Severe Hepatic Dysfunction Research Articles

Association of Asymmetric Dimethylarginine and Nitric Oxide with Cardiovascular Risk in Patients with End-Stage Liver Disease.

Background and objectives: Endothelial dysfunction has been proposed to be an underlying mechanism of the pronounced cardiovascular morbidity in end-stage liver disease (ESLD), but clinical evidence is still limited. In this study, we investigated the association of circulating levels of asymmetric dimethylarginine (ADMA) and nitric oxide (NO) with estimated cardiovascular risk in patients with ESLD awaiting liver transplantation. Materials and Methods: ADMA and NO levels were measured in the sera of 160 adult ESLD patients. The severity of hepatic dysfunction was assessed by the model for end-stage liver disease (MELD) score. The cardiovascular risk was estimated with the European Society of Cardiology Systematic Coronary Risk Estimation (SCORE) index, which was used to dichotomize patients in the subgroups depicting higher and lower cardiovascular risk. Results: Severe hepatic dysfunction (MELD ≥ 18) was present in 38% of the patients, and a higher cardiovascular risk was present in almost half of the patients (N = 74). ADMA and NO both significantly increased with the progression of liver disease and were independently associated with higher cardiovascular risk. Fasting glucose also independently predicted a higher cardiovascular risk, while HDL cholesterol and the absence of concomitant hepatocellular carcinoma were protective factors. Conclusions: These results suggest a remarkable contribution of the deranged arginine/NO pathway to cardiovascular risk in patients with end-stage liver disease.

Risk factors of major bleeding in elderly atrial fibrillation patients from the ANAFIE registry

Abstract Background Bleeding is associated with shorter life expectancy during anticoagulant treatment in atrial fibrillation (AF) patients. Prior studies showed bleeding during anticoagulant treatment occurred more frequently in elderly AF patients than in younger AF patients. HAS-BLED score is a risk assessment tool for bleeding. However, since it was developed from the database of patients with warfarin, it has not been clarified whether this score is applicable in the era of direct oral anticoagulant (DOACs), especially for elderly AF patients. Purpose All Nippon AF In the Elderly (ANAFIE) registry was designed to obtain real-world information regarding patients with non-valvular AF (NVAF) aged ≥75 years, including current status of anticoagulant therapy and prognosis. The present study aimed to determine factors that associate with major bleeding for elderly NVAF patients using the dataset of ANAFIE registry conducted in Japan. Methods Total of 32,099 patients aged ≥75 years with NVAF were enrolled in ANAFIE registry, and followed for 2 years. Incidence rates of major bleeding for total population, <85 years old group and ≥85 years old group were estimated using Kaplan-Meier method. Cox proportional hazards model was used to determine independent predictors of major bleeding. The factors included in the model were selected by backward elimination procedure. Results Mean age was 81.5 years. 23,738 (74.0%) was <85 years old and 8,361 (26.0%) was ≥85 years old. 92.5% of whole population used anticoagulants including warfarin (27.6%) or DOACs (72.3%). Major bleeding occurred in 279 patients at 12 months with 189 in <85 years and 90 in ≥85 years old group. The cumulative incidence rate of major bleeding at 12 months by Kaplan-Meier method was 0.9% in whole patients, and was slightly higher in ≥85 years than in <85 years old group (1.1% vs 0.8%). In multivariate analysis of the whole patients, history of major bleeding (hazard ratio [HR]: 2.17), severe hepatic dysfunction (HR: 3.62), malignancy (HR: 1.52), falling within a year (HR: 2.07), antiplatelet use (HR: 1.37) and warfarin use (HR: 1.81) emerged as independent predictors of major bleeding. Severe hepatic dysfunction (HR: 9.17), HbA1c <6.0% (HR: 2.19) and dementia (HR: 2.00) were associated with major bleeding in patients only in aged ≥85 years. On the other hand, proton pump inhibitor use (HR: 1.36), creatinine clearance <30 mL/min (HR: 1.53) and polypharmacy (HR: 1.61) were associated with major bleeding only in those aged <85 years. Conclusion Among elderly (≥75 years old) Japanese NVAF patients in the era of DOACs, prior major bleeding, severe hepatic dysfunction, malignancy, falling within a year, antiplatelet use and warfarin use were identified as independent predictors of major bleeding. Impact of some predictors differed between the 2 age groups (<85 years vs ≥85 years). Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo Co., Ltd.

