How biomarker patterns can be utilized to identify individuals with a high disease burden: a bioinformatics approach towards predictive, preventive, and personalized (3P) medicine

Prevalences of non-communicable diseases such as depression and a range of somatic diseases are continuously increasing requiring simple and inexpensive ways to identify high-risk individuals to target with predictive and preventive approaches. Using k-mean cluster analytics, in study 1, we identified biochemical clusters (based on C-reactive protein, interleukin-6, fibrinogen, cortisol, and creatinine) and examined their link to diseases. Analyses were conducted in a US American sample (from the Midlife in the US study, N = 1234) and validated in a Japanese sample (from the Midlife in Japan study, N = 378). In study 2, we investigated the link of the biochemical clusters from study 1 to childhood maltreatment (CM). The three identified biochemical clusters included one cluster (with high inflammatory signaling and low cortisol and creatinine concentrations) indicating the highest disease burden. This high-risk cluster also reported the highest CM exposure. The current study demonstrates how biomarkers can be utilized to identify individuals with a high disease burden and thus, may help to target these high-risk individuals with tailored prevention/intervention, towards personalized medicine. Furthermore, our findings raise the question whether the found biochemical clusters have predictive character, as a tool to identify high-risk individuals enabling targeted prevention. The finding that CM was mostly prevalent in the high-risk cluster provides first hints that the clusters could indeed have predictive character and highlight CM as a central disease susceptibility factor and possibly as a leverage point for disease prevention/intervention.

How Routinely Assessed Biomarkers Can Be Utilized To Identify Individuals With A High Disease Burden: A Bioinformatics Approach Towards Predictive, Preventive And Personalised (3P) Medicine

Prevalences of non-communicable diseases such as depression and a range of somatic diseases are continuously increasing requiring simple and inexpensive ways to identify high-risk individuals to target with predictive and preventive approaches. Using k-mean cluster analytics, in study 1, we identified biochemical clusters (based on C-reactive protein, interleukin-6, fibrinogen, cortisol, and creatinine) and examined their link to diseases. Analyses were conducted in a U.S. American sample (from Midlife in the United States study, N = 1,234) and validated in a Japanese sample (from Midlife in Japan study, N = 378). In study 2, we investigated the link of clusters to childhood maltreatment (CM). The three identified biochemical clusters included one cluster (with high inflammatory signaling and low cortisol and creatinine concentrations) indicating the highest disease burden. This high-risk cluster also reported the highest CM exposure. The current study demonstrates how biomarkers can be utilized to identify individuals with a high disease burden and thus, may help to target these high-risk individuals with tailored prevention/intervention, towards personalized medicine. Furthermore, our findings raise the question whether the found biochemical clusters have predictive character; as a tool to identify high-risk individuals enabling targeted prevention. The finding that CM was mostly prevalent in the high-risk cluster provides first hints that the clusters could indeed have predictive character and highlight CM as a central disease susceptibility factor and possibly as a leverage point for disease prevention/intervention.

Hypothyroxinaemia in refractory shock: a clue to diagnose hypopituitarism

The rarity of congenital hypopituitarism (CHP) makes it essential for clinicians to be aware of its varying clinical manifestations. We report a neonate with one such unique presentation. A preterm girl baby was managed for respiratory distress. Diffuse cutis marmorata was present since birth; septic screens were positive with placental histopathology showing chorioamnionitis. Newborn screening showed low free thyroxine and normal TSH. Transient hypothyroxinaemia of prematurity was considered. Her respiratory status worsened on day 9, followed by refractory shock. She was treated for sepsis. Further evaluation for absent heart rate variability in response to vasopressor resistant shock led to the detection of hypocortisolism. Low cortisol along with hypothyroxinaemia made hypopituitarism the working diagnosis. Owing to the variable clinical spectrum of CHP, diagnosis is challenging. We highlight a few clinical and laboratory features, which would help in earlier diagnosis of CHP.

