Проблемні питання диференційної діагностики жовтяниць у дітей. Випадки з практики (клінічна лекція)

Adeno-associated viral (AAV) vectors can target the liver, making them an attractive platform for gene therapy approaches that require the correction of hepatocytes. Crigler-Najjar syndrome is an autosomal recessive disorder of bilirubin metabolism that occurs when the liver's uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) enzyme activity is partially or completely absent. This syndrome is characterized by elevated bilirubin levels in the blood. An AAV8 vector was developed expressing a codon-optimized human version of UGT1A1 from a liver-specific promoter. High doses of the vector rescued neonatal lethality in newborn UGT1 knockout (KO) mice, which serve as a model of Crigler-Najjar syndrome, and significantly increased survival from 5 to 270 days. Newborn UGT1 KO mice treated with AAV had serum total bilirubin levels that were 5.7 times higher than the levels seen in heterozygous and wild-type mice, likely due to dilution of vector genome copies (GC) in the liver resulting from a proliferation of hepatocytes during growth of the animal. The elevation in serum total bilirubin levels in adult UGT1 KO mice depended on the AAV8 vector dose. At doses <1011 GC/mouse, total bilirubin levels returned to those seen in phototherapy-rescued UGT1 KO mice. Mice injected with vector at 1011 or 3 × 1011 GC/mouse had sustained reduced total bilirubin levels throughout the duration of the study. When an AAV8 vector was re-administered in mice with elevated total bilirubin levels, serum total bilirubin levels decreased to wild-type levels (0.1-0.3 mg/dL) in mice that received a vector dose of 3 × 1012 GC/kg. Therefore, a low-level and likely transient decrease in serum total bilirubin during the first days of life is necessary for rescuing the lethal phenotype present in the neonatal UGT1 KO mouse. Furthermore, it was possible to ablate the elevated total bilirubin levels in adult mice by re-administering an AAV8 vector.

Background: Present study was aimed to evaluate whether measurement of serum delta bilirubin and albumin level predict the chronicity and subsequent impaired hepatic function across the spectrum of different types of jaundice.Methods: Serum total bilirubin, Delta bilirubin, albumin and GGT activity was measured by reflectance spectrophotometry.Result: Decreased serum albumin was found in a significant inverse correlation with elevated delta bilirubin level among the subjects with obstructive (r=-0.4217,p=0.0023) and hepatic jaundice (r=-0.4214,p=0.0023). Conclusion:Significant inverse relationship between elevated delta bilirubin and lower albumin level might indicate that the chronicity of the disease may be the predominant factor in hepatobiliary obstruction or hepatocellular injury that may worsen the pathology of obstructive or hepatic jaundice.

A fetal wound healing program after intrauterine bile duct injury may contribute to biliary atresia

