Increased Serum Bilirubin Concentrations Research Articles

Jaundice in relation to immune activation during Epstein-Barr virus-induced infectious mononucleosis

BackgroundLiver involvement during infectious mononucleosis is common, but jaundice is considered rare. This study aimed to investigate serum bilirubin concentrations in patients with infectious mononucleosis and immune abnormalities associated with jaundice. MethodsWe report on an adult patient with monoclonal B lymphocytosis and IgM-lambda gammopathy who developed a severe icteric hepatitis during infectious mononucleosis. We then reviewed the clinical records of 389 patients admitted to the hospital with infectious mononucleosis between 1995 and 2018 (51.7% male patients; median age, 19 years; range, 15-87 years) with focus on liver abnormalities and associated factors. ResultsFifty-nine patients (15.1%) had serum bilirubin concentrations between 1.5 and 3 mg/dL, and 47 patients (12.0%) had serum bilirubin >3 mg/dL. Patients with increased bilirubin concentrations had a distinct clinical presentation, with more frequent abdominal pain, nausea and vomiting, and less frequent sore throat than patients with normal bilirubin. Age and sex were not significantly different for the patients with increased and normal serum bilirubin concentrations. The patients with increased serum bilirubin concentrations showed higher levels of immune activation markers than the patients with normal bilirubin, including blood lymphocyte counts, serum IgM, and β2-microglobulin concentrations. Heterophile antibody-positive patients (88.6%) showed similar bilirubin concentrations but higher aspartate aminotransferase and alkaline phosphatase levels than their heterophile-negative counterparts. Serum bilirubin elevations normalized quickly during follow-up. ConclusionsTransient hyperbilirubinemia is common during severe (in-hospital) infectious mononucleosis in adult patients. Patients with hyperbilirubinemia have less frequent pharyngitis symptoms and more frequent abdominal symptoms. Hyperbilirubinemia during infectious mononucleosis is associated with immune activation markers.

Delayed Antibiotic Therapy and Organ Dysfunction in Critically Ill Septic Patients in the Emergency Department.

Background: We investigated the effect of antibiotic timing on outcomes based on changes in surrogate markers of organ failure, including platelet, serum bilirubin, serum creatinine levels, and the PaO2/FiO2 (P/F) ratio. Methods: This was a single-center, retrospective observational study of critically ill septic patients who presented to the emergency department (ED). The study period extended from August 2008 to September 2016. The primary outcomes included changes in platelet, serum bilirubin, serum creatinine levels, and the P/F ratio (δ-platelet, δ-serum bilirubin, δ-serum creatinine, and δ-P/F ratio were calculated as values measured on Day 3; values measured at ED enrollment). A multivariable linear regression model was developed to assess variables related to outcomes (δ-platelet, δ-serum bilirubin, δ-serum creatinine, and δ-P/F ratio). Results: We analyzed 1784 patients who met the inclusion criteria. The overall 28-day mortality was 14% (n = 256/1784). On multivariable linear regression analysis, the hourly delay in antibiotic therapy was significantly associated with a decrease in δ-platelet count (coefficient, −1.741; standard error, 0.740; p = 0.019), and an increase in δ-serum bilirubin (coefficient, 0.054; standard error, 0.021; p = 0.009). In contrast, it was not associated with δ-creatinine (coefficient, 0.008; standard error, 0.010; p = 0.434) or the δ-P/F ratio (coefficient, −0.797; standard error, 1.858; p = 0.668). Conclusion: The hourly delay of antibiotic therapy was associated with decreased platelet count and increased serum bilirubin concentration in critically ill septic patients during the first three days of ED admission.

Genome-Wide Association Study (GWAS) on Bilirubin Concentrations in Subjects with Metabolic Syndrome: Sex-Specific GWAS Analysis and Gene-Diet Interactions in a Mediterranean Population.