S2632 A Rare Case of Spontaneous Intracranial Hemorrhage in a Young Female With Alcoholic Liver Disease

INTRODUCTION: Coagulopathy is an established manifestation of hepatic dysfunction that could lead to an increased risk of bleeding. However, it is unclear if underlying liver disease predisposes to the development of spontaneous intracranial hemorrhage. Only very few cases have described this unique presentation. In this report, we describe a case of a 27-year-old female presenting with features of decompensated alcoholic liver disease with computerized tomography of the head (CT) findings of intracranial hemorrhage. CASE DESCRIPTION/METHODS: A 27-year-old African-American female presented to the ED with non-bloody and non-bilious emesis. Her social history was significant for alcohol abuse. Notable findings on physical exam included scleral icterus and abdominal distension with hepatosplenomegaly. Laboratory report showed (Hb/HCT 6 g/dL/17.5%), acute kidney injury (BUN/Cr 20/4.46 mg/dl), lactic acidosis (4.4 mmol/L), elevated alkaline phosphatase (256 U/L), elevated transaminases (ALT/AST 34/263 U/L), and coagulopathy (INR 2.69). Abdomen ultrasound revealed hepatosplenomegaly with fatty infiltration and sludge in the gallbladder. CT Chest/Abdomen/Pelvis showed marked hepatic steatosis. She was subsequently admitted to the Intensive Care Unit. The patient was transfused with packed red blood cells, administered intravenous fluids, and antibiotics. On the first day of admission, a CT Head without contrast was obtained for a change in mental status, which showed a 17 mm × 13 mm x 10 mm intracranial hemorrhage in the inferior right frontal. Repeat CT Head performed after 24 hours showed an increase in the size of the intracranial hemorrhage. The patient subsequently was intubated for airway protection. She continued to have poor prognosis throughout the hospital stay, complicated by worsening hypotension, requiring full pressor support and she expired on hospital day 10. DISCUSSION: Several retrospective and autopsy-based studies have shown conflicting data on the association between hepatic dysfunction and the development of spontaneous intracranial hemorrhage in the presence of coagulopathy. Our case highlights the need for high suspicion of intracranial hemorrhage in the setting of severe hepatic dysfunction in patients with persistently altered mental status without another plausible etiology.Figure 1.: Intracranial hemorrhage in the inferior right frontal lobe.Figure 2.: Repeat CT head showing worsening of intracranial bleed.

The Safety and Efficacy of Second-Generation Basal Insulin Analogues in Adults with Type 2 Diabetes at Risk of Hypoglycemia and Use in Other Special Populations: A Narrative Review.

Hypoglycemia is a major barrier impeding glycemic control in persons with type 2 diabetes mellitus and creates a substantial burden on the healthcare system. Certain populations that require special attention, such as older adults and individuals with renal impairment, a longer duration of diabetes or those who have experienced prior hypoglycemia, may be at a higher risk of hypoglycemia, particularly with insulin treatment. Second-generation basal insulin analogues (insulin glargine 300 U/mL and degludec) have demonstrated reductions in hypoglycemia compared with insulin glargine 100 U/mL although evidence of this benefit across specific populations is less clear. In this review we summarize the literature with respect to the efficacy and safety data for second-generation basal insulin analogues in adults with type 2 diabetes mellitus who are at risk of hypoglycemia or who require special attention. Randomized controlled trials, meta-analyses and real-world evidence demonstrate that the use of second-generation basal insulin analogues is associated with less hypoglycemia compared with insulin glargine 100 U/mL without compromising glycated hemoglobin control. A reduced risk of hypoglycemia with second-generation basal insulin analogues was evident in older adults and in individuals with obesity, renal impairment, a history of cardiovascular disease or a long duration of insulin use. Further studies are needed in other populations, including those with more severe renal impairment or hepatic dysfunction, the hospitalized population and those with cognitive impairment. Overall, less hypoglycemia associated with second-generation basal insulin analogues may help reduce barriers for insulin use, improve adherence and offset the costs of hypoglycemia-related healthcare resource utilization.