Objective To investigate the clinical features and treatment of residual gallbladder lesions after cholecystectomy. Methods The retrospective cross-sectional study was conducted. The clinicopathological data of 83 patients with residual gallbladder lesions after cholecystectomy who were admitted to the Affiliated Hospital of Inner Mongolia Medical University between January 2009 and April 2016 were collected. Among the 83 patients, 74 had residual gallbladder (41 combined with bile duct stones and 33 with simple residual gallbladder) and 9 had simple residual bile duct stones. Patients received laboratory and imaging examinations, and then selected suitable surgery according to residual lesions. Observation indicators included: (1) clinical features: medical history, clinical manifestation, features of laboratory and imaging examinations; (2) surgical and postoperative situations: surgical procedure, operation time, volume of intraoperative blood loss, time of drainage-tube removal, postoperative complications and duration of postoperative hospital stay; (3) postoperative pathological examination; (4) follow-up situation. Follow-up using outpatient examination and telephone interview was performed to detect survival of patients and recurrence of lesions using abdomen color Doppler ultrasound up to October 2016. Measurement data with normal distribution were represented as ±s. Results (1) Clinical features: ① medical history: all the 83 patients had histories of cholecystectomy, including 57 with emergency operation and 26 with selective operation. ② Clinical manifestation: initial clinical manifestation occurred at 1-324 months postoperatively, with an average time of 96 months. Of 83 patients, 49 had right upper abdominal colic associated with right shoulder or back rediating pain, fever, nausea and vomiting, 24 had jaundice as the main symptoms, 8 had gradually worse conditions, with right upper quadrant abdominal pain, chills and fever associated with jaundice in the advanced stage and 2 had abdominal discomfort associated with incomplete intestinal obstruction. ③ Laboratory examination: elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels were detected in 48 patients, elevated total bilirubin (TBil) level in 28 patients and elevated serum and urinary amylase level in 4 patients, respectively. ④ Imaging examination: of 83 patients, 77 had positive results of magnetic resonanced cholangio-pancreatography (MRCP), 43 had positive results of abdominal color Doppler ultrasound and 39 (4 combined with pancreatitis) had positive results of abdominal computed tomography (CT). (2) Surgical and postoperative situations: all the 83 patients underwent surgery. Of 74 patients with residual gallbladder, 72 underwent residual gallbladder resection (of 41 combined with bile duct stones, 35 undergoing residual gallbladder resection + bill duct exploration and removing the stone + T-tube drainage, 6 initially undergoing endoscopic sphincterotomy for removing bile duct stones and then residual gallbladder resection and 31 undergoing simple residual gallbladder resection), 1 combined with residual gallbladder cancer underwent residual gallbladder resection + common bile duct resection + hepatic duct-jejunum internal drainage and 1 combined with residual gallbladder cancer and common bile duct space-occupying lesion underwent palliative biliary-enterostomy. Nine patients with simple residual bile duct stones underwent endoscopic sphincterotomy for removing bile duct stones. Operation time, volume of intraoperative blood loss, time of drainage-tube removal and duration of postoperative hospital stay were (92±39)minutes, (63±12)mL, (5±4)days and (9±5)days in 74 patients with residual gallbladder, respectively. There was no severe postoperative complication. Operation time, volume of intraoperative blood loss and duration of postoperative hospital stay were (57±33)minutes, (25±9)mL and (5±3)days in 9 patients with simple residual bile duct stones, respectively. No severe complication was occurred in 9 patients. (3) Postoperative pathological examination: the length of residual cystic duct in 74 patients with residual gallbladder was (2.8±1.0)cm, combining with stones. Of 74 patients, simple hyperplasia of residual gallbladder were detected in 54 patients, dysplasia in 14 patients, tumor-like hyperplasia and benign tumor in 4 patients and adenocarcinoma in 2 patients. (4) Follow-up situation: all the 83 patients were followed up for 6-71 months, with a median time of 33 months. Eighty-one patients were healthy survival, without recurrence of lesions. One patient had recurrence of bile duct stones at 34 months postoperatively, and then was cured by choledochojejunostomy, without recurrence up to the end of follow-up. One patient with residual gallbladder cancer complicated with common bile duct space-occupying lesion died at 9 months postoperatively. Conclusions Patients have recurrent right upper abdominal colic associated with right shoulder or back rediating pain, fever and jaundice after cholecystectomy, and lesions of residual gallbladder or bile duct stones should be considered. Reoperation is safe and feasible for patients, with a good clinical outcome. Key words: Remnant gallbladder; Cholelithiasis; Cholecystectomy

The protective effect of increased levels of indirect bilirubin on atherosclerotic heart disease in patients of Gilbert's syndrome is well known. The aim of the study was to investigate the effects of increased levels of bilirubin on the mean platelet volume (MPV) and other hematological parameters. Thirty-two men and 36 women (a total of 68 Gilbert's syndrome patients) and a similar age group of 68 healthy individuals (32 men and 36 women) were included in the study. Hematologic tests, C-reactive protein (CRP) and biochemical values of the two groups were checked. MPV level of Gilbert's syndrome group was 7.8±1.0fl and CRP 0.2±0.27mg/dl. In the control group MPV was 8.6±1.0fl and CRP 0.3±0.38mg/dl. MPV of patients group (P<0.001) and CRP (P=0.037) were significantly lower than the control group. When dividing Gilbert's syndrome and control groups according to sex into subgroups the level of indirect bilirubin in men with Gilbert's syndrome (1.8±0.8mg/dl) was found to be higher than other groups. Healthy men had higher levels of MPV (8.8±0.9fl) whereas Gilbert's syndrome male patients had lower levels (7.7±1.1fl), (P<0.001). The elevated levels of bilirubin and decreasing levels of MPV and CRP in Gilbert's syndrome patients may have an effect on the slowing down of the atherosclerotic process.