Although, for decades, increased serum bilirubin concentrations were considered a threatening sign of underlying liver disease and had been associated with neonatal jaundice, data from recent years show that bilirubin is a powerful antioxidant and suggest that slightly increased serum bilirubin concentrations are protective against oxidative stress-related diseases, such as cardiovascular diseases. Therefore, a better understanding of the gene-diet interactions in determining serum bilirubin concentrations is needed. None of the previous genome-wide association studies (GWAS) on bilirubin concentrations has been stratified by sex. Therefore, considering the increasing interest in incorporating the gender perspective into nutritional genomics, our main aim was to carry out a GWAS on total serum bilirubin concentrations in a Mediterranean population with metabolic syndrome, stratified by sex. Our secondary aim was to explore, as a pilot study, the presence of gene-diet interactions at the GWAS level. We included 430 participants (188 men and 242 women, aged 55–75 years, and with metabolic syndrome) in the PREDIMED Plus-Valencia study. Global and sex-specific GWAS were undertaken to analyze associations and gene-diet interaction on total serum bilirubin. Adherence (low and high) to the Mediterranean diet (MedDiet) was analyzed as the dietary modulator. In the GWAS, we detected more than 55 SNPs associated with serum bilirubin at p < 5 × 10−8 (GWAS level). The top-ranked were four SNPs (rs4148325 (p = 9.25 × 10−24), rs4148324 (p = 9.48 × 10−24), rs6742078 (p = 1.29 × 10−23), rs887829 (p = 1.39 × 10−23), and the rs4148324 (p = 9.48 × 10−24)) in the UGT1A1 (UDP glucuronosyltransferase family 1 member A1) gene, which replicated previous findings revealing the UGT1A1 as the major locus. In the sex-specific GWAS, the top-ranked SNPs at the GWAS level were similar in men and women (the lead SNP was the rs4148324-UGT1A1 in both men (p = 4.77 × 10−11) and women (p = 2.15 × 10−14), which shows homogeneous genetic results for the major locus. There was more sex-specific heterogeneity for other minor genes associated at the suggestive level of GWAS significance (p < 1 × 10−5). We did not detect any gene-MedDiet interaction at p < 1 × 10−5 for the major genetic locus, but we detected some gene-MedDiet interactions with other genes at p < 1 × 10−5, and even at the GWAS level for the IL17B gene (p = 3.14 × 10−8). These interaction results, however, should be interpreted with caution due to our small sample size. In conclusion, our study provides new data, with a gender perspective, on genes associated with total serum bilirubin concentrations in men and women, and suggests possible additional modulations by adherence to MedDiet.

Differential effects of hepatic cirrhosis on the intrinsic clearances of sorafenib and imatinib by CYPs in human liver

The tyrosine kinase inhibitors sorafenib and imatinib are important in the treatment of a range of cancers but adverse effects in some patients necessitate dosage modifications. CYP3A4 has a major role in the oxidation of sorafenib to its N-oxide and N-hydroxymethyl metabolites and also acts in concert with CYP2C8 to mediate imatinib N-demethylation. CYP3A4 expression and function are impaired in patients with advanced liver disease, whereas the functions of CYP2C enzymes are relatively preserved. We evaluated the biotransformation of sorafenib and imatinib in well-characterized microsomal fractions from 17 control subjects and 19 individuals with hepatic cirrhosis of varying severity. The principal findings were that liver disease impaired the microsomal oxidation of sorafenib to its major metabolites to 40–44% of control (P<0.01), whereas the N-demethylation of imatinib was relatively unimpaired. The impairments in sorafenib biotransformation were correlated with decreased serum albumin concentrations and increased serum bilirubin concentrations in patients with liver disease, but not with the overall grade of liver disease according to the Child-Pugh system. In contrast, there was no relationship between imatinib N-demethylation and clinicopathologic factors in liver disease patients. These findings were accounted for in terms of the differential roles of CYPs 3A4 and 2C8 in the intrinsic clearance of the drugs. CYP3A4 has the major role in the intrinsic clearance of sorafenib but plays a secondary role to CYP2C8 in the intrinsic clearance of imatinib. In agreement with these findings CYP2C protein expression and CYP2C8-mediated paclitaxel 6α-hydroxylation were unimpaired in cirrhotic livers. This information could be adapted in individualized approaches such as in vivo CYP3A4 phenotyping to optimize sorafenib safety and efficacy in cancer patients with liver dysfunction.