Macrophage-derived extracellular vesicles regulate concanavalin A-induced hepatitis by suppressing macrophage cytokine production

Acute liver failure is a clinical syndrome of severe hepatic dysfunction. Immune cells play an important role in acute liver failure. In recent years, the immunoregulatory function of extracellular vesicles (EVs) has been reported; therefore, it is inferred that EVs play a role in immune-mediated hepatitis. In this study, we investigated the immunoregulatory function of EVs in concanavalin A (Con A)-induced hepatitis. The mouse model was prepared by a single intravenous administration of 15 mg/kg Con A, in which there was a significant increase in the serum EVs number. In an in vitro study, the number of secreted EVs was also significantly increased in Con A-treated RAW264.7 cells, a mouse macrophage cell line, but not in Hepa1-6 cells, a mouse hepatoma cell line. In an in vitro EVs treatment study, EVs from Con A-treated mouse serum and Con A-treated RAW264.7 cells suppressed inflammatory cytokine production in Con A-stimulated RAW264.7 cells. miRNA sequencing analysis showed that the expression of mmu-miR-122-5p and mmu-miR-148a-3p was commonly increased in these EVs and EVs-treated cells. The pathways enriched in the predicted miRNA target genes included inflammatory response pathways. The mRNA levels of the target genes in these pathways (mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt and Rho/Rho-associated coiled-coil containing protein kinase pathways) were decreased in the EVs-treated cells. In an in vivo RNA interference study, the knockdown of liver RAB27A, an EVs secretion regulator, significantly exacerbated Con A-induced hepatitis. These data suggest that macrophage-derived EVs play an important role in Con A-induced hepatitis through immunoregulation.

Hepatic dysfunction in sepsis

Sepsis represents alife-threatening condition that frequently accompanies acute hepatic dysfunction. As aresult of systemic inflammation, immune dysregulation, and microcirculatory derangements, different types of liver dysfunction can occur, such as hypoxic hepatitis, sepsis-associated cholestasis, or liver failure. Avery serious and late sequela is secondary sclerosing cholangitis of the critically ill patient. Clinical management of sepsis-related liver dysfunction includes the rapid identification and treatment of the suspected underlying infection, hemodynamic stabilization to improve hepatic perfusion, and the optimization of oxygen delivery to the liver. Despite maximum efforts in supportive treatment, the outcome of patients with sepsis or septic shock and concomitant severe hepatic dysfunction remains very poor.

Evaluation of Protein S and Protein C Levels in B-Thalassemic Patients and Its Association with Blood Transfusion

Background: Thalassemia is a chronic hemolytic anemia due to a partial or complete deficiency in the synthesis of α-globin chains or β-globin chains that compose of the major adult hemoglobin (α 2β 2). Protein C is a vitamin K-dependent serine protease and naturally occurring anticoagulant that plays a role in the regulation of hemostasis by inactivating factors Va and VIIIa in the coagulation cascade.Protein S is a non-enzymatic cofactor for activated protein C–mediated inactivation of factor VIIIa and Va. In addition, protein S may have activated protein C–independent anticoagulant activity. Aim of study:To evaluate protein S&C levels in thalassemic patients &its relation to blood transfusion .Methods: the study included 80 subjects divided into two groups: Case group included 60 patients who were a known cases of transfusion dependent B-thalassemia and control group included 20 participants who were healthy and matched in age and gender with case group. Patients with other forms of hemolytic anemia like sickle thalassemia, who suffering from severe hepatic or cardiac dysfunction, those with other hemoglobinopathies, were excluded from the study. Plasma protein S and C Ag were calculatedin both patient groups and in control group by ELISA.Results: Plasma protein C was significantly lower in patients with splenectomy in comparison with patients without splenectomy.Protein C and S were significantly lower in patients with non-frequent than in patients with frequent blood transfusion. There was significant positive correlation between plasma protein C and protein S levels.Conclusion: Patients with thalassemia major have lower level of protein C and protein S than non-thalassemic patient.Frequency of blood transfusion can affect level of protein C & protein S. Splenoctomized patients have lower levels of protein C and S than non-splenoctomized.

The Hepatoprotective Effect of Taurisolo, a Nutraceutical Enriched in Resveratrol and Polyphenols, Involves Activation of Mitochondrial Metabolism in Mice Liver.

Liver diseases affect millions of people worldwide. In most of the cases, severe hepatic dysfunction and liver cancer stem from mild and common clinical signs including hepatic steatosis, insulin resistance, liver inflammation, and oxidative stress, all together referred to as Nonalcoholic Fatty Liver Disease (NAFLD). Nutraceuticals endowed with antioxidant activity have been shown to reduce NAFLD risk factors and exert hepatoprotective effects. Here, we test the protective effect exerted on liver by the antioxidant Taurisolo, a nutraceutical formulation produced by grape pomace and enriched in Resveratrol and Polyphenols. We analyze the effect of Taurisolo on liver cells by profiling the metabolome of in vitro cultured hepatic HuH7 cells and of C57BL-6J mice fed a High Fat Diet and treated with the nutraceutical. Both in vitro and in vivo, we provide evidence that Taurisolo reduces risk factor markers associated with NAFLD. Taurisolo stimulates glucose uptake and reduces hepatic cholesterol and serum triglycerides. Furthermore, we give new insights into the mechanism of action of Taurisolo. The nutraceutical increases mitochondrial activity and promotes respiration and ATP production, fostering catabolic reactions like fatty acid β-oxidation and amino acid catabolism. On the contrary, Taurisolo reduces anabolic reactions like biosynthesis of cholesterol, bile acids, and plasma membrane lipids.