Diagnosis and Management of Primary Sclerosing Cholangitis

Bile acids are implicated as aetiological factors in many types of gastrointestinal tract cancer including cholangiocarcinoma (CCA). Alterations in bile acid concentrations may affect the pathogenesis of these different types of cancer. Our aim was to determine the bile acid profile in gallbladder bile from patients who underwent liver resection. Thirty-seven patients with cholangiocarcinoma, 5 with hepatocellular carcinoma, and 7 with benign biliary diseases were studied. High pressure liquid chromatography was used to analyze conjugated and unconjugated bile acids. CCA patients with low (≤ 2 mg/dl) and high (>2 mg/dl) levels of total serum bilirubin had significantly higher total bile acid and conjugated bile acid concentrations than the benign biliary disease group. Markedly elevated levels of cholic and chenodeoxycholic acid were found in CCA cases with high levels of total serum bilirubin. Concentrations of total bile acids and primary bile acid were correlated with serum cholesterol, bilirubin and ALP in CCA. Notably, correlation of the carcinoembryonic antigen, a tumor marker, was found with level of total bile acids and chenodeoxycholic acid. These findings suggest a different pattern of bile acid concentration in cancer patients compared to patients with benign biliary diseases. Thus, accumulation of certain bile acids may be involved in carcinogenesis.

We performed this study to identify predictors of mortality in critically ill patients treated with continuous venovenous hemodiafiltration (CVVHDF) for acute renal failure in an intensive care setting. It was an uncontrolled, observational study that took place in a general intensive care unit in a university hospital. Forty-one patients undergoing CVVHDF for acute renal failure in a consecutive sample of 1,018 ICU treatments were studied. The underlying disease included 25 postsurgical cases and 16 medical cases. Between survivors (n = 23) and nonsurvivors (n = 18), the following factors were assessed: demographic data; the number and type of failed organs; Acute Physiology and Chronic Health Evaluation (APACHE) II scores; urine production; pH; base excess; serum creatinine levels; bilirubin levels; lactate levels; platelet counts; and hemodynamic variables, including cardiac index and central venous pressure. On univariate analyses, the number of failed organs (p < 0.01), presence of hepatic failure (p < 0.01), APACHE II scores (p < 0.01), pH (p < 0.01), base excess (p < 0.001), average urinary production before the initiation of CVVHDF (p < 0.05), and serum bilirubin (p < 0.01) and lactate levels (p < 0.001) were significantly different. Multiple regression analysis identified serum bilirubin (p < 0.01) and lactate levels (p < 0.01) as the predictors of hospital mortality. Presence of hepatic failure was also predictive of hospital mortality (p < 0.01) in the analysis of the type of organ failure. The cut-off value set at bilirubin levels > 10 mg/dl or arterial lactate levels > 3.5 mmol/L provided 83.3% sensitivity and 90.9% specificity in the prediction of hospital death. The crucial factors in predicting outcome of critically ill patients undergoing CVVHDF for renal failure are elevated serum bilirubin and lactate levels at the onset of CVVHDF. Presence of hepatic failure, defined as both jaundice and coagulopathy, may also worsen outcome of critically ill patients undergoing CVVHDF for renal failure. The cut-off value set at bilirubin levels > 10 mg/dl or arterial lactate levels > 3.5 mmol/L may serve as beneficial predictors of hospital mortality.

Biliary cystadenoma (also called mucinous cystic neoplasm with low-grade intraepithelial neoplasia) is a rare cystic tumor that arises from the biliary epithelium. The cause of biliary cystadenoma is still unclear. Jaundice is a rare presentation of intrahepatic biliary cystadenoma, which can lead to a diagnostic dilemma. Herein, we present a case of intrahepatic biliary cystadenoma that primarily exhibited as jaundice. A 56-year-old woman has suffered from yellow staining of her skin and sclera for more than 1 month. She had a poor appetite and mild epigastric pain. Laboratory examination showed elevated levels of total bilirubin and elevated carbohydrate antigen 19-9 (CA19-9). A contrast-enhanced computed tomography of the abdomen showed a 7.4 * 5.3-cm, oval, low-density lesion in the left liver parenchyma with a clear boundary and visible septa. The common bile duct was obviously dilated with wall thickening. On magnetic resonance imaging, the lesion in the liver showed a multilocular cystic, unenhanced long T2 signal. There was local thickening of the common bile duct wall with short T2-like filling defects and high signal intensity on diffusion-weighted imaging (DWI). The patient had no history of other malignant tumors and adjuvant therapy such as radiotherapy and chemotherapy. She was clinically suspected of having either biliary cystadenoma or a malignancy; hence, resection was performed. Macroscopically, the excised tissue specimen showed a polypoid mass in the common bile duct, which extended along the bile duct to the intrahepatic bile duct. There was a cystic and solid mass in the left liver with yellow turbid fluid, which was associated with the polypoid mass in the common bile duct. Histopathology suggests mucinous cystadenoma of the liver and hilar bile duct. The differential diagnosis of biliary cystadenoma and treatment selection have been discussed.

