Curcumin in Hepatobiliary Disease: Pharmacotherapeutic Properties and Emerging Potential Clinical Applications.

Curcumin, an aromatic phytoextract from the turmeric (Curcuma longa) rhizome, has been used for centuries for a variety of purposes, not the least of which is medicinal. A growing body of evidence suggests that curcumin has a broad range of potentially therapeutic pharmacological properties, including anti-inflammatory, anti-fibrotic, and anti-neoplastic effects, among others. Clinical applications of curcumin have been hampered by quality control concerns and limited oral bioavailability, although novel formulations appear to have largely overcome these issues. Recent in vitro and in vivo studies have found that curcumin's cytoprotective and other biological activities may play a role in an array of benign and malignant hepatobiliary conditions, including but not limited to non-alcoholic fatty liver disease, cholestatic liver disease (e.g. primary sclerosing cholangitis), and cholangiocarcinoma. Here we provide an overview of fundamental principles, recent discoveries, and potential clinical hepatobiliary applications of this pleiotropic phytocompound.

Heap of stones: an unusual cause for biliary colic and elevated liver function tests.

A 40-year old woman presented with symptomatic intrahepatic gallstones in one liver segment only four years after cholecystectomy for cholelithiasis. Multiple small, yellow and round calculi were completely removed from the intrahepatic bile ducts via ERCP. The young age of the patient, recurrence of gallstones after cholecystectomy and intrahepatic gallstones suggested a subtype of the low-phospholipid associated cholelithiasis syndrome, a monogenic form of cholesterol cholelithiasis due to variations of the ABCB4 gene that encodes the canalicular phospholipid transporter MDR3.

Hepatobiliary laboratory abnormalities among patients with chronic or persistent immune thrombocytopenia (ITP).

Therapies for immune thrombocytopenia (ITP) may be associated with abnormal hepatobiliary laboratory (HBL) values, but the epidemiology of these abnormalities is unknown in the ITP population. The study aim was to provide prevalence and incidence rates, as well as risk factors for abnormal HBL values among a cohort of patients with chronic or persistent primary ITP. Health insurance claims data from 3,244 patients with chronic or persistent ITP was examined to estimate the prevalence of abnormal HBL values: elevated levels of Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), total bilirubin, and Alkaline Phosphatase (ALP). Incidence of abnormal HBL values was estimated in a sub cohort of 2557 (79%) patients without evidence of comorbidities related to secondary thrombocytopenia, liver disease, or abnormal HBL values during the 12-month baseline period. The baseline prevalence of ALT and AST > 3x the upper limit of normal (ULN) was 4.6 and 3.7%, respectively. The baseline prevalence of total bilirubin and ALP >1.5x ULN was 4.2 and 3.2%, respectively. The incidence rate of new HBL abnormalities (HBLA) was 1.24/1,000 person-years (95% CI: 0.52-2.56) for ALT>3x ULN and 0.41/1,000 person-years (95% CI: 0.08-1.32) for AST>3x ULN. HBLAs were significantly associated with male gender, liver disease, diabetes, congestive heart failure, lupus, hematological cancers, and HIV infection. In conclusion, the prevalence of HBLA, specifically ALT>3x ULN, among the ITP population is relatively high compared with atrial fibrillation, though within the confidence interval for that estimate. HBLAs were significantly associated with male gender, liver disease, and several other comorbidities, thus, distinguishing drug-induced liver injury in this population is clinically challenging.

Oxidative stress: a radical way to stop making bile.

Oxidative stress is a common feature in most hepatopathies. In recent years, evidence has accumulated that reactive oxygen species (ROS) induce a number of functional changes either deleterious or adaptive in the capability of the hepatocytes to produce bile and to secrete exogenous and endogenous compounds. This review is aimed to describe the mechanisms involved in these alterations. For this purpose, we will summarize: 1) The current evidence that acutely-induced oxidative stress is cholestatic, by describing the mechanisms underlying the hepatocyte secretory failure, including the disorganization of the actin cytoskeleton and its most noticeable consequences, the impairment of tight-junctional structures and the endocytic internalization of canalicular transporters relevant to bile formation. 2) The role for oxidative-stress-activated signalling pathways in the pathomechanisms described above, particularly those involving Ca2+ elevation and its consequent activation of Ca2+ -dependent PKC isoforms. 3) The mechanisms involved in the adaptive response against oxidative stress mediated by ROS-responsive transcription factors, involving up-regulation of GSH-synthesizing enzymes, GSH-detoxifying enzymes and the hepatocellular efflux pumps; this response enhances the co-coordinated inactivation by GSH conjugation of lipid peroxides and their further cellular extrusion. 4) The manner this adaptive response can be surpassed by the sustained production of ROS, thus inducing transcriptional and posttranscriptional changes in transporters relevant to bile formation, as has been shown to occur, for example, after long-term administration of aluminum to rats, in the Long-Evans Cinnamon rat (a model of chronic hepatic copper accumulation mimicking Wilson's disease), and in ischemia-reperfusion injury.

Biliary secretion and excretion in health and disease: current concepts.