The Role of Allium saralicum Extract on Prevention of Acetaminophen-Induced Hepatic Failure: an Experimental Study

Background and objectives: Acetaminophen (APAP) is a common analgesic medicine whose overdose leads to severe hepatic dysfunction. Due to the known antioxidant properties of Alliumspecies, the present study aimed to evaluate the protective effects of Allium saralicum plant on APAP induced liver toxicity. Methods: The hydro-alcoholic extract of A. saralicum was prepared by maceration and ultrasonic methods. Forty-two rats in seven groups were treated by gavage as follows: groups 1 and 2 received normal saline, groups 3 received 400 mg/kg of A. saralicum hydro-alcoholic extract, and the groups 4-7 were treated with 50, 100, 200 and 400 mg/kg of A. saralicum extract, respectively. After two consecutive weeks, the therapeutic groups, as well as the positive control (APAP) group, were administered a single dose of APAP (2 g/kg). After 48 hours, the animals were anesthetized, and blood and liver samples were collected for histological and biochemical examinations.Results: Our findings indicated that APAP caused a significant rise in ALT (p<0.001), AST (p<0.001), ALP (p<0.001) and LDH (p<0.001) serum levels, total and direct bilirubin (p<0.001), hepatic lipid peroxidation (LPO; p<0.001) and nitric oxide (NO; p<0.001). In addition, APAP let to the decreasing of the total antioxidant capacity (TAC; p< 0.001), total thiol molecules (TTM; p<0.001), and structural changes in the hepatic tissue. Following administration ofA. saralicum extract, a remarkable improvement was observed in the functional and oxidative stress indices of liver tissue alongside histopathologic alterations. Conclusion: Our results showed that A. saralicum extractsignificantly improved APAP-induced hepatic failure through inhibition of oxidative/nitrosative stress.

Kвантитативно одредување на калпротектин во асцит кај пациенти со спонтан бактериски перитонитис

Спонтаниот бактериски перитонитис (СБП) кај пациентите со црнодробна цироза е новонастаната, спонтана бактериска инфекција на стерилна асцитна течност, во отсуство на интраабдоминални извори на инфекција или малигнитет. Најсензитивен показател за поставување на дијагнозата е бројот на полиморфонуклеарни клетки (ПМНК) ≥250 во 1 мл асцитна течност (рачно микроскопско или автоматизирано пребројување) и/или кога во микробиолошката култура биде изолиран еден бактериски вид. Цел на трудот е да се одреди концентрацијата на калпротектин во асцит кај пациентите со СБП и не-СБП, да се споредат просечните вредности на Turcotte-Pugh II и MELD скорот кај пациентите со СБП и не-СБП и просечните вредности на C-реактивниот протеин во серум и во асцит во испитуваните групи. Материјали и методи. Во оваа проспективно-аналитичко-опсервациска пилот студија беа вклучени 30 пациенти со црнодробна цироза и асцит, поделени во две групи, СБП и не-СБП. Квантитативното мерење на калпротектин во асцит се вршеше со тестот Quantum Blue Calprotectin Ascites (LF-ASC25). Тестот е дизајниран за селективно мерење на антигенот на калпротектинот (MRP8/14) со директен сендвич имуноесеј. Примероците од асцитот се разредуваа со Chase Buffer во однос 1:5 и по 12 минути инкубација на собна температура, интензитетот на сигналот на линијата за тестирање и контролната линија се мереа квантитативно со BÜHLMANN Quantum Blue®Reader. Собраните податоци се обработија со помош на статистичкиот програм SPSS 23 за Windows. Резултати. Во нашата студија просечната вредност на калпротектин кај пациентите со СБП изнесуваше 1,4 μg/mL. Најниската вредност на калпротектин во испитуваната група беше регистрирана кај еден пациент со вредност од 0,61 μg/mL, додека највисока вредност од 1,81μg/mL кај четири пациенти. Резултатите покажаа повисоки вредности на калпротектин во асцит кај пациентите со алкохолна болест на црниот дроб во споредба со останатите етиологии. Рефракторен асцит се регистрира кај 60,0% од испитаниците, а само кај еден пациент (6,7%) се регистрира Klepsiella pneumoniae во микробиолошката анализа на асцитот. Според Child-Turcotte-PughII класификација сите пациенти од испитуваната група беа класа C, додека просечната вредност на MELD скорот изнесуваше 29,8±6,14. Разликата помеѓу просечните вредности наC-реактивниот протеин во серум и во асцит кај пациентите со СБП беше статистички сигнификантна во споредба со не-СБП. Заклучок. Kвантитативното одредување на калпротектинот во асцит со тестот Quantum Blue Calprotectin Ascites(LF-ASC25) може да се користи како алтернатива наполиморфонуклеарните клетки (ПМНК) во асцит. СБП се јавува кај пациенти со сериозна црнодробна дисфункција пресметана според Child-Pugh II скорот и MELD скорот. Вредноста на C-реaктивниот протеин во серум и во асцит кај пациентите со СБП немаше високи вредности ,но сепак беше утврдена сигнификантна разлика во споредба со пациентите со не-СБП.&#x0D;