BackgroundAccording to the literature, benign bile duct tumors are exceedingly uncommon. To the best of our knowledge, we report the largest extrahepatic bile duct villous adenoma described in the literature.Case presentationWe present a case of a 77-year-old Caucasian woman with obstructive jaundice. Laboratory tests revealed that she had elevated bilirubin and liver enzyme levels. A computed tomographic scan showed a homogeneous 5 × 3–cm mass obstructing the common bile duct. The results of brush cytology were consistent with a bile duct villous papilloma. However, on the basis of the tumor’s radiological features, a preliminary diagnosis of extrahepatic bile duct malignant tumor was made. After discussion among the multidisciplinary team, a surgical resection of the bile duct tumor was performed. Histopathological examination confirmed a villous adenoma. The patient’s postoperative course was uneventful.ConclusionsIn patients with bulky extrahepatic bile duct tumors, surgical resection alone may be safe and curative.

In critically ill patients, liver dysfunction often results in coagulopathy and encephalopathy and is associated with high mortality. Extracorporeal clearance of hepatotoxic metabolites, including bilirubin and ammonia, aims to attenuate further hepatocyte damage and liver injury, resulting in decreased mortality. The efficacy of hemadsorption combined with conventional hemodialysis to eliminate bilirubin and ammonia to support the liver’s excretory function in acute liver injury has been described previously. However, the optimal use of liver support systems in chronic liver dysfunction due to secondary sclerosing cholangitis in critically ill patients (SSC-CIP) has not been defined yet. We herein describe the kinetics of successful bilirubin and ammonia elimination by hemadsorption in a patient with SSC-CIP after extracorporeal membrane oxygenation (ECMO) therapy for severe acute respiratory distress syndrome (ARDS) in a patient with coronavirus disease 2019 (COVID-19). During the course of the disease, the patient developed laboratory signs of liver injury during ECMO therapy before clinically detectable jaundice or elevated bilirubin levels. A diagnosis of SSC-CIP was confirmed by endoscopic retrograde cholangiopancreatography (ERCP) based on intraductal filling defects in the intrahepatic bile ducts due to biliary casts. The patient showed stable elevations of bilirubin and ammonia levels thereafter, but presented with progressive nausea, vomiting, weakness, and exhaustion. Based on these laboratory findings, hemadsorption was combined with hemodialysis treatment and successfully eliminated bilirubin and ammonia. Moreover, direct comparison revealed that ammonia is more efficiently eliminated by hemadsorption than bilirubin levels. Clinical symptoms of nausea, vomiting, weakness, and exhaustion improved. In summary, bilirubin and ammonia were successfully eliminated by hemadsorption combined with hemodialysis treatment in SSC-CIP following ECMO therapy and severe COVID-19. This observation is particularly relevant since it has been reported that a considerable subset of critically ill patients with COVID-19 suffer from liver dysfunction associated with high mortality.

Background: Neonatal jaundice, a common condition in new-borns characterised by elevated bilirubin levels, poses significant public health concerns due to its potential for neurological complications if left untreated. Zinc supplementation has been proposed to reduce bilirubin levels by enhancing bilirubin conjugation and excretion. This study aims to systematically evaluate the efficacy of zinc supplementation in reducing the incidence and severity of neonatal jaundice through a meta-analysis of randomised controlled trials. Methods: We conducted a thorough investigation by carefully examining various databases, including PubMed, Scopus, Web of Science and the Cochrane Central Register of Controlled Trials, until September 2024. The aim of our study was to identify the research assessing the effectiveness of zinc supplementation versus a placebo for neonatal jaundice. The primary objective of the study was to evaluate total serum bilirubin levels and the duration of phototherapy required. We employed the ROB2 methodology to assess the quality of the evidence, thereby ensuring the reliability of the conclusions derived from these studies. The data were systematically organised in a standardised online format and analysed with RevMan 5.4. Results: Systematic review and meta-analysis confirmed 16 clinical trials (n = 1915 patients) evaluating zinc supplementation versus placebo in relation to bilirubin levels and phototherapy outcomes. The results indicated no statistically significant differences in total serum bilirubin at various time points (mean difference [MD] = −0.71, P = 0.12; MD = −0.41, P = 0.15; MD = −0.63, P = 0.24; MD = −0.38, P = 0.10; MD = −0.15, P = 0.40) compared to placebo. However, zinc supplementation significantly reduced the duration of phototherapy (MD = −4.34 h, P &lt; 0.00001). Analysis of secondary outcomes revealed no significant differences in the incidence of hyperbilirubinaemia (risk ratio [RR] =1.12, P = 0.48), requirements for phototherapy (RR = 0.90, P = 0.69) or associated side effects such as vomiting (RR = 0.99, P = 0.98), diarrhoea (RR = 0.84, P = 0.68) and skin rash (RR = 1.28, P = 0.62). Conclusion: Zinc supplementation did not significantly reduce total serum bilirubin levels or the incidence of hyperbilirubinaemia in neonates with jaundice. However, it was associated with a shorter duration of phototherapy, suggesting a potential role as an adjunct treatment. Further research is required to confirm these findings and establish clinical guidelines for the use of zinc in managing neonatal jaundice.