Acquired Proximal Renal Tubular Dysfunction in 9 Labrador Retrievers with Copper‐Associated Hepatitis (2006–2012)

Copper-associated hepatitis (CAH) has been well described in Labrador Retrievers. However, the association of CAH with proximal renal tubular dysfunction in this breed has not been characterized. To report clinical features, hepatic and renal histopathologic findings, tissue copper concentrations, and outcome of Labradors with CAH and proximal renal tubular disease. Nine Labrador Retrievers with renal glucosuria and biopsy-confirmed CAH. Clinical, clinicopathologic, and light microscopic findings were retrospectively reviewed. Rhodanine staining or atomic emission spectroscopy was performed on all hepatic samples and available renal tissue (4 dogs) to assess copper concentrations. Eight dogs had a history of polyuria and polydipsia, and all dogs had increased serum bilirubin concentrations. Five dogs had hyperchloremic metabolic acidosis. Three dogs with acidemia had paradoxical alkalinuria. All renal specimens had increased copper concentrations. Renal tubular vacuolization, degeneration, and regeneration were observed on light microscopy. Four dogs died within 10 days of diagnosis. One dog survived 2 months; 4 dogs survived more than 1 year. In long-term survivors, including 2 that did not undergo immediate copper chelation, resolution of renal tubular dysfunction occurred within weeks to months. Labrador Retrievers with CAH can develop clinical and laboratory evidence of renal tubular dysfunction in association with increased renal copper concentrations. Given the rarity of renal tubular disorders, detection of renal glucosuria and increased ALT activity in a Labrador Retriever is suggestive of CAH. Although renal tubular dysfunction may indicate advanced disease, successful long-term outcome is possible with a variety of therapies.

Endoscopic Surveillance and Primary Prophylaxis Sclerotherapy of Esophageal Varices in Biliary Atresia

Evidence-based recommendations on endoscopic screening and prophylactic treatment of esophageal varices in patients with biliary atresia (BA) are scarce. We assessed the efficiency of endoscopic surveillance and risk factors of esophageal varices and associated upper gastrointestinal bleeding. A total of 47 consecutive children with BA and portoenterostomy underwent yearly endoscopies and prophylactic injection sclerotherapy of esophageal varices between 1987 and 2009. The median follow-up was 1.7 years (range 0.5-18.9) and overall 2-year survival 71%. Disease characteristics, clearance of jaundice, laboratory tests reflecting liver function and hypersplenism, as well as sonographic signs of portal hypertension were related to endoscopic findings and bleeding episodes. Grade 2 to 3 varices developed with similar frequency after failed (18/28, 64%) and successful portoenterostomy (10/19, 53%) in 28 patients. Following failed portoenterostomy, esophageal varices were encountered significantly earlier (8 [4-23] vs. 19 [4-165] months, P = 0.004), and they reappeared after eradication more often (16/16 vs. 4/10, P = 0.001). Varices bled only after failed portoenterostomy (13/28 vs. 0/19, P < 0.001). Increased serum bilirubin concentration >40 μmol/L at 3 months after portoenterostomy was a risk factor of upper gastrointestinal bleeding (odds ratio [OR] 17, 95% confidence interval [CI] 1.7-175, P = 0.017). In future studies as well as clinical surveillance of BA patients' varices, successful and failed portoenterostomy patients should be approached as separate groups with divergent prognoses. After failed portoenterostomy, surveillance should start early, for example, at 6 months.

Acquired Liver Injury in the Intensive Care Unit

HE liver plays a key role in the synthesis of proteins, metabolism of toxins and drugs, and in modulation of immunity. In critically ill patients, hypoxic, toxic, and inflammatory insults can affect hepatic excretory, synthetic, and/or purification functions, leading to systemic complications such as coagulopathy, increased risk of infection, hypoglycemia, and acute kidney injury. In severe cases, hepatic encephalopathyorbraindysfunction(acuteliverfailure)may occur. Because of the lack of specificity of standard laboratory investigations, identifying liver injury or dysfunction in critically ill patients remains a significant challenge. In addition, the great heterogeneity of criteria used to define the consequences of liver insults increases the difficulties for the clinician to properly interpret hepatic biochemical abnormalities. In this review, we choose to defineliver injuryas an elevation in serum concentrations of routinely measured hepatic enzymes, including aminotransferases (aspartate aminotransferase [AST]; alanine aminotransferase, [ALT]), alkaline phosphatase (ALP), or!-glutamyl transpeptidase. Hepatic dysfunctionrefers to derangement of pathways related to synthetic or clearance function, including international normalized ratio (INR) and bilirubin.Hepatotoxicity refers to hepatic injury and dysfunction caused by a drug or another noninfectious agent. 1 Acute liver failuredesignates

