RESUMO
OBJECTIVE: HbA1C is the "gold standard" parameter to evaluate glycemic control in diabetes; however, its correlation with mean glucose is not always perfect. The objective of this study was to correlate continuous glucose monitoring (CGM)-derived hemoglobin glycation index (HGI) with microvascular complications. METHODS: We conducted a cross-sectional study including permanent users of CGM with type 1 diabetes mellitus or latent autoimmune diabetes of the adult. HGI was estimated, and presence of microvascular complications was compared in subgroups with high or low HGI. A logistic regression analysis to assess the contribution of high HGI to chronic kidney disease (CKD) was performed. RESULTS: In total, 52 participants who were aged 39.7 ± 14.7 years, with 73.1% women and 15.5 years (IQR, 7.5-29 years) since diagnosis, were included; 32.7% recorded diabetic retinopathy, 25% CKD, and 19.2% neuropathy. The median HbA1C was 7.6% (60 mmol/mol) and glucose management indicator (GMI) 7.0% (53 mmol/mol). The average HGI was 0.55% ± 0.66%. The measured HbA1C was higher in the group with high HGI (8.1% [65 mmol/mol] vs 6.9% [52 mmol/mol]; P < .001), whereas GMI (7.0% [53 mmol/mol] vs 7.0% [53 mmol/mol]; P = .495) and mean glucose were similar in both groups (153 mg/dL vs 153 mg/dL; P = .564). In the high HGI group, higher occurrence of CKD (P = .016) and neuropathy were observed (P = .025). High HGI was associated with increased risk of CKD (odds ratio [OR]: 5.05; 95% CI: 1.02-24.8; P = .04) after adjusting for time since diagnosis (OR: 1.09; 95% CI: 1.02-1.16; P = .008). CONCLUSION: High HGI measured by CGM may be a useful marker for increased risk of microvascular diabetic complications.
Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Insuficiência Renal Crônica , Adulto , Humanos , Feminino , Masculino , Diabetes Mellitus Tipo 1/complicações , Hemoglobinas Glicadas , Glicemia , Diabetes Mellitus Tipo 2/complicações , Reação de Maillard , Automonitorização da Glicemia , Estudos Transversais , HemoglobinasRESUMO
BACKGROUND: Familial hypertriglyceridemia (FHTG) is a partially characterized primary dyslipidemia which is frequently confused with other forms hypertriglyceridemia. The aim of this work is to search for specific features that can help physicians recognize this disease. METHODS: This study included 84 FHTG cases, 728 subjects with common mild-to-moderate hypertriglyceridemia (CHTG) and 609 normotriglyceridemic controls. All subjects underwent genetic, clinical and biochemical assessments. A set of 53 single nucleotide polymorphisms (SNPs) previously associated with triglycerides levels, as well as 37 rare variants within the five main genes associated with hypertriglyceridemia (i.e. LPL, APOC2, APOA5, LMF1 and GPIHBP1) were analyzed. A panel of endocrine regulatory proteins associated with triglycerides homeostasis were compared between the FHTG and CHTG groups. RESULTS: Apolipoprotein B, fibroblast growth factor 21(FGF-21), angiopoietin-like proteins 3 (ANGPTL3) and apolipoprotein A-II concentrations, were independent components of a model to detect FHTG compared with CHTG (AUC 0.948, 95%CI 0.901-0.970, 98.5% sensitivity, 92.2% specificity, P < 0.001). The polygenic set of SNPs, accounted for 1.78% of the variance in triglyceride levels in FHTG and 6.73% in CHTG. CONCLUSIONS: The clinical and genetic differences observed between FHTG and CHTG supports the notion that FHTG is a unique entity, distinguishable from other causes of hypertriglyceridemia by the higher concentrations of insulin, FGF-21, ANGPTL3, apo A-II and lower levels of apo B. We propose the inclusion of these parameters as useful markers for differentiating FHTG from other causes of hypertriglyceridemia.
