Chronic Hepatic Insufficiency Research Articles

Vitamin D distribution by month, sex, and season in Turkey, Niğde province: A retrospective cohort study

Background/Aim: Epidemiological investigations consistently indicate a widespread deficiency and insufficiency of vitamin D on a global scale. Vitamin D deficiency can lead to various acute and chronic diseases, including pre-eclampsia, autoimmune disorders, cardiovascular diseases, certain cancers, type 2 diabetes, and neurological disorders. However, the relationship between vitamin D status and its implications for global and public health has not been comprehensively explored. Notably, the differing clinical decision thresholds for diagnosing vitamin D deficiency and insufficiency established by various associations can create diagnostic confusion. Therefore, our study aimed to assess the distribution of vitamin D levels in Niğde province, considering variations by month, gender, and season, with respect to the clinical decision thresholds defined by different associations. Methods: The study sample comprised 57,731 cases (71% women and 19% men) admitted to our hospital between January 2021 and December 2022. We retrospectively evaluated 25-hydroxyvitamin D (25(OH)D) levels based on months, seasons, age, and gender. Additionally, we examined 25(OH)D levels separately using the clinical decision thresholds set by the Vitamin D Council, the Endocrine Society, and the Food and Nutrition Board. Patients with chronic renal insufficiency, hepatic insufficiency, and gastrointestinal malabsorption were excluded from the study, encompassing patients of all age groups. Furthermore, we categorized patients into different age decades and analyzed their vitamin D levels. We compared the same months in 2021 and 2022, monitoring changes in vitamin D levels throughout the year. Vitamin D levels were measured using the electrochemiluminescence assay (ECLIA) on a Roche Cobas E801 instrument. Results: When comparing the same months in 2021 and 2022, there was no statistically significant decrease or increase in 25(OH)D levels (The P-values for January and December were 0.066, 0.395, 0.907, 0.465, 0.705, 0.541, 0.625, 0.860, 0.695, 0.549, 0.892, and 0.838, respectively). Vitamin D insufficiency was observed in 70.3% of women and 29.7% of men. Participants under one year of age exhibited the highest mean 25(OH)D level (34.9 ng/mL), while participants between 20 and 29 years of age had the lowest mean 25(OH)D level (15.7 ng/mL). The lowest mean 25(OH)D level was recorded in April 2022 (15.6 ng/mL), whereas the highest mean 25(OH)D level was observed in July 2021 (22.7 ng/mL). There was a slight negative correlation between age and 25(OH)D levels (r=-0.038, P<0.001). The Vitamin D Council classification identified the highest number of patients with vitamin D deficiency (n=50,833; 88%). The Food and Nutrition Board included the lowest number of patients with vitamin D deficiency (n=15,049; 26.1%). Conclusion: Vitamin D deficiency is prevalent in Niğde province, particularly among women, and remains a significant public health concern. We advocate for the adoption of a unified clinical decision threshold and the expansion of the national vitamin D supplementation program to encompass adolescents and adults.

Fibroblasts: Immunomodulatory factors in refractory diabetic wound healing.

Diabetes is a systemic disease in which patients with diabetes may develop peripheral neuropathy of the lower extremities and peripheral vascular disease due to long-term continuous exposure to high glucose. Delayed wound healing in diabetes is one of the major complications of diabetes. Slow wound healing in diabetic patients is associated with high glucose toxicity. When the condition deteriorates, the patient needs to be amputated, which seriously affects the quality of life and even endangers the life of the patient. In general, the delayed healing of diabetes wound is due to the lack of chemokines, abnormal inflammatory response, lack of angiogenesis and epithelial formation, and fibroblast dysfunction. The incidence of several chronic debilitating conditions is increasing in patients with diabetes, such as chronic renal insufficiency, heart failure, and hepatic insufficiency. Fibrosis is an inappropriate deposition of extracellular matrix (ECM) proteins. It is common in diabetic patients causing organ dysfunction. The fibrotic mechanism of diabetic fibroblasts may involve direct activation of permanent fibroblasts. It may also involve the degeneration of fibers after hyperglycemia stimulates immune cells, vascular cells, or organ-specific parenchymal cells. Numerous studies confirm that fibroblasts play an essential role in treating diabetes and its complications. The primary function of fibroblasts in wound healing is to construct and reshape the ECM. Nowadays, with the widespread use of single-cell RNA sequencing (scRNA-seq), an increasing number of studies have found that fibroblasts have become the critical immune sentinel cells, which can detect not only the activation and regulation of immune response but also the molecular pattern related to the injury. By exploring the heterogeneity and functional changes of fibroblasts in diabetes, the manuscript discusses that fibroblasts may be used as immunomodulatory factors in refractory diabetic wound healing, providing new ideas for the treatment of refractory diabetic wound healing.