SOS for veno-occlusive disease: defibrotide prophylaxis

Sinusoidal obstruction syndrome (SOS), better known as veno-occlusive disease, is a serious and life-threatening complication that mainly occurs after high-dose myeloablative conditioning therapy and haemopoietic stem-cell transplantation (HSCT). The disease can affect about 20% of such patients and is characterised clinically by increased serum bilirubin concentrations, tender hepatomegaly, fluid retention, and weight gain. Liver injury occurs early after transplantation and results in occluded venules, sinusoidal fibrosis, and hepatocyte necrosis.

Methotrexat in der Therapie der primären biliären Zirrhose*

In a pilot study 5 females with primary biliary cirrhosis (PBC), histological stages I-III, were treated with methotrexate (7.5-15.0 mg by mouth weekly) for 15 months. Pruritus and fatigue decreased in 3 patients and cholestyramine could be reduced or discontinued. The concentration of alkaline phosphatase decreased significantly until the 6th month of treatment (P less than 0.002), but only after the methotrexate dosage had been increased to 15 mg weekly. However, the improvement in cholestasis parameters persisted until the end of the period of observation in only 3 patients in stages I and II. In only one case, initially in stage III with increased serum bilirubin concentration of 3.5 mg/dl, was there a change in the histological stage, to stage IV, after treatment. These preliminary results indicate that methotrexate can influence the symptoms and cholestasis enzymes in the early stages of PBC. Controlled studies should therefore only be conducted on anicteric patients in an early stage of the disease.

Associação da concentração de bilirrubina sérica com a carga aterosclerótica em pacientes com doença arterial coronariana estabelecida

FUNDAMENTOS: As doenças cardiovasculares são um importante problema de saúde pública, e as respostas adaptativas e protetoras da vasculatura contra o estresse oxidativo são importantes na prevenção da aterosclerose. A bilirrubina tem sido considerada um antioxidante, com capacidade de remover espécies reativas de oxigênio. Estudos têm demonstrado que a concentração de bilirrubina sérica aumentada promove proteção contra aterosclerose. OBJETIVO: Avaliar a possível existência de relação entre a carga aterosclerótica de pacientes com doença arterial coronariana e a concentração de bilirrubina. MÉTODO: Estudo transversal composto por 81 pacientes com diagnóstico angiográfico estabelecido de doença arterial coronariana, submetidos a revascularização miocárdica. Foram avaliados os fatores de risco clássicos e a dosagem de bilirrubina. Foram utilizados os testes do qui-quadrado, teste t de Student ou Mann-Whitney, sendo considerado p < 0,05 estatisticamente significativo. RESULTADOS: A amostra foi composta predominantemente por homens, com média de idade de 59,32 ± 9,28 anos no grupo com lesão mínima/moderada e 61,79 ± 7,55 anos no grupo com lesão grave. A mediana da bilirrubina total no grupo com lesão mínima/moderada foi de 0,34 mg/dL, enquanto no grupo com lesão grave foi de 0,43 mg/dL, diferente do esperado. A concentração de bilirrubina total foi maior no grupo com carga aterosclerótica grave que no grupo com carga mínima/moderada, embora sem significância estatística (p = 0,241). CONCLUSÃO: Níveis séricos de bilirrubina não se mostraram úteis na detecção ou predição da gravidade da lesão aterosclerótica dos pacientes com doença arterial coronariana.