Assuntos
Proteínas Semelhantes a Angiopoietina/genética , Apolipoproteína A-II/genética , Fatores de Crescimento de Fibroblastos/genética , Hiperlipoproteinemia Tipo IV/diagnóstico , Hipertrigliceridemia/diagnóstico , Adulto , Proteína 3 Semelhante a Angiopoietina , Apolipoproteína A-V/genética , Apolipoproteína C-II/genética , Apolipoproteínas B/genética , Diagnóstico Diferencial , Feminino , Humanos , Hiperlipoproteinemia Tipo IV/genética , Hiperlipoproteinemia Tipo IV/metabolismo , Hiperlipoproteinemia Tipo IV/patologia , Hipertrigliceridemia/genética , Hipertrigliceridemia/metabolismo , Hipertrigliceridemia/patologia , Insulina/genética , Lipase Lipoproteica/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Receptores de Lipoproteínas/genética , Triglicerídeos/genéticaRESUMO
SGLT2 inhibitors (SGLT2i) are now the mainstay therapy for both diabetes and heart failure. Post-hoc publications, meta-analysis, and conference presentations of the eight SGLT2i Cardiovascular Outcomes trials (CVOTS) done in diabetic patients constantly echo that this class of drug decreases mortality, reduces cardiovascular events, and prevents heart failure and kidney disease. This review of medical agencies' SGLT2i analysis (FDA and EMA) helps to understand the reality of SGLT2i results in those trials, avoiding to consider observational and statistically undemonstrated endpoints as validated. They also confirmed the unique diuretic mode of action of SGLT2i, promoting osmotic diuresis, and its potential adverse events secondary to hypovolemia and hematocrit increase. They also support the understanding that the beliefs in SGLT2i morbi-mortality benefits are largely overstated mostly based on undemonstrated endpoints. Finally, it is clear that SGLT2i's antidiabetic action, secondary to its renal mode of action, plateaued after a few months and decreased strongly over time, questioning its long-term goal of maintaining diabetic patients' HbA1c below 7%. Also, this effect in patients with renal impairment is quasi null. We think that this review would be very helpful to every physician treating diabetic patients to better balance belief and reality of SGLT2i prescription effects.
Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diuréticos/uso terapêutico , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/complicações , Estudos Observacionais como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversosRESUMO
Corticotroph tumors (CTs) are pituitary neoplasms arising from the Tpit lineage, which may or not express adrenocorticotrophic hormone (ACTH). Functioning CTs cause Cushing's disease (CD), which has high morbidity and mortality due to hypercortisolemia. "Non-functioning" or silent CTs (SCT) and the Crooke's cell subtypes do not cause CD and may be asymptomatic until manifested by compressive symptoms and are more frequently found as macroadenoma. Both tend toward more aggressive behavior, recurrence, and a higher rate of malignant transformation to pituitary carcinoma. Tumorigenesis involves genetic, epigenetic, and post-transcriptional disruption of cell-cycle regulators, which increase cell proliferation, POMC overexpression, ACTH transcription, and/or hypersecretion. Furthermore, functioning CTs develop resistance to glucocorticoid-mediated negative feedback on ACTH secretion, through increased expression of testicular orphan nuclear receptor 4 (TR4), heat-shock protein 90 (HSP90), and loss-of-function mutation of CDK5 and ABL enzyme substrate 1 (CABLES1) gene. Overt autonomous hypercortisolemia is difficult to control, and multiple diagnostic studies and therapeutic modalities are commonly required. Cell-cycle regulation depends mainly on p27, cyclin E, cyclin-dependent kinases (CDKs), and the retinoblastoma protein (Rb)/E2F1 transcription factor complex. Gain-of-function mutations of ubiquitin-specific protease (USP) 8, USP48, and BRAF genes may subsequently cause overexpression of epithelial growth factor receptor (EGFR), and enhance POMC transcription, cell proliferation, and tumor growth. Epigenetic changes through micro RNAs and decreased DNA deacetylation by histone deacetylase type 2 (HDAC2), may also affect tumor growth. All the former mechanisms may become interesting therapeutic targets for CTs, aside from temozolomide, currently used for aggressive tumors. Potential therapeutic agents are EGFR inhibitors such as gefitinib and lapatinib, the purine analog R-roscovitine by dissociation of CDK2/Cyclin E complex, the HSP90 inhibitor silibinin (novobiocin), to reduce resistance to glucocorticoid-mediated negative feedback, and BRAF inhibitors vemurafenib and dabrafenib in BRAF V600E positive tumors. This review summarizes the molecular mechanisms related to CTs tumorigenesis, their diagnostic approach, and provides an update of the potential novel therapies, from the lab bench to the clinical translation.