Modern possibilities and prospects in evaluating the anticoagulant effect of direct oral anticoagulants

Currently, direct oral anticoagulants (DOACs) should be preferred when prescribing anticoagulant therapy to atrial fibrillation patients because of their lower potential for interactions and risk of bleeding than warfarin. However, in the absence of standardized laboratory tests and a specific antidote (except dabigatran), prescribing and monitoring DOAC therapy remains a challenge for clinicians and patients. The present review focuses on the problems of DOAC laboratory evaluation, indications, and prospects for its use. Routine coagulation tests including activated partial thromboplastin time, prothrombin time and thrombin time are not recommended for DOAC therapy. Currently, there are specific coagulation tests (anti-Xa activity factor determination for apixaban/ rivaroxaban and diluted thrombin time for dabigatran) that allow judging the presence of the drug in the blood. According to current recommendations, these tests should be used only to assess anticoagulant concentrations and not to adjust doses and decide on the timing of withdrawal before invasive intervention. Nevertheless, the issue of determining DOAC concentration during invasive interventions, the need for which only increases with age, is most relevant. Also a possible additional factor that may alter the bioavailability and pharmacokinetics of DOAC and be taken into account in the evaluation of laboratory activity is the presence of chronic renal disease, hepatic insufficiency, low or excess body weight. The use of specific coagulation tests for patients undergoing elective and urgent surgery among special categories of patients (with chronic kidney disease, low or excess body weight, renal failure) is promising.

Long term erectile function results of radical perineal prostatectomy

IntroductionAlthough many patients are being treated by radical prostatectomy (RP), there is still insufficient information about the changes in long-term erectile function after RP. Our aim is to examine long term, up to 5 year erectile function status of patients after Radical Perineal Prostatectomy (RPP). Materials and methodsOne hundred and thirty-two patients, who underwent bilateral nerve-sparing Radical Perineal Prostatectomy (RPP) in between January 2012 and January 2017, with preoperative age≤70, prostate volume<80g, transrectal ultrasound (TRUS) guided biopsy Gleason score (GS)<7, prostate specific antigen (PSA) value<10ng/mL, and cT stage≤2 (N0, M0) were included into this study. Exclusion criteria were previous cardiovascular diseases, serious chronic renal and/or hepatic insufficiency, neurological diseases, uncontrolled diabetes mellitus, and severe lung diseases. Patients who received additional treatment (hormonal and/or radiotherapy) after RPP were also excluded from the study group. Erectile function was evaluated before surgery and at postoperative 3rd, 12th, and 60th months. Patients with an “International Index of Erectile Function (IIEF) – 5” score of ≥21 and patients whose IIEF-5 scores were between 16 and 20 but responded as “yes” to the “Sexual Encounter Profile (SEP) – 2” and “SEP-3” questions were accepted as having normal erectile function. ResultsOut of the 132 patients, 96 (72.7%) of the patients were found to be potent in the first postoperative year. A total of 118 patients were evaluated at the end of 5 years. Eighty seven (73.7%) patients had normal erectile function according to our criteria. DiscussionAccording to the results of our study, short term and long term erectile function outcomes of patients undergoing RPP were favorable and there was no statistically significant difference between short and long term results.

