What the Eye Cannot See: A Case of Persistent Altered Mental Status in a Patient With Cholestatic Liver Disease?

Introduction: Altered mental status (AMS) is a common symptom in patients with liver disease with a wide list of differential diagnoses. Knowledge of etiologies of AMS unique to patients with hepatic dysfunction is vital in order to help recognize, diagnose, and treat the underlying cause in a timely manner. Case Description/Methods: A 46-year-old man with a history of recent COVID infection was transferred to our hospital for further evaluation of acute liver injury and AMS. On arrival, his labs were notable for AST of 408 U/L, ALT of 620 U/L, ALP of 5942 U/L, TB of 11.0 mg/dL, and an INR of 1.1. His work-up included an MRCP that showed segmental biliary ductal dilation with associated restricted diffusion and peribiliary enhancement concerning for sclerosing cholangitis. ERCP revealed a 3cm biliary cast that was removed and noted diffuse rarefaction of ducts throughout the entire biliary tree. A liver biopsy revealed centrizonal cholestasis with portal-based bile ductular reaction and mild bile duct injury. Despite adequate treatment of suspected infection and hepatic encephalopathy, his AMS persisted. His basic metabolic panel (BMP) was notable for Na of 143 mEq/L. A send-out lipid panel that was obtained to work-up his dyslipidemia revealed a total cholesterol of 1018 mg/dL, triglycerides of 420mg/dL, and the presence of lipoprotein X. A venous blood gas (VBG) was obtained showing a Na of 157 mEq/L and serum osmolality was 322 mmol/kg, confirming true hypernatremia. He was slowly treated with hypotonic solutions with significant improvement in his mentation. On follow-up one year later, he has persistent cholestasis and is currently being considered for liver transplant. Discussion(s): The final diagnosis was COVID-related ischemic cholangitis and disappearing bile ducts with persistent cholangiopathy, presenting with severe cholestasis, accumulation of lipoprotein X, and pseudonormonatremia. When faced with severe cholestatic liver disease, clinicians should keep in mind the possibility of accumulation of lipoprotein X and its association with hyperviscosity and spurious electrolyte abnormalities. Clinicians should rely on obtaining blood gas analyses for accurate electrolyte measurement in such cholestatic patients as blood gas analyses utilize direct ion-sensitive electrodes (ISE) to measure electrolytes, whereas routine basic metabolic panels utilize indirect ISE that are liable to spurious results in the presence of hyperlipoproteinemia/lipoprotein X.

Endocrine disorders in COVID-19: a look from a different perspective

Background: COVID-19 is an infectious disease caused by the SARS-CoV-2 virus, particularly known for its respiratory symptoms. Nevertheless, a wide variety of clinical manifestations has been associated with COVID-19, including Kawasaki disease, Guillain- Barré syndrome and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Clinical Case: A 55-years-old woman, affected by immune thrombocytopenia on prednisone therapy, presented with intense fatigue, hyporexia and vomit. She had no fever, no cough, nor other symptoms. She referred a quick prednisone decalage in previous days. ABG showed metabolic alkalosis, severe hyponatremia and hypokalemia. The patient tested positive for SARS-CoV-2. Further investigation showed euvolemic hyponatremia (102 mEq/L) with normal urine osmolality (275 mOsm/Kg), findings consistent with COVID-19-related SIADH. We set a corticosteroid therapy with Prednisone 37,5 mg/die for 5 days, then 25 mg/die for 2 days. After 7 days of hospitalization, the patient tested negative for SARS-CoV-2. In the meantime, kalemia and natremia were back in range. Conclusions: Despite COVID-19 being identified as severe respiratory viral infection, progressively many relevant endocrine manifestations have been reported greatly contributing to the severity of the clinical presentation. There is the urgent need to collect in international multicentric efforts data on all these aspects of the pituitary involvement in COVID-19 patients.