Assuntos
Adenoma/patologia , Corticotrofos/patologia , Regulação Neoplásica da Expressão Gênica , Recidiva Local de Neoplasia/patologia , Adenoma/metabolismo , Corticotrofos/metabolismo , Humanos , Recidiva Local de Neoplasia/metabolismoRESUMO
OBJECTIVE: Accumulating clinical evidence indicates an inverse relationship between oxidative stress and unconjugated hyperbilirubinemia. This study aimed to compare the prevalence of diabetes microvascular complications in patients with Gilbert syndrome and type 2 diabetes mellitus (T2D). METHODS: A total of 1200 electronic records with T2D were reviewed. From them, 50 patients with Gilbert syndrome (cases [indirect bilirubin ≥1.2 mg/dl without evidence of hemolysis or liver disease]) and 50 controls (T2D without hyperbilirubinemia) were included. Linear and logistic regression models were performed to evaluate the independent association between indirect hyperbilirubinemia with microvascular complications related with T2D. RESULTS: Both case and control group had the same proportion of gender (female = 20 [40 %]) and diabetes duration (14.0 ± 6.5 years) and similar mean of age (60 ± 9.6 and 60 ± 9.2 years, respectively, p = 0.91). The median of unconjugated bilirubin of case and control group was 1.4 (1.2-1.6) vs. 0.4 (0.2-0.6) mg/dl (p < 0.001), respectively. Patients with elevated unconjugated bilirubin had less urine albumin-creatinine ratio compared with control group (8.5 [4.3-23] vs. 80 [8-408] mg/g, p < 0.001), and lower rate of diabetes microvascular complications and metabolic syndrome. After adjustment for BMI, age, HbA1c, blood pressure, triglycerides, and the metabolic syndrome, the lineal regression analysis showed that unconjugated bilirubin protects against microalbuminuria in T2D patients (ß = -414.11, 95 % CI [-747.9, -80.3], p = 0.006. Also, unconjugated hyperbilirubinemia was independently associated with a better glomerular filtration rate (GFR) (ß = 9.87, 95 % CI [1.5, 18.3], P = 0.02). CONCLUSIONS: Patients with Gilbert syndrome and T2D had a lower prevalence of diabetes microvascular complications.
RESUMO
OBJECTIVE: The presence of primary hyperparathyroidism (PHPT) and Klinefelter syndrome (KS) is rare, and its association with KS mosaicism is even rarer. We report an unusual combination of these entities with a mild phenotype of KS. METHODS: The patient was a 44-year-old male with a history of PHPT who had recurrent urolithiasis despite being treated with a successful parathyroidectomy. On examination, he had axillary hair growth, bilateral gynecomastia, a large port-wine stain at the right hemithorax and upper right limb, and genitalia and pubic hair corresponding to Tanner IV classification with small, normal consistency testicles. RESULTS: Laboratory findings were unremarkable except for a slightly elevated luteinizing hormone, which was normal on repeat testing. Because of the picture of unexplained gynecomastia, laboratory findings, and low-volume testis, a diagnosis of KS was considered. Chromosomal analysis revealed a rare 45,X/46,XY/47,XXY/48,XXYY/48,XXXY KS mosaic. CONCLUSIONS: KS phenotypes are largely variable, and their association with PHPT remains to be elucidated.