Relationship between Pre-Eclampsia, Renal Impairment and Hepatic Insufficiency among Pregnant Women in Al-Jouf Area

Background: Pre-eclampsia is a pregnancy-specific syndrome. It affects 3-5% of pregnant women and is characterized by oedema, high blood pressure, and proteinuria. Moreover, in women with pre-eclampsia dysfunction of many organs, such as kidney and liver, is diagnosed, while in the case of foetus growth restriction is observed. Pre-eclampsia, when left untreated, can lead to a high mortality rate. In low-income countries, this disorder is one of the main causes of maternal and child mortality. Pre-eclampsia predisposes women in later life to cardiovascular diseases. So far, in acute cases of pre-eclampsia stabilization of the mother and fotus, and finally, termination of pregnancy at a time optimal for both sides can only be considered.Methods: The present work is designed to investigate the relationship between pre-eclampsia, renal and hepatic insufficiency in the Al-Jouf area through collecting information from the electronic database of maternity hospital for 100 pregnant women who suffered from pre-eclampsia compared with normal pregnancies.Results: The prevalence of pre-eclampsia is more prone in eldest women (older than 35 years old) almost 45% than younger women (20-25 years old), PC to MPV ratio value showed a significant suppression in pre-eclamptic pregnancies in comparison with normal pregnant women while HbA1c % value indicated a significant increase in the pre-eclamptic cases than the healthy pregnant women. Renal indices, serum creatinine, urea, and albumin were significantly higher in the pre-eclamptic women than in women with normal pregnancies.Conclusion: There is a tight relationship between hypertensive disorders during pregnancies, chronic renal disorders and hepatic insufficiency.

The Lymphatic Headmaster of the Mast Cell-Related Splanchnic Inflammation in Portal Hypertension

Portal hypertension is a common complication of liver disease, either acute or chronic. Consequently, in chronic liver disease, such as the hypertensive mesenteric venous pathology, the coexisting inflammatory response is classically characterized by the splanchnic blood circulation. However, a vascular lymphatic pathology is produced simultaneously with the splanchnic arterio-venous impairments. The pathological increase of the mesenteric venous pressure, by mechanotransduction of the venous endothelium hyperpressure, causes an inflammatory response involving the subendothelial mast cells and the lymphatic endothelium of the intestinal villi lacteal. In portal hypertension, the intestinal lymphatic inflammatory response through the development of mesenteric-systemic lymphatic collateral vessels favors the systemic diffusion of substances with a molecular pattern associated with damage and pathogens of intestinal origin. When the chronic hepatic insufficiency worsens the portal hypertensive inflammatory response, the splanchnic lymphatic system transports the hyperplasied intestinal mast cells to the mesenteric lymphatic complex. Then, an acquired immune response regulating a new hepato-intestinal metabolic scenario is activated. Therefore, reduction of the hepatic metabolism would reduce its key centralized functions, such as the metabolic, detoxifying and antioxidant functions which would try to be substituted by their peroxisome activity, among other functions of the mast cells.

Clinical Analysis of Hospital-acquired Bloodstream Infection in the Elderly

Objective: This study was designed to get epidemiological characteristics, etiology characteristics, prognosis assessment and prognostic factors of hospital-acquired bloodstream infection (HABSI) in the elderly in Chinese PLA General Hospital and aimed at providing a reference for HABSI in the elderly on clinical diagnosis and treatment to improve the prognosis. Methods: The clinical data and pathology data of 210 cases of the elderly patients with HABSI from 2009 to 2012 in geriatric wards were retrospectively analyzed. Compare the clinical assessment effects of APACHE-II score, SAPS-II score and SOFA score to HABSI prognosis in the elderly by plotting the receiver operating characteristic curve. Use univariate and multivariate logistic regression analysis to get prognostic factors of HABSI in the elderly. Results: Univariate analysis of mortality: Day 1 apache -&gt; 18 II score, lung infection, invasive ventilation, chronic hepatic insufficiency, chronic renal insufficiency, substantive organ malignant tumor, deep venipuncture, indwelling gastric tube indwelling ureter, complicated with shock and acquired bloodstream infections in the elderly patients with 7 days survival state association is significant. Day-1 SOFA score&gt;7, chronic liver dysfunction, chronic renal insufficiency, concurrent shock, hemodialysis and 28-day survival status of patients with acquired bloodstream infection in elderly hospitals were significantly associated. Multivariate unconditioned logistic regression analysis related to death: Day-1APACHE-II score&gt;18, parenchymal malignant tumors, and concurrent shock are independent risk factors for 7-day death in elderly patients with acquired bloodstream infection. Day-1 SOFA score&gt;7, chronic renal insufficiency, and concurrent shock are independent risk factors for 28-day mortality in elderly patients with acquired bloodstream infection. Conclusion: The incidence of acquired bloodstream infections in the elderly was 1.37%. The 7-day and 28-day mortality rates were 8.10% and 22.38%, respectively. Concurrent shock is 26.7%. The 28-day mortality rate of concurrent shock patients was 48.21%. The best outcome score for the 7-day prognosis of elderly patients with acquired bloodstream infection was the Day-1APACHE-II score, followed by the Day-1 SOFA score. The best score for the 28-day prognostic assessment was the Day-1 SOFA score.

