome were heterozygous carriers of a germ-line mutation and MEN1-related disorders were only evident in their first-degree relatives who also carried the mutation. All patients with an enteropancreatic lesion were mutation carriers and the absence of mutation in three apparently sporadic MEN1 patients with only hyperparathyroidism and pituitary microadenoma might represent the presence of MEN1 phenocopy. CONCLUSIONS: The finding of MEN1 germ-line mutation in all patients with familial MEN1 syndrome suggests that genetic screening should be useful in our population to identify affected individuals within a kindred and allow early detection of MEN1-related tumours.