RESUMO
INTRODUCTION: The role of insulin resistance in diabetic chronic complications among individuals with type 1 diabetes (T1D) has not been clearly defined. The aim of this study was to examine the performance of insulin resistance, evaluated using the estimated glucose disposal rate (eGDR) for the identification of metabolic syndrome (MS) and diabetic chronic complications. METHODS: Cross-sectional study in a tertiary care centre. We included patients of 18 years and older, with at least 6 months of T1D duration. Anthropometric, clinical and biochemical data were collected. RESULTS: Seventy patients, 41 (58.6%) women, with a median age of 36.6 years (range 18-65). Mean age of onset and duration of diabetes was 13.5 ± 6.5 and 23.6 ± 12.2 years, respectively. Twenty-one (30%) patients met the metabolic syndrome (MS) criteria. Patients with MS had lower eGDR compared to patients without (5.17 [3.10-8.65] vs. 8.86 [6.82-9.85] mg/kg/min, respectively, p = .003). Median eGDR in patients with nephropathy, retinopathy and neuropathy compared with those without was 6.75 (4.60-8.20) versus 9.53 (8.57-10.3); p < .001, 6.45 (4.60-7.09) versus 9.50 (8.60-10.14); p < .001, 5.56 (4.51-6.81) versus 9.49 [8.19-10.26] mg/kg/min; p < .001, respectively. The eGDR showed an area under the curve of 0.909, 0.879, 0.897 and 0.836 for the discrimination of MS, retinopathy, neuropathy and nephropathy, respectively. CONCLUSIONS: Patients with T1D diabetic complications have higher insulin resistance. The eGDR discriminates patients with chronic diabetic complications and MS. While more ethnic-specific studies are required, this study suggests the possibility to incorporate eGDR into routine diabetes care.
Assuntos
Complicações do Diabetes , Diabetes Mellitus Tipo 1 , Resistência à Insulina , Adolescente , Adulto , Idoso , Criança , Estudos Transversais , Complicações do Diabetes/complicações , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Glucose/metabolismo , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
CONTEXT: Inherited MYC-associated factor X (MAX) gene pathogenic variants (PVs) increase risk for pheochromocytomas (PCCs) and/or paragangliomas (PGLs) in adults and children. There is little clinical experience with such mutations. OBJECTIVE: This report highlights an important approach. METHODS: Clinical assessment, including blood chemistry, imaging studies, and genetic testing were performed. RESULTS: A 38-year-old Hispanic woman was diagnosed with PCC in 2015, treated with adrenalectomy, and referred to endocrinology clinic. Notably, she presented to her primary care physician 3 years earlier complaining of left flank pain, intermittent diaphoresis, and holocranial severe headache. We confirmed severe hypertension (180/100 mm Hg) over multiple antihypertensive regimens. Biochemical and radiological studies workup revealed high plasma metanephrine of 255 pg/mL (normal range, <â 65 pg/mL) and plasma normetanephrine of 240 pg/mL (normal range, <â 196 pg/mL). A noncontrast computed tomography scan of the abdomen revealed a 4.2â ×â 4.3â ×â 4.9-cm, round-shaped and heterogenous contrast enhancement of the left adrenal gland, and a 2-mm nonobstructive left kidney stone. A presumptive diagnosis of secondary hypertension was made. After pharmacological therapy, laparoscopic left adrenalectomy was performed and confirmed the diagnosis of pheochromocytoma. Based on her age, family history, and a high suspicion for genetic etiology, genetic testing was performed that revealed the presence of a novel likely pathogenic variant involving a splice consensus sequence in the MAX gene, designated c0.64-2Aâ >â G. CONCLUSION: The phenotype of MAX PV-related disease and paraganglioma are highlighted. The novel c0.64-2Aâ >â G mutation is reported here and should be considered in the diagnostic workup of similar cases.