The Association of Low Blood Glucose and Low Serum Cortisol Levels in Severely Ill Children Admitted to Tertiary Referral Hospitals in Malawi: A Case-Control Study

Low blood glucose concentrations (< 5 mmol/L) in severely ill children presenting to hospitals in low-income countries are associated with mortality. Adrenal insufficiency with low cortisol levels may contribute to low blood glucose concentrations. Understanding the association between low cortisol and low blood glucose may assist in improving guidelines for management of severely ill children. The study aimed to determine the association between low serum cortisol and low blood glucose in severely ill children. A matched case-control study of children aged 1 month to 15 years was conducted at two tertiary hospitals in Malawi. Cases were children with blood glucose <5 mmol/L. Two age-matched controls with blood glucose of ≥5–15 mmol/L were enrolled per case. Low cortisol was defined as serum cortisol of <25 µg/dL (690 nmol/L) and adrenal insufficiency as serum cortisol of <10 µg/dL (276 nmol/L). A total of 54 cases and 108 controls were enrolled with, median age of 2.8 years (interquartile range [IQR]: 1.7–4.4). The median cortisol level was 58.7 µg/dL (IQR: 42.3–61.8) in cases and 40.9 µg/dL (IQR: 33.7–51.2) in controls (P = 0.911). The proportion of low cortisol was 4/54 (7.4%) in cases and 9/108 (8.3%) in controls. Logistic regression shows no association between low cortisol and low blood glucose (adjusted odds ratio: 0.33; 95% confidence interval, 0.04–3.02). Results suggest that there is no association between low cortisol and low blood glucose among severely ill children presenting to hospitals in Malawi. The reason for low blood glucose needs further investigation.

A rare and preventable aetiology of neurodevelopmental delay and epilepsy: familial glucocorticoid deficiency

Objectives Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterised by isolated glucocorticoid deficiency. Melanocortin receptor 2 (MC2R) mediates the functions of adrenocorticotropic hormone (ACTH) in the adrenal cortex. MC2R accessory protein (MRAP) is a transmembrane protein involved in the trafficking of MC2R to the cell surface. Mutations in MC2R and MRAP genes cause FGD type 1 and 2. In the present case series, we evaluate the clinical characteristics and long-term follow-up of six cases with FGD due to mutations in MC2R and MRAP. Case presentation Data of six cases with FGD (five with mutations in MC2R and one with a mutation in MRAP) who were being followed at our paediatric endocrine centre was evaluated. Diagnosis of FGD was considered in case of elevated ACTH and inappropriately low cortisol level, and exclusion of other aetiologies. The main presenting complaints were hyperpigmentation and hypoglycaemic convulsion in all cases. During a follow-up period of 26–115 months, one patient with homozygous 560delT mutation in MC2R, one female with G226R mutation in MC2R and one female with IVS3ds+1delG mutation in MRAP had a neurodevelopmental delay (NDD), while the other three patients had normal neurodevelopment. Conclusions FGD patients due to MC2R and MRAP mutations with early diagnosis and compliance to the hydrocortisone therapy had normal neurodevelopment, while delay in diagnosis and poor compliance was associated with severe hypoglycaemic convulsions and subsequent complications NDD.

The Role of Personal Biological Resource in the Job Demands-Control-Support Model: Evidence From Stress Reactivity