Outcomes after pancreatectomy for intraductal papillary mucinous neoplasms of the pancreas: An institutional experience

To evaluate the experience with pancreatectomy for intraductal papillary mucinous neoplasm (IPMN) at a single academic institution. A prospective pancreatic database was reviewed and identified 43 patients with IPMN who were managed operatively. Clinicopathologic features and predictors of outcome were examined. The World Health Organization pathologic classification of IPMN was utilized. IPMN was diagnosed in 21% of patients who underwent pancreatic resection for solid or cystic mass lesions. Ninety-five percent of patients were symptomatic. Patients were managed with total pancreatectomy, pancreaticoduodenectomy, distal pancreatectomy, central pancreatectomy, or enucleation. Nine patients had adenomas, 14 had borderline neoplasms, 10 had carcinoma in situ, and 9 had invasive carcinoma. Overall, 23 patients (53%) had lesions with main duct involvement. Frozen section transection margins were positive for malignancy in 2 patients. With a mean follow-up of 17 months, the 5-year disease-specific survival for patients with main duct involvement was 67%. The 5-year disease-specific survival for patients with benign lesions was 100%, and 61% for patients with malignant lesions (P = .02). The presence of symptoms, increased CA 19-9, and tumor size were not predictive of malignancy. Increased serum bilirubin concentrations were predictive of malignancy (P = .03). Main duct involvement was also associated with malignancy (P < .02). Cancer is found in 65% of patients with IMPN involving the main duct. Based on our data, patients with symptomatic, main duct involvement, especially those with an increased serum bilirubin, should be offered resection. Alternatively, patients with side branch IPMN may be managed conservatively.

LABORATORY FINDINGS IN ACUTE CYTAUXZOON FELIS INFECTION IN COUGARS (PUMA CONCOLOR COUGUAR) IN FLORIDA

Intraerythrocytic piroplasms, morphologically indistinguishable from Cytauxzoon felis, were identified in stained blood films from more than one third of free-ranging cougars (Puma concolor couguar) in southern Florida in a study that failed to demonstrate negative effects of piroplasm infection on measured hematologic parameters. However, a recent study with a nested 18s rRNA polymerase chain reaction (PCR) assay identified only 9% of the free-ranging cougars in southern Florida as infected with C. felis but found 83% of these animals were infected with an unnamed small Babesia sp. In this study, hematology and clinical chemistry parameters were determined during the initial appearance of piroplasms in stained blood films of three western cougars housed in northern Florida. One animal became ill, but the remaining two animals did not exhibit clinical signs of disease. The hematocrit decreased in all three cougars concomitant with the first recognized parasitemia. A regenerative response to anemia (increased polychromasia, increased mean cell volume, and increased red cell distribution width) was recognized in two cougars that were examined twice during the following 2 weeks. Thrombocytopenia and probable leukopenia occurred in one animal. The most consistent clinical chemistry findings were increased serum bilirubin concentrations and increased alanine aminotransferase and aspartate aminotransferase activities at the time of initial recognition of parasitemia. Serum protein findings were not consistent in these cougars. The use of PCR and determination of 18S rRNA gene sequences in the blood from these three animals revealed infection with C. felis, but not with the Babesia sp. In this report, we demonstrate that mild hemolytic anemia, and probably liver injury, occurs concomitant with the initial discovery of C. felis piroplasms in stained blood films.

Atazanavir Plasma Concentrations Vary Significantly Between Patients and Correlate with Increased Serum Bilirubin Concentrations

Background: Atazanavir (ATV) is recommended to be dosed at 400 mg once daily or 300 mg daily coadministered with 100 mg ritonavir (RTV). Method: 31 male patients receiving ATV either alone or boosted with RTV for more than 2 weeks had ATV concentration measured by high performance liquid chromatography (HPLC). ATV concentrations were adjusted to obtain a 24-hour trough level using a standard pharmacokinetic formula. Results: 25 samples were taken from patients who received 300 mg ATV, 6 with 200 mg, 3 with 400 mg, and 2 with 150 mg, all boosted with 100 mg RTV. In the unboosted group, patients received 400 mg (7) or 600 mg (2). The median adjusted 24-hour trough ATV concentration was 630 ng/mL (interquartile range [IQR] 355-1034) in the boosted and 113 ng/mL (IQR 50-225) in the unboosted group (p = .001). Median serum bilirubin concentration was 34 IU/L (IQR 27.5-49) and 41 IU/L (IQR 31-45) in the boosted and unboosted groups, respectively. In the boosted group, high ATV concentrations were significantly correlated with increased serum bilirubin concentrations (p = .003). Conclusion: ATV concentrations showed considerable interpatient variability. Bilirubin concentrations are an indicator of high ATV concentrations and may prove to be useful in selecting patients for therapeutic drug monitoring (TDM).

Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children

Descriptions of the pharmacokinetics and metabolism of morphine and its metabolites in young children are scant. Previous studies have not differentiated the effects of size from those related to age during infancy. Postoperative children 0-3 yr old were given an intravenous loading dose of morphine hydrochloride (100 micro g kg(-1) in 2 min) followed by either an intravenous morphine infusion of 10 micro g h(-1) kg(-1) (n=92) or 3-hourly intravenous morphine boluses of 30 micro g kg(-1) (n=92). Additional morphine (5 micro g kg(-1)) every 10 min was given if the visual analogue (VAS, 0-10) pain score was >/=4. Arterial blood (1.4 ml) was sampled within 5 min of the loading dose and at 6, 12 and 24 h for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). The disposition of morphine and formation clearances of morphine base to its glucuronide metabolites and their elimination clearances were estimated using non-linear mixed effects models. The analysis used 1856 concentration observations from 184 subjects. Population parameter estimates and their variability (%) for a one-compartment, first-order elimination model were as follows: volume of distribution 136 (59.3) litres, formation clearance to M3G 64.3 (58.8) litres h(-1), formation clearance to M6G 3.63 (82.2) litres h(-1), morphine clearance by other routes 3.12 litres h(-1) per 70 kg, elimination clearance of M3G 17.4 (43.0) litres h(-1), elimination clearance of M6G 5.8 (73.8) litres h(-1). All parameters are standardized to a 70 kg person using allometric 3/4 power models and reflect fully mature adult values. The volume of distribution increased exponentially with a maturation half-life of 26 days from 83 litres per 70 kg at birth; formation clearance to M3G and M6G increased with a maturation half-life of 88.3 days from 10.8 and 0.61 litres h(-1) per 70 kg respectively at birth. Metabolite formation decreased with increased serum bilirubin concentration. Metabolite clearance increased with age (maturation half-life 129 days), and appeared to be similar to that described for glomerular filtration rate maturation in infants. M3G is the predominant metabolite of morphine in young children and total body morphine clearance is 80% that of adult values by 6 months. A mean steady-state serum concentration of 10 ng ml(-1) can be achieved in children after non-cardiac surgery in an intensive care unit with a morphine hydrochloride infusion of 5 micro g h(-1) kg(-1) at birth (term neonates), 8.5 micro g h(-1) kg(-1) at 1 month, 13.5 micro g h(-1) kg(-1) at 3 months and 18 micro g h(-1) kg(-1) at 1 year and 16 micro g h(-1) kg(-1) for 1- to 3-yr-old children.

Biliary atresia.

Biliary atresia.

Bile Duct Obstruction Is not a Prerequisite for Type I Biliary Epithelial Cell Hyperplasia