RESUMO
CONTEXT: Cushing's disease (CD) is a life-threating disease, with increased mortality in comparison with the general population. OBJECTIVE: This study aimed to evaluate standardized mortality ratios (SMRs) in CD patients. We also analyzed independent risk factors related to increased mortality. DESIGN: We conducted a longitudinal cohort study in a 3rd level specialty center, from 1979 to 2018, in patients with CD. RESULTS: From 1375 cases with a pathology diagnosis of pituitary adenoma, 191 cases had the confirmed diagnosis of CD (14%). A total of 172 patients completed follow-up, with a mean age at diagnosis of 33â ±â 11 years, female predominance (nâ =â 154, 89.5%), majority of them with microadenoma (nâ =â 136, 79%), and a median follow-up of 7.5 years (2.4-15). Eighteen patients (10.5%) died, 8 of them (44%) were with active CD, 8 (44%) were under remission, and 2 (11%) were under disease control. Estimated all-cause SMRâ =â 3.1, 95% confidence interval (CI) 1.9-4.8, Pâ <â 0.001. Cardiovascular disease was the main cause of death (SMRâ =â 4.2, 1.5-9.3, Pâ =â 0.01). Multivariate Cox regression models adjusted for potential cofounders showed that diabetes (HRâ =â 5.2, IC 95% 1.8-15.4, Pâ =â 0.002), high cortisol levels after 1600 hours at diagnosis (3.4, 2.3-7.0, Pâ =â 0.02), and active CD (7.5, 3.8-17.3, Pâ =â 0.003) significantly increased the risk of mortality. CONCLUSIONS: Main cause of CD mortality was cardiovascular disease. Main risk factors for mortality were uncontrolled diabetes, persistently high cortisol levels after 1600 hours at diagnosis, and active disease at last follow-up.
Assuntos
Hidrocortisona/sangue , Hipersecreção Hipofisária de ACTH/diagnóstico , Hipersecreção Hipofisária de ACTH/mortalidade , Adenoma/sangue , Adenoma/complicações , Adenoma/diagnóstico , Adenoma/mortalidade , Adulto , Ritmo Circadiano , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , História do Século XX , História do Século XXI , Humanos , Estudos Longitudinais , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Mortalidade , Hipersecreção Hipofisária de ACTH/sangue , Hipersecreção Hipofisária de ACTH/etiologia , Neoplasias Hipofisárias/sangue , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/mortalidade , Prognóstico , Adulto JovemRESUMO
Synchronous parathyroid and papillary thyroid carcinoma are extremely rare. To our knowledge, only 15 cases have been reported in the last four decades. We describe a 50-year-old female without significant past medical or family history and no previous trauma presented with left heel pain that prompted her to seek medical attention. Physical examination was notable for a painless nodule at the left thyroid lobe. Laboratory evaluation showed a serum calcium level of 14.3 mg/dL (8.6-10.3 mg/dL) and intact parathyroid hormone level of 1160 pg/mL (12-88 pg/mL). 99Tc-sestamibi dual-phase with single-photon emission computed tomography fused images showed increased uptake at the left-sided inferior parathyroid gland. Neck ultrasound showed a 1.4 cm heterogeneous nodule in the middle-third of the left thyroid gland and a solitary 1.9 cm vascularized and hypoechoic oval nodule that was considered likely to represent a parathyroid adenoma. Due to its clinical context (severe hypercalcemia and very high levels of PTH), parathyroid carcinoma (PC) was suspected although imaging studies were not characteristic. The patient underwent en bloc resection of the parathyroid mass and left thyroid lobe and central neck compartment dissection. Pathology analysis revealed classical papillary thyroid carcinoma of classical subtype and parathyroid carcinoma. Immunohistochemical staining was positive for cyclidin D1 and negative for parafibromin. High clinical suspicion is required for parathyroid carcinoma diagnosis in the presence of very high level of parathyroid hormone, marked hypercalcemia, and the existence of any thyroid nodule should be approached and the coexistence of other carcinomas should be considered.
RESUMO
OBJECTIVE: Liposarcoma is the most common histotype of retroperitoneal sarcomas, representing up to 45% of all cases. We report a rare combination of acromegaly and liposarcoma in the same individual. METHODS: Laboratory and imaging studies including an oral glucose tolerance test, measurements of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), and a computed tomography scan were performed. RESULTS: The patient was a 60-year-old male with a history of acromegaly diagnosed on the basis of elevated IGF-1 at 1,373 ng/mL (age-appropriate reference range is 87 to 225 ng/mL) and macroadenoma treated with transsphenoidal surgery. He presented 8 years later with a history of abdominal distension and weight loss. Physical examination was notable for a right-sided abdominal mass that was tense and non-fluctuant. Two years earlier, he had a post oral glucose tolerance test GH level <0.25 ng/mL and IGF-1 level of 256 ng/mL (age-appropriate reference range is 55 to 206 ng/mL). Pituitary magnetic resonance imaging reported a 3.7 × 2.0-mm left-sided parasagittal lesion. Computed tomography scan showed a 25.0 × 22.0 × 32.3-cm heterogeneous giant mass in the right abdomen corresponding to a liposarcoma causing displacement of kidney, liver, and bowel loops. The patient was treated with a complete en bloc resection of the liposarcoma with the right kidney (45 × 33 × 17 cm) and tumor (9,400 g). Immunohistochemical examination revealed positive IGF-1 and GH staining. The patient suffered postoperative gastrointestinal bleeding that resulted in hemorrhagic shock and died on the 29th postoperative day after a cardiorespiratory arrest. CONCLUSION: Acromegalic patients are at increased risk of developing various types of neoplasms. This is the first documented coexistence of liposarcoma and history of acromegaly.