Job resources can buffer the deleterious effect of adverse work environments. Extant studies on the interaction pattern between job resources and adverse environments were confined to the diathesis stress model. This traditional perspective has received the challenge from the differential susceptibility model and the vantage sensitivity model. Additionally, stress reactivity may be one of the important job resources at the personal biological level, but its moderating role was short of empirical research. This study aimed to examine how stress reactivity interacts with work environments in predicting job burnouts among 341 Chinese hospital female nurses. This study selected job control and job support representative of supportive environments and psychological demands representative of an adverse environment and the cortisol content in 1-cm hair segment as a biomarker to assess individual’s stress reactivity in 1 month. The nurses self-reported their work environments and job burnouts and provided 1-cm hair segments closest to the scalp. Hair cortisol content was measured with high-performance liquid chromatography-tandem mass spectrometry. The interaction pattern was examined with multiple linear regressions and the analysis of region of significance (RoS). The regression revealed that the interaction of hair cortisol content with job control could positively predict professional efficiency among nurses, with psychological demands could negatively predict emotional exhaustion, and with coworker support could negatively predict professional efficiency. The RoS analysis revealed that nurses with high cortisol levels had not only significantly higher professional efficiency than those with low cortisol levels in high job control but also significantly lower professional efficiency in low job control. Nurses with high cortisol levels had significantly higher emotional exhaustion than those with low cortisol levels in low psychological demands. Nurses with low cortisol levels had not only significantly higher professional efficiency than those with high cortisol levels in high coworker support but also significantly lower professional efficiency in low coworker support. The interaction patterns of stress reactivity with both job control and coworker support were consistent with the differential susceptibility model, but the interaction between stress reactivity and psychological demands supported the vantage sensitivity model.

Late Onset of Abiraterone Severe Hypokalemia Due to Unsuspected ACTH-Secreting NEC

Clinical Case: 68-year-old male, Active smoker (30-40 packs/year), and moderate alcohol drinker. An increase in urinary frequency, nocturia, and a PSA of 116 µg/L led to the diagnosis of disseminated castration-sensitive prostate cancer (CSPC), advanced Gleason score (3 + 4 pT2), with bone and retroperitoneal metastases (CT). By 02/2018, he started androgen deprivation therapy (ADT) with Abiraterone (AB) 1000 mg, prednisone, and LHRH agonist. 15 months later, PSA levels decreased to 0.75 ng/ml without side effects and normal K+(3.7 mEq/L), when a CT scan revealed both liver and bone metastasis. During the progression study, two months later, the patient was admitted to the hospital for severe hypoK+ (1.7 mEq / L), normal renal function and metabolic alkalosis. Although abiraterone was discontinued, up to 460 mEq iv per day of K+ and spironolactone were required to maintain serum K+ above 2.5. 3 days later, the hormonal study revealed TSH 1.13 mU /L, ACTH 162 pmol/L, cortisol 258 nmol/L, aldosterone 105 pmol/L, renin (protein) 0.7 µU/mL and deoxycorticosterone 507 pmol/L. 11 days later, plasma cortisol was 967 nmol/L, ACTH 132pmol/L, and cortisoluria 1456 nmol/d. The suppression test with 1 mg of DXM for cortisol was 1162,5 nmol/L. DHEAS was &lt; 407 nmol/L. Liver biopsy showed a small cell neuroendocrine carcinoma (NEC), chromogranin (+), synaptophysin (+), CD56 (+), TTF-1 (+), PSA (-), Ki-67 90% and the granular cytoplasmic ACTH (+). The octreotide scan (+) revealed pathological uptake in L4, multiple uptakes in the liver, and in the axial skeleton. Treatment with Carboplatin plus Paclitaxel for NEC was started, completing 3 weekly doses with good tolerance and clinical benefit, but with the persistence of severe hypoK+ (2.5 mEq/L). Treatment with lanreotide 120 mg every 4 weeks was added, following a feeling of clinical improvement, the disappearance of edema, asthenia, and normalization of plasma K+ (3,4mEq/L). The patient died two months later from respiratory sepsis. Discussion: Several clinical trials have demonstrated that the combination of AB plus ADT prolongs overall survival in DCSPC. The CYP17 inhibition by AB increases ACTH leading to early secondary mineralocorticoid excess with hypokalemia and hypertension while the cortisol levels remain normal or low. Cortisol serum levels increased after AB was discontinued, whereas aldosterone serum levels remained low due to K+ regulatory feedback. The hormonal profile and the pathological and radiological studies revealed an ACTH-producing small cell NEC. In this patient, the previous treatment with BA has masked the clinical and hormonal profile of an ectopic Cushing syndrome. Therefore, Cyp17 inhibitors can mask adrenal or extra-adrenal processes characterized by alterations in steroid metabolism. This case has suggested a more thorough assessment of the adrenal hormonal profile including ACTH during BA treatment.