Critical care management in patients with acute liver failure.

Acute liver failure (ALF) is defined as severe hepatic dysfunction (marked transaminases elevation, detoxification disorder (jaundice and coagulopathy with international normal ratio (INR)>1.5), the presence of hepatic encephalopathy, and exclusion of underlying chronic liver disease, and a secondary cause like sepsis or cardiogenic shock. Reasons for ALF include paracetamol and warfarin toxicity, autoimmune and viral (mainly hepatitis B and E) hepatitis, and herbal and dietary supplements. Even in terms of meticulous and careful review of the patient, around 20-30% of the reasons remains unknown. In order of its rarity, a randomized controlled trial could hardly be done. However, because of improved ICU treatment, the mortality, even in the advanced stage of ALF decreased. However, in 5-10% of the cases an emergency transplantation is required. This justifies the treatment of this patient cohort in institutions that can provide this kind of treatment.

2508 A Case of Graves Disease Presenting With Severe Hepatic Dysfunction

INTRODUCTION: Cholestatic hepatitis attributed to thyroid disease is a rare presentation with only a handful cases reported in the literature. Often confused as a potential adverse effect of anti-thyroid therapy, this entity can prove to be elusive to diagnose and challenging to manage. CASE DESCRIPTION/METHODS: A 37-year old healthy male presented complaining of jaundice, pruritus, fatigue and significant weight loss over 3 months. His only medication was oxycodone for chronic back pain after a remote accident. Physical examination demonstrated scleral icterus with no hepatosplenomegaly or stigmata of chronic liver disease. Diagnostic evaluation demonstrated (1) Lymphocytic leukocytosis of 14,000 cells/mm3, microcytic anemia, normal platelet count, kidney function, serum albumin and INR, (2) mixed LFT pattern (R factor: 2.6) with marked cholestasis with ALP of 222 IU/L, AST of 132 IU/L, ALT of 192 IU/L, total bilirubin of 17.3 mg/dl with a direct fraction of 9.4 mg/dl (3) negative hepatitis, viral serologies, ANA, and AMA (4) elevated ferritin of 2,938 ng/ml with heterozygous H63D mutation, (5) normal MRCP (6) liver biopsy demonstrating cholestatic changes not compatible with autoimmune hepatitis, minimal iron deposition, and no evidence of fibrosis (7) TSH &lt; 0.01, fT4 (free thyroxine) of 1.5, fT4 (free triiodothyronine) of 4.3 and strongly positive thyroid stimulating immunoglobulins, TSH receptor antibodies, and anti-TPO antibodies. A radioiodine uptake scan (RAI) was consistent with Grave's disease. The patient was started on methimazole, propranolol and underwent subsequent surgical thyroidectomy with complete resolution of his symptoms and near complete resolution of his hepatitis in 3 months duration. DISCUSSION: Thyrotoxicosis presenting with severe hepatic dysfunction can prove a challenging entity to treat. Challenges include potential hepatotoxic effects of methimazole, propylthiouracil or radioactive iodine, and the risks of inducing thyroid storm by performing a surgical thyroidectomy without appropriate pre-treatment. The case reported highlights the importance of recognizing liver injury secondary to thyrotoxicosis, and reports successful treatment with surgical thyroidectomy after pre-treatment with methimazole and propanolol.