Clinical Analysis of Hospital-acquired Bloodstream Infection in the Elderly

Objective: This study was designed to get epidemiological characteristics, etiology characteristics, prognosis assessment and prognostic factors of hospital-acquired bloodstream infection (HABSI) in the elderly in Chinese PLA General Hospital and aimed at providing a reference for HABSI in the elderly on clinical diagnosis and treatment to improve the prognosis. Methods: The clinical data and pathology data of 210 cases of the elderly patients with HABSI from 2009 to 2012 in geriatric wards were retrospectively analyzed. Compare the clinical assessment effects of APACHE-II score, SAPS-II score and SOFA score to HABSI prognosis in the elderly by plotting the receiver operating characteristic curve. Use univariate and multivariate logistic regression analysis to get prognostic factors of HABSI in the elderly. Results: Univariate analysis of mortality: Day 1 apache -&gt; 18 II score, lung infection, invasive ventilation, chronic hepatic insufficiency, chronic renal insufficiency, substantive organ malignant tumor, deep venipuncture, indwelling gastric tube indwelling ureter, complicated with shock and acquired bloodstream infections in the elderly patients with 7 days survival state association is significant. Day-1 SOFA score&gt;7, chronic liver dysfunction, chronic renal insufficiency, concurrent shock, hemodialysis and 28-day survival status of patients with acquired bloodstream infection in elderly hospitals were significantly associated. Multivariate unconditioned logistic regression analysis related to death: Day-1APACHE-II score&gt;18, parenchymal malignant tumors, and concurrent shock are independent risk factors for 7-day death in elderly patients with acquired bloodstream infection. Day-1 SOFA score&gt;7, chronic renal insufficiency, and concurrent shock are independent risk factors for 28-day mortality in elderly patients with acquired bloodstream infection. Conclusion: The incidence of acquired bloodstream infections in the elderly was 1.37%. The 7-day and 28-day mortality rates were 8.10% and 22.38%, respectively. Concurrent shock is 26.7%. The 28-day mortality rate of concurrent shock patients was 48.21%. The best outcome score for the 7-day prognosis of elderly patients with acquired bloodstream infection was the Day-1APACHE-II score, followed by the Day-1 SOFA score. The best score for the 28-day prognostic assessment was the Day-1 SOFA score.

Hepatic encephalopathy: definition, etiology, pathogenesis factors, clinical picture, diagnostic and treatment methods

The review presents modern information on such an actual clinical problem as hepatic encephalopathy syndrome upon acute and chronic hepatic insufficiency: its definition, etiology, detailed description of pathogenesis factors, clinical features, classification, diagnostic methods (clinical and laboratory-instrumental). The possibilities of treatment are fully highlighted: dietotherapy and pharmacotherapy of hepatic encephalopathy upon acute and chronic hepatic insufficiency.