PTH-Independent Hypercalcemia in Undiagnosed Adrenal Insufficiency

In contrast to PTH-dependent hypercalcemia, the differential diagnosis of PTH-independent hypercalcemia is extensive. Thorough history and physical examination can help direct the clinician in the right direction and avoid extensive and unnecessary work up. A 27-year-old-female with a medical history significant only for untreated subclinical hypothyroidism was admitted to the hospital for hypercalcemia and acute kidney injury after presenting with dizziness, nausea, vomiting, dyspnea, and multiple syncopal episodes prior to admission. Serum calcium on presentation was elevated to 15.9 (8.5–10.2 mg/dL) with an intact parathyroid hormone level of 3.6 (8.5–75 pg/mL). On initial presentation, she was hypotensive, tachycardic, and was noted to be underweight with a body mass index of 17 kg/m2. The patient’s skin was diffusely hyperpigmented, with increased pigmentation in the creases of her hands and on the sides of her fingers. Further lab evaluation was remarkable for hyponatremia and hyperkalemia as well as an undetectable 8 AM cortisol of &lt;1.0 (7–25 µg/dL), adrenocorticotropic hormone (ACTH) level significantly elevated to &gt;1,250 (6–58 pg/mL), aldosterone &lt;4 (&lt;21 ng/dL), and plasma renin activity elevated to 18 (&lt;0.6–3 ng/mL/h). Antibodies to 21-alpha hydroxylase were positive, confirming a diagnosis of Addison’s disease. Prior to the workup confirming an elevated ACTH and low cortisol levels, the patient was treated with aggressive intravenous fluid repletion and calcitonin with overnight improvement in calcium to 11.4 mg/dL. After the diagnosis of primary adrenal insufficiency was confirmed, she was treated with stress doses of intravenous hydrocortisone then gradually tapered to physiologic doses of oral hydrocortisone and fludrocortisone with resolution of her hypercalcemia by the fourth day of hospitalization. Adrenal insufficiency is a known but uncommon cause of PTH-independent hypercalcemia, but the exact mechanism is unknown. Hypercalcemia is thought to result from a combination of a hypovolemic state seen in adrenal insufficiency which leads to decreased urinary calcium excretion as well as increased bone resorption, which may result from increased serum sclerostin concentrations. Adrenal insufficiency should be considered in the differential of PTH-independent hypercalcemia. This case highlights the improvement in hypercalcemia that is seen with correction of glucocorticoid deficiency, and supports delaying additional work up for other PTH-independent causes until appropriate treatment has been given.