DEVELOPMENT OF A NASAL SPRAY CONTAINING A NOVEL HUMAN RECOMBINANT ANTIBODY FOR SARS-COV-2 THERAPY

A novel human recombinant antibody for prophylactic treatment against SARS-CoV-2 was formulated in a nasal solution comprising chitosan as mucoadhesive polymer. Two levels of protein concentration have been assessed and formulations loaded into Aptar VP3 nasal pump. The formulations produced showed values of pH (6.2- 6.3) and osmolality (414 and 421 mosm/kg) suitable to prevent precipitation of the antibody in the final solution and for nasal administration. Assay of the protein after formulation manufacturing showed a lower dimeric fraction than the reference standard and hydrodynamic diameter of the final formulations was also comparable to the unprocessed antibody solution (10 nm). Zeta-potential values were higher than 25mV, indicating colloidal stability against aggregation due to charge stabilization for the formulations obtained. Spray performance did not evidence any difference between protein levels in the final formulations when combined with VP3 nasal pump. Particularly, droplet size distribution (mean volume diameter of 55.13 lm for the low dose formulation and 57.21 lm for the high dose), spray pattern and plume geometry resulted to be applicable for nasal delivery. Finally, for both solutions sprayed antibody content was within 75-125% of the target delivered dose with a very low variability on ten consecutive shots (5%). Future studies will assess the formulations stability under refrigerated and ambient storage conditions of the combination product and of the antibody comprised in the formulation,whereas in vivo studieswill define pharmacokinetics and pharmacodynamics profile of these final formulations. Key Message: The possibility to deliver to the nose a novel human antibody for prophylactic treatment against SARS-CoV-2 employing Aptar VP3 pump was assessed. Spray performance of the formulations manufactured was characterized and no protein agglomeration was observed in the formulations and after spraying, indicating favourable results in applying this system for delivery of antibodies to the nose.

The Beverage Hydration Index: Influence of Electrolytes, Carbohydrate and Protein.

The beverage hydration index (BHI) facilitates a comparison of relative hydration properties of beverages using water as the standard. The additive effects of electrolytes, carbohydrate, and protein on rehydration were assessed using BHI. Nineteen healthy young adults completed four test sessions in randomized order: deionized water (W), electrolytes only (E), carbohydrate-electrolytes (C + E), and 2 g/L dipeptide (alanyl-glutamine)-electrolytes (AG + E). One liter of beverage was consumed, after which urine and body mass were obtained every 60 min through 240 min. Compared to W, BHI was higher (p = 0.007) for C + E (1.15 ± 0.17) after 120 min and for AG + E (p = 0.021) at 240 min (1.15 ± 0.20). BHI did not differ (p > 0.05) among E, C + E, or AG + E; however, E contributed the greatest absolute net effect (>12%) on BHI relative to W. Net fluid balance was lower for W (p = 0.048) compared to C + E and AG + E after 120 min. AG + E and E elicited higher (p < 0.001) overall urine osmolality vs. W. W also elicited greater reports of stomach bloating (p = 0.02) compared to AG + E and C + E. The addition of electrolytes alone (in the range of sports drinks) did not consistently improve BHI versus water; however, the combination with carbohydrate or dipeptides increased fluid retention, although this occurred earlier for the sports drink than the dipeptide beverage. Electrolyte content appears to make the largest contribution in hydration properties of beverages for young adults when consumed at rest.

Calculated plasma osmolality at hospital admission correlates well with eGFR and D-Dimer, a simple outcome predictor and guiding tool for management of severe COVID-19 patients.

AIMS: To evaluate calculated total plasma osmolality as a marker of outcome prediction, fluid and metabolic balance, thrombotic risk in severe COVID-19 patients. METHODS: Retrospective data of RT-PCR confirmed hospitalized severe COVID-19 patients (total: n = 175 patients, including diabetic subset: n = 102) were analyzed. Clinically applicable cut-offs were derived using receiver operating characteristic (ROC) curve analysis for calculated total osmolality, eGFR, and D-dimer, and their correlations were studied. RESULTS: Among 175 severe COVID-19 patients, a significant association with mortality was seen with respect to calculated total osmolality (p < 0.001), eGFR (p < 0.001), and D-dimer (p < 0.001). In the total cohort, applicable cut-offs based on ROC curve in predicting outcome were, for total osmolality 299 mosm/kg (area under the curve (AUC)-0.773, odds ratio (OR)-1.09), eGFR 61.5 ml/min/m2 (AUC-0.789, OR-0.96), D-dimer 5.13 (AUC-0.814, OR-2.65) respectively. In diabetic subset, the cut-offs for total osmolality were 298 mosm/kg (AUC-0.794, OR-1.12), eGFR 44.9 ml/min/m2 (AUC-0.774, OR-0.96) and D-dimer 1.59 (AUC-0.769, OR-1.52) respectively. CONCLUSIONS: Applicable cut-offs for calculated total plasma osmolality, eGFR, and D-dimer predicts clinical outcome in severe COVID-19 with and without diabetes. Correlation studies validated calculated total osmolality as a marker of the combined effect of fluid and metabolic imbalance, compromised renal function and hypercoagulability.