Thyroid Hormone Receptor-β Agonist GC-1 Inhibits Met-β-Catenin–Driven Hepatocellular Cancer

The thyromimetic agent GC-1 induces hepatocyte proliferation via Wnt/β-catenin signaling and may promote regeneration in both acute and chronic liver insufficiencies. However, β-catenin activation due to mutations in CTNNB1 is seen in a subset of hepatocellular carcinomas (HCC). Thus, it is critical to address any effect of GC-1 on HCC growth and development before its use can be advocated to stimulate regeneration in chronic liver diseases. In this study, we first examined the effect of GC-1 on β-catenin-T cell factor 4 activity in HCC cell lines harboring wild-type or mutated-CTNNB1. Next, we assessed the effect of GC-1 on HCC in FVB mice generated by hydrodynamic tail vein injection of hMet-S45Y-β-catenin, using the sleeping beauty transposon-transposase. Four weeks following injection, mice were fed 5 mg/kg GC-1 or basal diet for 10 or 21 days. GC-1 treatment showed no effect on β-catenin-T cell factor 4 activity in HCC cells, irrespective of CTNNB1 mutations. Treatment with GC-1 for 10 or 21 days led to a significant reduction in tumor burden, associated with decreased tumor cell proliferation and dramatic decreases in phospho-(p-)Met (Y1234/1235), p-extracellular signal-related kinase, and p-STAT3 without affecting β-catenin and its downstream targets. GC-1 exerts a notable antitumoral effect on hMet-S45Y-β-catenin HCC by inactivating Met signaling. GC-1 does not promote β-catenin activation in HCC. Thus, GC-1 may be safe for use in inducing regeneration during chronic hepatic insufficiency.

Adipose-derived mesenchymal stem cells slow disease progression of acute-on-chronic liver failure.

A serious complication of chronic hepatic insufficiency is acute-on-chronic liver failure, a recognized syndrome characterized by acute decompensation of cirrhosis and organ/system failure. We investigated the use of adipose-derived mesenchymal stem cells (AD-MSCs) in an experimental model of acute-on-chronic liver failure, developed by microsurgical extrahepatic cholestasis in rats. Rats undergoing microsurgical extrahepatic cholestasis were treated by intraparenchymal liver injection of human or rat AD-MSCs, undifferentiated or previously differentiated in vitro toward the hepatocyte lineage. The groups treated with rat AD-MSCs showed less ascites, lower hepato- and splenomegaly, less testicular atrophy, and an improvement in serum biochemical hepatic parameters. There was also an improvement in histological liver changes, in which the area of fibrosis and bile duct proliferation were significantly decreased in the group treated with predifferentiated rat AD-MSCs. In conclusion, an isograft of hepatocyte-predifferentiated AD-MSCs injected intraparenchymally 2 weeks after microsurgery in extrahepatic cholestatic rats prevents secondary complications of acute-on-chronic hepatic failure. These data support the potential use of autologous AD-MSCs in the treatment of human cholestasis, and specifically of newborn biliary atresia, which could be beneficial for patients awaiting transplant.

The Relationship between Extensively Drug-Resistant Tuberculosis and Multidrug-Resistant Gram-Negative Bacilli.

ObjectiveThe relationship between extensively drug-resistant tuberculosis (XDR-TB) and multidrug-resistant Gram-negative bacilli (MDR-GNB) is unclear. Identification of the relationship between XDR-TB and MDR-GNB would have important implications for patient care.MethodsWe conducted a retrospective study reviewing the records of patients admitted with a confirmed pulmonary TB from 2011 to 2014. To identify the relationship between XDR-TB and MDR-GNB, univariable comparison and multivariable logistic regression were performed.ResultsAmong 2962 pulmonary TB patients, 45(1.5%) patients had a diagnosis of XDR-TB. A total of 165 MDR-GNB strains were detected in 143 (4.8%) pulmonary TB patients. XDR-TB patients had a significantly higher occurrence of MDR-GNB than non-XDR-TB patients (24.4% vs. 4.5%; P<0.001). Age (OR 1.02, 95% CI 1.01–1.03), hypoalbuminemia (OR 1.48, 95% CI 1.18–1.85), chronic renal failure (OR 6.67, 95% CI 1.42–31.47), chronic hepatic insufficiency (OR 1.99, 95% CI 1.15–3.43), presence of XDR-TB (OR 6.56, 95% CI 1.61–26.69), and duration of TB diagnostic delay (OR 1.01, 95% CI 1.00–1.02) were the independent risk factors for MDR-GNB infection.ConclusionsPatients with XDR-TB have a significantly higher risk of being affected by MDR-GNB pathogen. The underlying mechanism association warrant further studies.