2257 Hepatic Dysfunction as a Result of Multiple Myeloma

INTRODUCTION: Plasma cell infiltration of the liver can be detected in up to 45% of patients with multiple myeloma (MM) at autopsy. However, only a few cases have been reported of plasma cell infiltration of the liver leading to plasmacytoma formation and non-obstructive cholestasis with progression to liver failure. CASE DESCRIPTION/METHODS: A 53-year-old African American male with history of IgG multiple myeloma status post AlloimmuneStem Cell transplant (ASCT) in 2010 was admitted for intermittent epistaxis, hemoptysis and fatigue found to have relapse. Patient was started on salvage therapy with bortezomib, dexamethasone, cyclophosphamide, etoposide and cisplatin (VDCEP). Physical exam revealed an alert and lethargic male in no acute distress but with asterixis. Sclera were icteric. Abdominal exam revealed marked hepatomegaly without tenderness. Laboratory data showed an ALT of 60 IU/L, total bilirubin of 11mg/dL and normal AST and ALP . INR was 3.0, platelets 38 × 103 mcL, Hgb 7.6gm/dL and WBC 1.6 × 103 mcL. Factor VIII activity was 311.1%. Ammonia levels were 67mcmol/L. Imaging with MRI showed an enlarged liver measuring 22.4cm without mass lesions. A transjugular liver biopsy was then performed revealing atypical mononuclear cell infiltration with positive stain for CD138 and MUM1 consistent with patient’s known history of labda-restricted plasma cell neoplasm (Figures 1 and 2). His clinical course deteriorated with worsening total bilirubin, hepatic encephalopathy and coagulopathy consistent with liver dysfunction and acute liver failure. Eventually there was development of multiorgan failure and death. Autopsy confirmed presence of myeloma cells in the liver forming a subcapsular plasmacytoma with associated extensive cholestasis and hepatocyte necrosis. DISCUSSION: Hepatic involvement of multiple myeloma most commonly presents with hepatomegaly and portends poor prognosis. It is important to recognize that patients may present with a cholestatic pattern of liver injury which can lead to severe hepatic dysfunction and liver failure such as the case of our patient. The histological pattern of liver involvement in MM can be in the form of light chain deposition disease, extramedullary plasmacytoma, amyloidosis, or a diffuse infiltrative pattern. Liver biopsy is thus an imperative way of diagnosis particularly to differentiate it from other entities causing similar pattern of injury such as sinusoidal occlusive syndrome or drug induced liver injury.

Advanced Hepatic Disease

Advanced liver disease poses many challenges to the anesthesiologist. In this focused review, we will identify the varying etiologies and demographics of the disease before detailing the wide-ranging impact on various organ systems. The effects of liver disease are often profound and require a thorough understanding of the underlying pathophysiology. Particular attention will be paid to those areas in which a thorough evaluation and optimization can enhance perioperative outcomes of those with advanced liver disease. Given the liver’s extensive involvement in drug metabolism, we will also review drug dosing and how it is altered in advanced disease. Procedures commonly performed on patients with advanced hepatic dysfunction will be discussed as their role is increasing in the management of the disease. While liver disease is familiar to the medical community, there have been recent advances that provide the anesthesiologist with new evidence-based management strategies. Though there is still much work to be done to understand the complex interactions of severe hepatic dysfunction, these recent advances will be highlighted to improve current management of these ill patients. This review contains 5 tables, and 51 references. Key Words: Thromboelastogram (TEG), MELD-Na, Prothrombin complex concentrates, Hepatopulmonary Syndrome, Portopulmonary Hypertension, Hepatic hydrothorax, Large volume paracentesis, Non-Alcoholic Fatty Liver Disease (NAFLD)

Integrated population pharmacokinetic (PopPK) modeling of cabozantinib (C) in patients (pts) with various cancer types including hepatocellular carcinoma (HCC).