Effects of Exogenous Glucocorticoid Administration on Feed Intake in Beef Cattle

Calves (n = 63) from Angus crossbred cows were weighed and randomly assigned to treatments within 4 h of parturition (d 0). Each calf was intravenously infused with either a low cortisol [LC; n = 22, 3.5 µg hydrocortisol sodium succinate/kg body weight (BW)], high cortisol (HC; n = 20, 7.0 µg/kg BW), or a sham infusion control (CON; n = 21, similar volume of saline). Each calf was administered a second infusion of its respective treatment 24 h postpartum. Blood was collected via jugular venipuncture before infusion and daily from d 0–17 of age and analyzed for leptin concentrations using a validated radioimmunoassay. Animal BW was collected every 14 d from d 0 until the end of the study. Heifers (n = 31; 367±4 d of age) and steers (n = 32; 385±4 d of age) entered a Growsafe system to measure feed intake (FI) and were allowed a 2-wk adjustment period to a commercial ration (1.27 Mcal NEm/kg and 15.8% CP and 0.45 Mcal NEg/kg and 13.8% CP, respectively; DM basis). Heifer body condition score (BCS) was collected at the beginning and end of the trial. Heifers were fed for 70 d and steers until they obtained a 12th rib back fat (BF) thickness of 1.15 cm. Data were analyzed via ANOVA or repeated measures using appropriate models of SAS. Serum leptin concentrations observed a treatment by day interaction (P = 0.0028), in which HC and LC were decreased compared to CON from d 2–17 of age. Calf birth BW and adjusted 205-d BW did not differ (P &gt; 0.056) between treatments. Heifer BW gain, BCS change, and number of feed events were increased (P = 0.001) in LC compared to HC and CON. Steers did not differ between treatments (P &gt; 0.080) in BW, BW gain, or BF thickness. However, LC steers observed greater daily FI (P = 0.047) and tended to have greater final BW (P = 0.080). In summary, exogenous cortisol administered to calves at parturition reduced leptin concentrations and improved FI of beef steers during a feeding trial.

Cushing Syndrome in Carney Complex: Unilateral or Bilateral Adrenalectomy?

Carney Complex (CNC) is a rare multiple endocrine syndrome dueto PRKR1A germline mutations. Primary pigmented nodular adrenal disease (PPNAD), the most frequent manifestation of the disease is responsible for non-ACTH dependent Cushing syndrome and bilateral adrenalectomy is the recommended treatment. We had followed up a CNC family with mainly Cushing syndrome disease secondary to PPNAD for more than 40 years over 2 generations. Six members carry the disease and present a germline mutation of PRKR1A, 4 women and 2 men. One patient accidently died one year after surgery and the others 5 patients were regularly followed up. The index case, a 25 years woman, was diagnosed with Cushing syndrome in 1972 with hyperandrogenism, short stature and mild manifestations of hypercortisolism. Unilateral adrenalectomy was performed on the side of a nodular adrenal and pathology described PPNAD. Her sister was subsequently diagnosed and treated the same way. The 2 sisters did well, with pregnancies for both of them but different post surgery hormonal results. The index case had partial cortisol deficiency with persistent low cortisol level at 108 nmol/L. Her sister presented a moderate increase in cortisol in the evening or after dexamethasone at 306 nmol/L at last evaluation. The only events possibly associated to hypercortisolism in this patient were central overweight and three episodes of spontaneous pulmonary embolism and veinous thrombosis. Their 2 brothers were evaluated at 17 and 39 years while they developed cushing syndrome signs (round face, HTA, amyotrophy and fatigability). As CNC have been recognized at this time by Dr Carney, bilateral adrenalectomy was performed in one patient who died accidentally a few months later. His brother chose unilateral adrenalectomy on the side of the macronodular gland, recovered hypercortisolism signs and still needs adrenal substitution. The daughter of the index case demonstrated at 21 years old a mild Cushing syndrome and chose unilateral adrenalectomy like her mother. Symptoms resumed without any recurrence during 20 years follow up. The daughter of the patient II.2 was diagnosed earlier at seven years of age because she developed hyperandrogenism, central weight gain and growth arrest due to Cushing syndrome. Bilateral adrenalectomy was successfully performed and adrenal substitution was prescribed. Surprisingly, adrenal function seemed to recover 5 to 6 years post surgery and treatment was decreased then stopped. Adrenal CT scan did not show any residual gland but noriodocholesterol scintigraphy confirmed bilateral adrenal uptake. She is now mother of 2 and present a near normal cortisol circadian rythm without any treatment. Finally, we showed in this long-term study that unilateral adrenalectomy in PPNAD could be an option for the treatment of mild Cushing syndrome in adults. Recovery after bilateral adrenalectomy occurred in one patient.