Reference ranges for serum and salivary testosterone in young men of Mediterranean region

Background and aimsThe interassay variability found in the measurement of testosterone (T) levels warrants the need for laboratories to validate their methods to establish trustworthy cut-off points for diagnosis of male hypogonadism. The aims of this study were to validate measurement of total T (TT) at our laboratory in order to obtain reference ranges for TT, calculated free T (CFT), calculated bioavailable T (CBT), and salivary T (ST) in healthy young men from the Mediterranean region, and to evaluate the potential clinical value of ST by establishing its correlation with serum T. MethodsAn observational, cross-sectional study with sequential sampling. Inclusion criteria: men aged 18–30 years with body mass index (BMI)<30. Exclusion criteria: chronic diseases, hepatic insufficiency or use of drugs altering circulating T levels. Main outcome measures TT (chemiluminescent immunoassay UniCell DXI 800 [Access T Beckman Coulter]), CFT and CBT (Vermeulen's formula), and ST (radioimmunoassay for serum TT modified for saliva [Coat-A-Count, Siemens]). Descriptive statistical analyses and correlation by Spearman's rho (SPSS 19.0 Inc., Chicago) were used. ResultsOne hundred and twenty-one subjects aged 24±3.6 years with BMI 24±2.5kg/m2 were enrolled. Hormone study: TT, 19±5.5nmol/L (reference range [rr.] 9.7–33.3); CFT, 0.38nmol/L (rr. 0.22–0.79); CBT, 9.7nmol/L (rr. 4.9–19.2); and ST, 0.35nmol/L (rr. 0.19–0.68). Correlation between ST and CFT was 0.46. ConclusionsIn men from the Mediterranean region, values of TT>9.7nmol/L, CFT>0.22nmol/L, and/or CBT>4.9nmol/L make the presence of biochemical hypogonadism unlikely. According to the correlation between serum and ST, the clinical value of ST remains to be established.

Lactate Clearance is a Prognostic Factor in Patients on Shock State

Aim is to determine whether lactate clearance has value as mortality prognostic factor in shock patients, or not. A scrutiny, descriptive, prolective, homodemic, longitudinal study in patients older than 19 years, excluding chronic renal illness, hepatic insufficiency, neoplasias and diabetics on biguanides treatment, was performed. Arterial gasometry was used to obtain lactate rates at admission, 6, 12, and 24 hours as well as lactate’s clearance. Determinations between survivors and not survivors were compared, as well as correlation with APACHE II was performed. 41 patients were studied, 53.7% women and 46.3% men, mean age was 63.95 years. The diagnostics were septic shock in 29.2%, hypovolemic 63.4%, and cardiogenic 7.3%. The mortality in cardiogenic shock was 100%, with null lactate clearance. The survival rate was higher in hypovolemic shock as its lactate clearance rates (at 12 and 24 hours). Lactate clearance rates of less than 0 at 24 hours had a positive predictive value and a sensitivity of 80%. Lactate clearance at 6, 12, 24 hours among survivors and not survivors demonstrated statistical significance in the Univariate Analysis (p<0.002, p<0.000, p<0.000) respectively. The lactate clearance rate at 24 hours is a prognostic factor for mortality in patients in shock state.

P-1347 - Reboxetine-treated narcolepsy: case report

Narcolepsy is a disabling sleep disorder affecting 0.02% of adults worldwide. It is characterized by irresistible daytime sleepiness, catalepsy and can be associated with sleep paralysis, and hipnagogic hallucinations. The treatment is essentially symptomatic with stimulant drugs (mostly dopaminergic) for daytime sleepiness and sleep attacks, antidepressants (mostly noradrenergic) for catalepsy and hypnotics for disturbed night-time sleep. Special care must be taken, with close blood monitoring for toxicity, in the prescription of these drugs to patients with concurrent renal or hepatic disease. The authors present a case of a 72 year-old female patient with the diagnoses of narcolepsy and conjoint severe chronic renal and hepatic insufficiency, with intolerance for most of the recommended treatments for her sleep disorder. The patient is observed in a psychiatric consultation after several bone fractures due to cataleptic phenomena. We describe a successful therapeutical approach with reboxetine, with a significant improvement in daytime sleepiness, reflected by a decrease of 52% on the Epworth Sleepiness Scale. Furthermore, a significant reduction in the cataplexy subscore of the Ullanlinna Narcolepsy Scale was also found. Consequently, this treatment led to a decrease in the frequency of catalepsy attacks and secondary traumatic injuries and an increase in the Global Assessment of Functioning scale.