Biliary obstruction, produced by common bile duct ligation or α-naphthylisothiocyanate (ANIT) treatment in rats, has been associated with the development of type I biliary epithelial cell (BEC) hyperplasia. However, the exact mechanism(s) by which bile duct obstruction lead(s) to this proliferative lesion are not clear. The present studies were designed to determine if cholestasis, in the absence of biliary obstruction, would result in type I BEC hyperplasia. Male Sprague–Dawley rats were given a single oral dose of 150 mg/kg ANIT or iv doses of estradiol glucuronide (E2–17G; 21 μmol/kg/h for 48 h) to produce obstructive and non-obstructive cholestasis, respectively. E2–17G treatment resulted in cholestasis that was comparable in extent and duration to that observed following ANIT treatment. E2–17G and ANIT treatments produced comparable increases in serum bile acids (55- to 60-fold) and activities of ALT (36- to 38-fold), ALP (4- to 5-fold), and 5′-nucleotidase (7- to 11-fold), respectively, compared to controls. Both ANIT and E2–17G also increased serum bilirubin concentrations. ANIT treatment resulted in significant increases in biliary glucose concentrations that were associated with BEC damage/necrosis and obstruction of the bile duct lumen. Conversely, no evidence of BEC damage was observed in E2–17G-treated rats. Nonetheless, BEC hyperplasia was observed in the majority of rats following treatment with either ANIT or E2–17G, assessed by light microscopy and by BrdU immunohistochemistry. These data indicate that E2–17G treatment produces nonobstructive cholestasis and type I BEC hyperplasia, suggesting that biliary obstruction is not a prerequisite for type I BEC hyperplasia in rats. Differences in the time of onset of hyperplasia were observed: hyperplasia was noted immediately following 48 h of E2–17G-induced cholestasis but occurred several days after ANIT-induced cholestasis had subsided. Since the magnitude/duration of cholestasis was similar in the two models but the temporal association between cholestasis and type I BEC hyperplasia were different, these data suggest that the proliferative stimulus may be different in the two models and that E2–17G-induced type I BEC hyperplasia may not be attributed solely to cholestasis.

Hepatic steatosis as a potential risk factor for major hepatic resection

Hepatic steatosis is a recognized risk factor for primary nonfunction of hepatic allografts, but the effect of steatosis on postoperative recovery after major liver resection is unknown. Our aim was to determine if hepatic steatosis is associated with increased perioperative morbidity and mortality in patients undergoing major resection. A retrospective review of medical records of 135 patients who had undergone major hepatic resection from 1990 to 1993 was performed. Histopathology of the hepatic parenchyma at the resection margin was reviewed for the presence of macro- or microvesicular steatosis. The extent of steatosis was graded as none (group 1), mild with less than 30% hepatocytes involved (group 2), or moderate-to-severe with 30% or more hepatocytes involved (group 3). Outcome of patients was correlated with extent of steatosis. Patients with moderate-to-severe steatosis were obese (body mass index = 25.8 ± 0.5 vs. 26.5 ± 1.0 vs. 33.4 ± 2.9; P ≤0.05 groups 1, 2, and 3, respectively) and had an increased serum bilirubin concentration preoperatively. Hepatectomy required a longer operative time for group 3 (290 ± 9 minutes vs. 287 ± 13 minutes vs. 355 ± 24 minutes; P <0.05 groups 1, 2, and 3, respectively). Likelihood of blood transfusion was 51% in group 1, 52% in group 2, and 71% in group 3. Mortality was 14% in group 3 vs. 3% in group 1, and 7% in group 2; and liver failure occurred in 14% of patients in group 3 compared to 4% and 9% in groups 1 and 2, respectively. Patients in group 3 also had increased post-operative bilirubin levels compared to preoperative values. Moderate-to-severe hepatic steatosis may be associated with increased perioperative morbidity and mortality, and preoperative identification of steatosis warrants caution prior to major resection.

Primary sclerosing cholangitis. Requiem for biliary drainage operations?

To review the outcome of a consecutive number of patients with primary sclerosing cholangitis (PSC) treated at one institution to define prognostic variables and determine the influence of surgery on outcome. Case series of patients with PSC seen in Cape Town, South Africa, between 1981 and 1991. Tertiary referral center. Thirty-six patients with PSC were studied. Diagnosis was based on cholangiographic findings of multiple strictures of the bile ducts together with compatible clinical and biochemical features. Thirty-two patients were followed up prospectively for up to 9 years. Patient outcome was defined as good (stable or slowly progressive disease) or poor (death or liver transplantation). During the follow-up period, seven patients with PSC died and two underwent liver transplantation. Actuarial survival at 5 years was 52%. An increased serum bilirubin concentration was the only variable at presentation that independently predicted a poor outcome. Cholangiography was unhelpful in predicting patient outcome. Six patients who developed obstructive jaundice associated with advanced liver disease underwent biliary drainage operations for surgically correctable strictures, but this did not seem to prevent progression of the disease. Two patients who progressed to end-stage liver disease went on to have liver transplantation and were alive with functioning grafts at 7 and 14 months, respectively. Symptomatic PSC is a progressive disorder with a poor prognosis. Our experience suggests that patients with advanced liver disease caused by PSC should be considered directly for liver transplantation rather than biliary bypass operations.