BackgroundThough sepsis is common in patients with cancer, there are limited studies that evaluated sepsis and septic shock in this patient population. The objective of this study was to evaluate the outcomes and to identify predictors of mortality in cancer patients admitted to the intensive care unit (ICU) with septic shock.MethodsThis was a retrospective study conducted at a medical-surgical oncologic ICU of a comprehensive cancer center. Adult cancer patients admitted with septic shock between January 1, 2008 and December 31, 2019 were enrolled. Septic shock was defined as an ICU admission diagnosis of sepsis that required initiating vasopressors within 24 h of admission. Patient baseline characteristics, ICU length of stay and ICU and hospital mortality were recorded. Univariate analysis and logistic regression were performed to identify predictors associated with ICU and hospital mortality.ResultsDuring the study period, 1408 patients met the inclusion criteria. The mean age was 56.8 ± 16.1 (SD) years and mean Acute Physiology and Chronic Health Evaluation (APACHE) II was 23.0 ± 7.91 (SD). Among the enrolled patients, 67.8% had solid tumors while the remaining had hematological malignancies. Neutropenia and thrombocytopenia were reported in 19.3 and 39.5% of the patients, respectively, and mechanical ventilation was required for 42% of the patients. Positive cultures were reported in 836 (59.4%) patients, most commonly blood (33%) and respiratory (26.6%). Upon admission, about half the patients had acute kidney injury, while elevated total bilirubin and lactic acid levels were reported in 13.8 and 65.2% of the patients, respectively. The median ICU length of stay was 4 days (IQR 3–8), and ICU and hospital mortality were reported in 688 (48.9%) and 914 (64.9%) patients, respectively. Mechanical ventilation, APACHE II, thrombocytopenia, positive cultures, elevated bilirubin and lactic acid levels were significantly associated with both ICU and hospital mortality.ConclusionsIn a relatively large cohort of patients with solid and hematological malignancies admitted to the ICU with septic shock, hospital mortality was reported in about two-third of the patients. Mechanical ventilation, APACHE II, thrombocytopenia, positive cultures, elevated bilirubin and lactic acid levels were significant predictors of mortality.

Colonic Bleeding and a Displaced Biliary Stent

Bilirubin is an effective antioxidant and is influenced by both genetic and environmental factors. Recent genome-wide association studies (GWAS) have identified multiple loci affecting serum total bilirubin levels. However, most of the studies were conducted in European populations and little attention has been devoted either to genetic variants associated with direct and indirect bilirubin levels or to the gene-environment interactions on bilirubin levels. In this study, a two-stage GWAS was performed to identify genetic variants associated with all types of bilirubin levels in 10,282 Han Chinese individuals. Gene-environment interactions were further examined. Briefly, two previously reported loci, UGT1A1 on 2q37 (rs6742078 and rs4148323, combined P = 1.44 × 10(-89) and P = 5.05 × 10(-69) , respectively) and SLCO1B3 on 12p12 (rs2417940, combined P = 6.93 × 10(-19) ) were successfully replicated. The two loci explained 9.2% and 0.9% of the total variations of total bilirubin levels, respectively. Ethnic genetic differences were observed between Chinese and European populations. More importantly, a significant interaction was found between rs2417940 in SLCO1B3 gene and smoking on total bilirubin levels (P = 1.99 × 10(-3) ). Single nucleotide polymorphism (SNP) rs2417940 had stronger effects on total bilirubin levels in nonsmokers than in smokers, suggesting that the effects of SLCO1B3 genotype on bilirubin levels were partly dependent on smoking status. Consistent associations and interactions were observed for serum direct and indirect bilirubin levels.