Fatal pulmonary microthrombi during surgical therapy for end-stage heart failure: Possible association with antifibrinolytic therapy

Maintaining hemostasis in patients with end-stage heart failure undergoing cardiac surgery is always challenging. These patients have chronic hepatic insufficiency, resulting in derangement of coagulation. In addition, they are commonly receiving both systemic anticoagulation (warfarin or heparin) and antiplatelet therapy. The introduction of antifibrinolytics has had a significant effect on postoperative coagulopathy. We report fatal pulmonary microthrombi in patients receiving antifibrinolytics who developed suprasystemic pulmonary artery pressures and right heart failure that was impossible to overcome despite insertion of a right ventricular assist device. We reviewed the surgical procedure and autopsy reports to identify patients with high pulmonary artery pressures caused by pulmonary microthrombi after a cardiac surgical procedure for end-stage heart failure. Patient demographics and preoperative, intraoperative, and postoperative variables were collected from a retrospective review of the patients' medical records. We identified 9 patients (7 men and 2 women; mean age, 45 +/- 16 years) who died of pulmonary microthrombi after cardiac surgery between January 1997 and January 2004. Surgical procedures included 5 left ventricular assist device implantations, 2 heart transplantations, and 2 left ventricular reconstructions with mitral valve repair or replacement. Eight patients received aprotinin, and 1 patient received epsilon-aminocaproic acid immediately before and during cardiopulmonary bypass. All patients had severe suprasystemic pulmonary artery pressures after protamine administration for heparin reversal, a complication that proved fatal in all cases. Intraoperative wedge biopsy of the lungs revealed multiple microthrombi within capillaries and in the small- and medium-sized pulmonary arterioles. We report 9 cases for which fatal pulmonary microthrombi might be associated with the use of prophylactic antifibrinolytic therapy. Mortally ill patients with multiorgan failure who are receiving systemic anticoagulation and undergoing surgical procedures require careful perioperative monitoring to identify potential hazards. Anticoagulation and antifibrinolytic therapy protocols may require adjustment in such patients.

The fetal circulation and essential organs—a new twist to an old tale

The fetal circulation and essential organs—a new twist to an old tale

Pharmacokinetic Profile of the Somatostatin Analogue Lanreotide in Individuals with Chronic Hepatic Insufficiency

The somatostatin analogue lanreotide is indicated for the treatment of acromegaly and to relieve the symptoms of neuroendocrine tumours. The objective of the present study was to compare the pharmacokinetic profile and safety of intravenous lanreotide in healthy volunteers and individuals with hepatic impairment. Immediate-release lanreotide was administered at 7 microg/kg during a 20-minute intravenous infusion. Blood samples were collected over 24 hours and lanreotide serum levels determined by radioimmunoassay. Pharmacokinetic parameters were estimated by non-compartmental analyses. Two study centres recruited 53 individuals. Study A comprised 10 individuals with hepatic insufficiency Child-Pugh grade A (mild), 7 with grade B (moderate) and 12 healthy volunteers - all Caucasian. Study B comprised 4 individuals with hepatic insufficiency Child-Pugh grade A, 6 with grade B, 2 with grade C (severe) and 12 healthy volunteers - all Chinese. All participants were included in the safety analysis. The pharmacokinetic analysis included all participants from study B, but only 12 with hepatic impairment and 11 healthy volunteers from study A. Combined analysis of both studies showed an increased serum elimination half-life (57%; p < or = 0.001), mean residence time (53%; p < or = 0.001) and volume of distribution (at steady state, 57%; at terminal disposition phase, 64%; both p < or = 0.001) in individuals with mild hepatic insufficiency compared with healthy volunteers. These differences were more pronounced in individuals with moderate-to-severe hepatic insufficiency compared with healthy volunteers; additionally, the area under the serum concentration-time curve from time zero to infinity (AUC(infinity)) was increased (23%; p < or = 0.05) and clearance (CL) decreased (19%; p < or = 0.05) compared with healthy volunteers. The peak serum concentration of lanreotide tended to be lower in individuals with hepatic insufficiency than in healthy volunteers (statistically non-significant). There were no pharmacokinetic differences between the two groups of healthy volunteers. Lanreotide was well tolerated with only two mild adverse events that were considered to be possibly related to treatment (both nausea and headache with either vomiting or dizziness). There were no clinically relevant changes in laboratory parameters or vital signs during the study. The pharmacokinetic profile of lanreotide depends on the severity of hepatic insufficiency with CL and AUC(infinity), which are only slightly altered with moderate-to-severe insufficiency. The changes in exposure do not, however, require dosage adjustment. Moreover, lanreotide is usually given as a prolonged-release microparticle or Autogel formulation, and terminal half-life and serum concentrations depend on the release properties of the formulation. Dosing is also adapted for each patient, based on therapeutic response. Thus, hepatic insufficiency does not require additional dosage adjustments.