Detrimental Effects of High-Dose Methylprednisolone Sodium Succinate on Serum Concentrations of Hepatic and Renal Function Indicators in Severe Sepsis and Septic Shock

OBJECTIVE To evaluate the effects of high-dose methylprednisolone sodium succinate on biochemical markers of hepatic and renal function in patients with severe sepsis and septic shock. DESIGN Retrospective analysis of serial serum chemistries in 382 patients who were entered prospectively into a randomized, placebo-controlled, double-blind clinical trial of high-dose methylprednisolone or placebo in the sepsis syndrome. SETTING The original study was conducted at 19 academic centers. PATIENTS Adult patients in severe sepsis or septic shock who met the study entry criteria, which included a clinically defined source of infection and signs of systemic sepsis, were enrolled into the study. Three hundred eighty-two patients were evaluated. INTERVENTIONS Patients received either methylprednisolone (30 mg/kg) or placebo by iv infusion every 6 hrs for four doses. Hemodynamic variables and serum concentrations of creatinine, urea nitrogen, bilirubin, and aspartate aminotransferase (AST) were recorded on entering the study, at 12 and 24 hrs, and at 3, 7, and 14 days after the first infusion of methylprednisolone or placebo. These data were analyzed retrospectively. MAIN OUTCOME MEASUREMENTS Hemodynamic and biochemical data were analyzed to determine whether or not hepatic and renal function in the sepsis syndrome had been influenced by methylprednisolone treatment. RESULTS Differences between methylprednisolone and placebo in hemodynamic variables, the occurrence rate of shock and recovery from shock, mortality rates and serum concentrations of creatinine and AST were not statistically significant. At 12 and 24 hrs, and at 3 and 7 days after the first drug infusion (of methylprednisolone or placebo), blood urea nitrogen was increased from baseline values in a significantly (p < .01) greater proportion of the methylprednisolone-treated patients compared with placebo-treated patients. The frequency of increased serum bilirubin concentrations was significantly (p < .01) greater among methylprednisolone patients vs. the placebo group at 12 and 24 hrs. CONCLUSIONS The frequency of acutely increased blood urea nitrogen and bilirubin concentrations in severe sepsis was increased significantly with high-dose methylprednisolone therapy. Similar frequencies of circulatory shock in the study groups excluded differences in global perfusion as a cause of this phenomenon. Possible adverse effects of pharmacologic concentrations of methylprednisolone in critically ill patients should be considered in planning treatment.

Estrogen and androgen dynamics in liver disease.

Constant infusions of 3H-androgen/14C-estrogen were given to 18 men with increased serum bilirubin concentrations and biopsy proven hepatic cirrhosis. From data obtained from the infusions and the radioimmunoassay of circulating endogenous steroid levels metabolic clearance rates (MCR), blood production rates (PB), aromatization rates (fraction of androgen infused into and measured as estrogen in blood; [p]And, Est BB) and conversion ratios (ratio of concentration of radioactivity of infused precursor to product steroid in blood; CRPREC,PROD were calculated. These data were compared to normal data obtained from similar studies in a group of normal men similar in age and weight. The mean concentrations of testosterone (T), and dihydrotestosterone (DHT), were decreased but those of estrone (E1) and estradiol (E2) were increased, and the concentration of androstenedione, (A), was similar compared to the normal values. Compared to the values in normal men the mean MCR of T was decreased those of A and E2 were normal, and that of E1 was slightly increased. However, the PB's of both estrogens were increased while that of A was normal T was decreased. The increase in the PB's of the estrogens could be explained on the basis of a marked increase in [p]And, Est BB probably due to a shift in blood flow from the liver to peripheral tissue. These findings were noted in men with alcoholic cirrhosis as well as cardiac cirrhosis and in 1 subject with infectious hepatitis. Abnormalities in steroid metabolism occur in men with several types of liver disease and are not limited to those with alcoholic liver disease.