RESUMO
Ectopic ACTH-secretion causing Cushing's syndrome is unusual and its diagnosis is frequently challenging. The presence of high-molecular-weight precursors throughout pro-opiomelanocortin (POMC) translation by these tumors is often not reported. We present the case of a 49-year-old woman with a 3-month history of proximal muscular weakness, skin pigmentation, and weight loss. Upon initial evaluation, she had a full moon face, hirsutism, and a buffalo hump. Laboratory workup showed hyperglycemia, hypokalemia and metabolic alkalosis. ACTH, plasma cortisol, and urinary free cortisol levels were quite elevated. Serum cortisol levels were not suppressed on dexamethasone suppression testing. An octreo-SPECT scan showed enhanced nucleotide uptake in the liver and pancreas. Transendoscopic ultrasound-guided biopsy confirmed the diagnosis of a pancreatic ACTH-secreting neuroendocrine tumor (NET). Surgical excision of both pancreatic and liver lesions was carried out. Western blot analysis of the tumor and metastases revealed the presence of a high-molecular-weight precursor possibly POMC (at 30 kDa) but not ACTH (normally 4.5 kDa). ACTH-precursor secretion is more frequent in ectopic ACTH-secreting tumors compared with other causes of Cushing's syndrome. Hence, the measurement of such ACTH precursors warrants further evaluation, especially in the context of ACTH-dependent hypercortisolism.
Assuntos
Síndrome de ACTH Ectópico/etiologia , Hormônio Adrenocorticotrópico/sangue , Tumores Neuroendócrinos/complicações , Neoplasias Pancreáticas/complicações , Síndrome de ACTH Ectópico/sangue , Síndrome de ACTH Ectópico/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Tumores Neuroendócrinos/sangue , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/secundárioRESUMO
Currently, research in physiology focuses on molecular mechanisms underlying the functioning of living organisms. Reductionist strategies are used to decompose systems into their components and to measure changes of physiological variables between experimental conditions. However, how these isolated physiological variables translate into the emergence -and collapse- of biological functions of the organism as a whole is often a less tractable question. To generate a useful representation of physiology as a system, known and unknown interactions between heterogeneous physiological components must be taken into account. In this work we use a Complex Inference Networks approach to build physiological networks from biomarkers. We employ two unrelated databases to generate Spearman correlation matrices of 81 and 54 physiological variables, respectively, including endocrine, mechanic, biochemical, anthropometric, physiological, and cellular variables. From these correlation matrices we generated physiological networks by selecting a p-value threshold indicating statistically significant links. We compared the networks from both samples to show which features are robust and representative for physiology in health. We found that although network topology is sensitive to the p-value threshold, an optimal value may be defined by combining criteria of stability of topological features and network connectedness. Unsupervised community detection algorithms allowed to obtain functional clusters that correlate well with current medical knowledge. Finally, we describe the topology of the physiological networks, which lie between random and ordered structural features, and may reflect system robustness and adaptability. Modularity of physiological networks allows to explore functional clusters that are consistent even when considering different physiological variables. Altogether Complex Inference Networks from biomarkers provide an efficient implementation of a systems biology approach that is visually understandable and robust. We hypothesize that physiological networks allow to translate concepts such as homeostasis into quantifiable properties of biological systems useful for determination and quantification of health and disease.