Successful combined liver and kidney transplant for COACH syndrome and 5‐yr follow‐up

The COACH syndrome is a very rare disorder with cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis. Nineteen cases with COACH diagnosis have been reported. Neurologic abnormalities are the first symptoms in most cases. Complications of the hepatopathy [portal hypertension, esophageal varices, and gastrointestinal (GI) bleeding] contribute extensively to the morbidity and lethality in the course of the disease. We describe a 28-yr-old female with COACH syndrome resulting in chronic renal and hepatic insufficiency. The patient was found to have significant mental retardation, truncal ataxia, motor abnormality and occulomotor abnormality. She began to develop GI bleeding and encephalopathy because of biopsy-confirmed cirrhosis. We performed combined liver and kidney transplant after challenging discussion. Her postoperative course was uneventful, and she was discharged on the ninth postoperative day (POD). She has not had any problems at 1, 3 and 5-yr follow-up with excellent liver and renal function. This is the first description of successful combined liver and kidney transplant with long-term follow-up. The decision for transplant is challenging because COACH syndrome is rare with only descriptive characterization and patients have non-progressive ataxia and mental retardation. However, our case shows that liver and kidney transplant can be medically successful, and the individuals achieve long-term success if they have a stable neurological condition and an excellent support system.

Characterization of Long-Term Survival of Syngeneic Hepatocytes in Rat Peritoneum.

Hepatocyte transplantation is a potential therapy for both acute and chronic hepatic insufficiency and also for treatment of inborn errors of metabolism affecting the liver. The peritoneum is one site for implantation and has several advantages: cells implanted there can be easily identified and observed, and it has a relatively large capacity. Long-term survival using "pure" hepatocytes in the peritoneum have been disappointing. We hypothesized that cotransplantation of hepatocytes with nonparenchymal cells would help maintain differentiated hepatocyte function. Rat liver cells transplanted intraperitoneally into August rats were sacrificed at 7 days, 1, 3, 6, 9, and 12 months and analyzed for presence, basal proliferation, and functionality of hepatocytes. To demonstrate that ectopic hepatocytes remained susceptible to exogenous growth factors affecting cell proliferation, rats 9 and 12 months after transplantation were stimulated with tri-iodothyronine and KGF. Hepatocytes were identified 7 days to >12 months, by H&E and immunohistochemically, as ectopic islands in the omental fat. Functionality was confirmed by glycogen deposition. Basal proliferation in 7-day rats was 28.0 ± 10/1000 hepatocytes in ectopic islands (cf. 5.70 ± 2.7/1000 in recipient liver). Proliferation in ectopic islands was greater than host liver. Growth factor-stimulated proliferation in ectopic islands induced a 70-fold increase in DNA synthesis. In conclusion, hepatocytes transplanted with nonparenchymal cells survive, proliferate, and function in the peritoneum of normal rats, and respond to exogenous growth stimuli. Their survival and proliferation in the presence of a normal functioning liver has implications for the potential use of the peritoneal site clinically for supplementation of liver function in metabolic disorders.