305 Background: C significantly improved overall survival vs placebo in pts with previously treated advanced HCC in the phase 3 CELESTIAL trial (NCT01908426). In a previous single dose PK study, increased C exposure was observed in healthy volunteers (HV) with mild or moderate hepatic impairment (Nguyen, J Clin Pharmacol, 2016). An integrated PopPK model was recently developed to characterize C concentration data from HV and pts with various cancers, including renal cell carcinoma, castration-resistant prostate cancer, and medullary thyroid cancer (MTC) (Lacy, Cancer Chemother Pharmacol, 2018). Here, we update the model to include data for pts with advanced HCC from CELESTIAL and a prior phase 2 trial. Methods: The updated PopPK model was developed using nonlinear mixed effects modeling methodology (NONMEM v7.3) and incorporated data from 10 clinical studies with 9510 measurable C concentrations from 2023 subjects, including 489 pts with advanced HCC. Eligible pts with HCC were Child-Pugh class A. Evaluated covariates included age, gender, race, body weight, cancer type, and liver dysfunction as defined by the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG). Results: Overall, 70% of pts had normal hepatic function by NCI-ODWG criteria; 28% had mild, 1% had moderate, and &lt;1% had severe hepatic dysfunction. A 2-compartment model with first-order elimination and dual first- and zero-order absorption processes adequately described the data. As in the previous model, the MTC population was the only cancer type to have a notable difference in C PK, with ~90% increase in apparent clearance (CL/F) versus HV and pts with other cancers including HCC. For a White male, CL/F was estimated as 2.48 L/hr and apparent volume of the central compartment (Vc/F) as 212 L. Inter-individual variability was ~46% for CL/F and ~67% for Vc/F. Other demographic covariates were predicted to have a small to moderate impact on C CL/F. Liver dysfunction, per NCI-ODWG criteria, had no discernable effect on C CL/F. Conclusions: C exposure at an equivalent daily dose is predicted to be similar in pts with several cancer types including advanced HCC with mild liver dysfunction.

Heart and liver are infected in fatal cases of dengue: three PCR based case studies

BackgroundDengue is a global problem mainly in the tropics. Meticulous clinical management of cases has reduced the death rate significantly, but large numbers of people still succumb to severe complications of the infection. Presence of myocarditis is often overlooked leading to a poor outcome. Clinical management guidelines of dengue do not stress the importance of myocarditis as a manifestation in dengue infection. Severe hepatic dysfunction also needs emphasis.Case presentationWe present three patients who had come to hospital on the 3rd day of fever. Two of them (case 1 and 3) were in shock on admission and case 2, who was stable on the3rd day, went into the critical phase and developed shock while in the hospital on the 4thday. All three had tachycardia on admission that got worse with time. The clinical course was unstable with fluctuations in urine output and deterioration of organ function. Despite frequent monitoring and life support they survived only 2–3 days in hospital. All three patients had myocarditis during the critical phase. In the first case, myocarditis was confirmed by troponin estimation and echocardiogram. In the second and third cases, histopathology confirmed myocarditis. Haemorrhagic necrosis of the liver was found in case 2 and 3 with exponential rise of transaminases. In all three cases, viral RNA was detected in both heart and liver tissues by PCR amplification.ConclusionsWe stress that detection of myocarditis and liver involvement in any dengue patient is important from the onset of the illness where treatment should be tailored to prevent development of hypotension. Our findings are novel as PCR and histology are rarely done on tissues of deceased dengue patients in the world. Studies are needed to find therapeutic interventions to reverse cardiac and hepatic dysfunction in dengue infection.

Epidemiology and outcome of acute kidney injury due to venomous animals from a subtropical region of India

Aim: To study the epidemiology and outcome of acute kidney injury (AKI) caused by venomous animals.Methods: A retrospective study of patients admitted at Indira Gandhi Medical College Hospital, Shimla, with AKI due to venomous animals over a period of 15 years (January 2003–December 2017). Medical records were evaluated for patient information on demographic factors, clinical characteristics, complications, and outcome. Outcomes of requirement for intensive care unit (ICU) support, treatment with dialysis, survival, and mortality were analyzed. The survival and non-survival groups were compared to see the difference in the demographic factors, laboratory results, clinical characteristics, and complications.Results: One hundred and eighty-one patients were diagnosed with AKI caused by venomous creatures. Mean age was 44 ± 15.4 years, and the majority (54.1%) was women. Snakebite (77.9%) and wasp stings (19.9%) were the leading causes of AKI. Clinical details were available in 148 patients. The median duration of arrival at hospital was two days. 81.8% had oliguria, and 54.7% had a history of hematuria or having passed red or brown colored urine. The hematological and biochemical laboratory abnormalities were as follows: anemia (75%), leukocytosis (75.7%), hyperkalemia (35.8%), severe metabolic acidosis (46.6%), hepatic dysfunction (54.7%), hemolysis (85.8%), and rhabdomyolysis (65.5%). Main complications were as follows: gastrointestinal bleed (9.5%), seizure/encephalopathy (10.8%), and pneumonia/acute respiratory distress syndrome (ARDS) (11.5%). 82.3% of the patients required dialysis. 154 (85.1%) patient survived, and 27 (14.9%) patients died. As compared to the survival group, the white blood cell count, serum bilirubin, aspartate aminotransferase, alanine aminotransferase, creatine kinase, and lactate dehydrogenase were significantly higher, and serum albumin levels were significantly lower in patients who died. The proportion of patients with leukocytosis, hyperkalemia, metabolic acidosis, pneumonia/ARDS, seizure/encephalopathy, need for ICU support, and dialysis was significantly higher in patients who died.Conclusions: Snakebite and multiple Hymenoptera stings (bees and wasps) were the leading causes of AKI due to venomous animals. AKI was severe, a high proportion required dialysis, and the mortality was high.