Acute Metabolic Emergencies in Diabetes: DKA, HHS and EDKA.

Emergency admissions due to acute metabolic crisis in patients with diabetes remain some of the most common and challenging conditions. DKA (Diabetic Ketoacidosis), HHS (Hyperglycaemic Hyperosmolar State) and recently focused EDKA (Euglycaemic Diabetic Ketoacidosis) are life-threatening different entities. DKA and HHS have distinctly different pathophysiology but basic management protocols are the same. EDKA is just like DKA but without hyperglycaemia. T1D, particularly children are vulnerable to DKA and T2D, particularly elderly with comorbidities are vulnerable to HHS. But these are not always the rule, these acute conditions are often occur in different age groups with diabetes. It is essential to have a coordinated care from the multidisciplinary team to ensure the timely delivery of right treatment. DKA and HHS, in many instances can present as a mixed entity as well. Mortality rate is higher for HHS than DKA but incidences of DKA are much higher than HHS. The prevalence of HHS in children and young adults are increasing due to exponential growth of obesity and increasing T2D cases in this age group. Following introduction of SGLT2i (Sodium-GLucose co-Transporter-2 inhibitor) for T2D and off-label use in T1D, some incidences of EDKA has been reported. Healthcare professionals should be more vigilant during acute illness in diabetes patients on SGLT2i without hyperglycaemia to rule out EDKA. Middle aged, mildly obese and antibody negative patients who apparently resemble as T2D without any precipitating causes sometime end up with DKA which is classified as KPD (Ketosis-prone diabetes). Many cases can be prevented by following 'Sick day rules'. Better access to medical care, structured diabetes education to patients and caregivers are key measures to prevent acute metabolic crisis.

Hypotheses about sub-optimal hydration in the weeks before coronavirus disease (COVID-19) as a risk factor for dying from COVID-19.

To address urgent need for strategies to limit mortality from coronavirus disease 2019 (COVID-19), this review describes experimental, clinical and epidemiological evidence that suggests that chronic sub-optimal hydration in the weeks before infection might increase risk of COVID-19 mortality in multiple ways. Sub-optimal hydration is associated with key risk factors for COVID-19 mortality, including older age, male sex, race-ethnicity and chronic disease. Chronic hypertonicity, total body water deficit and/or hypovolemia cause multiple intracellular and/or physiologic adaptations that preferentially retain body water and favor positive total body water balance when challenged by infection. Via effects on serum/glucocorticoid-regulated kinase 1 (SGK1) signaling, aldosterone, tumor necrosis factor-alpha (TNF-alpha), vascular endothelial growth factor (VEGF), aquaporin 5 (AQP5) and/or Na+/K+-ATPase, chronic sub-optimal hydration in the weeks before exposure to COVID-19 may conceivably result in: greater abundance of angiotensin converting enzyme 2 (ACE2) receptors in the lung, which increases likelihood of COVID-19 infection, lung epithelial cells which are pre-set for exaggerated immune response, increased capacity for capillary leakage of fluid into the airway space, and/or reduced capacity for both passive and active transport of fluid out of the airways. The hypothesized hydration effects suggest hypotheses regarding strategies for COVID-19 risk reduction, such as public health recommendations to increase intake of drinking water, hydration screening alongside COVID-19 testing, and treatment tailored to the pre-infection hydration condition. Hydration may link risk factors and pathways in a unified mechanism for COVID-19 mortality. Attention to hydration holds potential to reduce COVID-19 mortality and disparities via at least 5 pathways simultaneously.