LAPAROSCOPIC BILATERAL ADRENALECTOMY FOR REFRACTORY CUSHING DISEASE: A CASE REPORT

A 64-year-old man was diagnosed as having Cushing's disease due to multiple lumbar compression fracture in 2009. Although various treatments including three times transsphenoidal surgery and twice radiotherapy were performed, his serum cortisol level rose again and intractable cutaneous ulcer occurred. Just after discontinuation of medication to treat the progression due of severe hepatic dysfunction, deep vein thrombosis and pulmonary artery embolism occurred. To control the Cushing's disease, laparoscopic bilateral adrenalectomy was performed.

Stability of a type 2 diabetes rat model induced by high-fat diet feeding with low-dose streptozotocin injection.

The present study aims at determining the stability of a popular type 2 diabetes rat model induced by a high-fat diet combined with a low-dose streptozotocin injection. Wistar rats were fed with a high-fat diet for 8 weeks followed by a one-time injection of 25 or 35 mg/kg streptozotocin to induce type 2 diabetes. Then the diabetic rats were fed with regular diet/high-fat diet for 4 weeks. Changes in biochemical parameters were monitored during the 4 weeks. All the rats developed more severe dyslipidemia and hepatic dysfunction after streptozotocin injection. The features of 35 mg/kg streptozotocin rats more resembled type 1 diabetes with decreased body weight and blood insulin. Rats with 25 mg/kg streptozotocin followed by normal diet feeding showed normalized blood glucose level and pancreatic structure, indicating that normal diet might help recovery from certain symptoms of type 2 diabetes. In comparison, diabetic rats fed with high-fat diet presented decreased but relatively stable blood glucose level, and this was significantly higher than that of the control group (P<0.05). This model easily recovers with normal diet feeding. A high-fat diet is suggested as the background diet in future pharmacological studies using this model.

DENGUE HEPATIC SEVERITY SCORE: A GLIMMER TO THE CLINICIAN

Introduction: Recent studies from India and Thailand show that dengue infection was the most compelling cause of acute hepatic failure in children contributing to 18.5% and 34.3%, respectively, and till now, there is no proper dengue severity score based on the hepatic dysfunction, i.e. laboratory as well as clinical hepatic parameters. Objective: The objective of this study was to develop a new dengue hepatic severity score (DHSS) based on only hepatic dysfunction parameters. Methods: The present cross-sectional analytical study was conducted in the Department of Paediatrics, Burla, Sambalpur, Odisha, from November 2015 to October 2017 after getting the institutional ethical clearance. A total of 76 cases selected as per predefined inclusion and exclusion criteria, categorized into three groups after taking written informed consent of their legal hare. Relevant hepatic parameters (both clinical and laboratory) were collected, and data were finally analyzed using receiver operating characteristic curve to get a cutoff value for each group. Results: The cutoff value of DHSS of ?7 between Group 1 and Group 2 evidenced by area under the curve (AUC)=99.6% with 95% confidence interval (CI) (95.6–100%), sensitivity - 100%, specificity - 94.6%, and a cutoff ?18 between Groups 2 and 3 exhibited by AUC=100% with 95% CI (94.6–100%), sensitivity - 100%, and specificity - 94.6%. Hence, the DHSS is formulated as ?6 (no severe hepatic dysfunction), 7–17 (severe), and ?18 (very severe). Mean duration of hospitalization in days between three groups of hepatic dysfunction was statistically significant as evidenced by one-way ANOVA; F (2, 73)=19.83, p=0.000. Conclusion: DHSS system will help the primary health caregiver for triaging, early recognition, and prompt management to prevent additional deterioration.