Biliary secretion in health and disease is reviewed. The powerful techniques of molecular biology have enabled cloning of the transporters involved in biliary secretion and the enterohepatic circulation of bile acids. This, in turn has permitted elucidation of their function as well as their regulation by nuclear receptors. Bile acid secretion is required for efficient lipid absorption, and bile acids also possess powerful direct and indirect antimicrobial functions in the small intestine. The enterohepatic circulation results from efficient ileal absorption, and is highly regulated at two sites. In the hepatocyte, biosynthesis of bile acids is regulated in negative feedback manner by the nuclear receptor FXR as well as by cytokines and by a peptide (FGF-19) liberated by bile acids from the ileal enterocyte. In the ileal enterocyte, bile acid reclamation is regulated in negative feedback manner by FXR and other nuclear receptors. The bile salt export pump (BSEP) mediates uphill canalicular bile acid secretion. Inborn defects in its function cause intrahepatic cholestasis in infants; inhibition of its function by drugs causes hepatotoxicity. Bile acid therapy is based on correction of bile acid deficiency by supplemental bile acids or displacement in which a noncytotoxic bile acid (ursodeoxycholic acid, ursodiol, UDCA) is administered and dilutes out the endogenous cytotoxic bile acids. Administration of primary bile acids may be lifesaving in inborn defects of bile acid biosynthesis. A synthetic bile acid, norUDCA is absorbed by the biliary ductules after secretion and cures the peribiliary fibrosis occurring in the MDR2-/- mouse which lacks biliary phospholipid.

Suprapapillary needle puncture for common bile duct access: laboratory profile

BACKGROUD: Biliary cannulation to perform endoscopic retrograde cholangiopancreatography may be difficult due to technical reasons and often is necessary to perform papillotomy, where complications as pancreatitis and perforation may occur AIM: To show minimal complications by a new model of biliary access by means of the suprapapillary needle puncture and its laboratory profile. PATIENTS AND METHODS: After the approval of the protocol by the Scientific Ethics Committee of the institution a free and informed consent was signed by all patients participating in the study. From July 2003 to August 2004, fulfilling the inclusion and exclusion criteria, 30 patients were selected for endoscopic retrograde cholangiopancreatography, using the suprapapillary puncture technique. All patients remained hospitalized, fasting and with basal hydroelectrolytic replacement, were clinically followed up and samples for the determination of serum amylase, lipase and C-RP (C-reactive protein) were collected before and 4 h, 12 h and 24 h after the procedure and reevaluated 60 days after the procedure. Laboratory parameters were submitted to statistical study using analysis of variance for repeated measurements. Multiple comparisons were made based on Wald's statistics RESULTS: The technique was successful in 93.4 percent (28/30) of the patients. No statistically significant difference regarding to the laboratory profile were observed. Complications related to the technique of papillary puncture occurred in 1/28 patients by not using the guide wire and in 1/28 where mild hemorrhage after dilation of the papillary fistula occurred. Regarding complications related to therapeutic procedures, there were 2/28 retroduodenal perforations, with one (1/30) following unsuccessful puncture and another due to the passage of Dormia's basket through the dilated fistula path. All patients submitted to diagnostic puncture and evaluated 60 days after the procedure presented...

RACIONAL: A cateterização para acesso às vias biliares na colangiopancreatografia retrógrada pode apresentar dificuldades técnicas, sendo necessário freqüentemente efetuar-se papilotomia, procedimento não isento de complicações como perfuração e pancreatite OBJETIVOS: Demonstrar menor incidência de complicações a partir do perfil laboratorial, através de nova técnica desenvolvida, a punção suprapapilar MATERIAL E MÉTODOS: Após aprovação pelo Comitê de Ética em Pesquisa da instituição, 30 pacientes foram selecionados no período de julho de 2003 a agosto de 2004. Preenchidos os critérios de inclusão e exclusão, os pacientes, após explicação do protocolo e a assinatura do consentimento livre e esclarecido, foram submetidos a colangiopancreatografia retrógrada pela técnica de punção suprapapilar. Após o procedimento, foi feito seguimento com o paciente internado para avaliar possíveis complicações, bem como determinação dos níveis séricos da amilase, lipase e proteína C reativa nas 4 h, 12 h e 24 h subseqüentes e reavaliados 60 dias após. O estudo estatístico foi feito por análise de variância para medidas múltiplas e comparações múltiplas foram feitas por meio do teste de Wald RESULTADOS: O sucesso da técnica ocorreu em 93,4 por cento (28/30) dos pacientes. Não foram observadas alterações estatisticamente significantes no perfil laboratorial. Complicações relacionadas à técnica de punção ocorreram em dois pacientes: um pelo não uso do fio guia e em outro por hemorragia, após dilatação da papila. Relacionadas ao procedimento, ocorreram duas perfurações retroduodenais: uma decorrente de punção e outra após passagem do cesto de Dormia pela fístula dilatada. Após seguimento de 60 dias, nenhuma complicação foi observada CONCLUSÃO: Punção suprapapilar permite procedimentos investigativos e terapêuticos sem aumento significativo da amilase, lipase e proteína C reativa. Na punção diagnóstica ocorre reepitelização completa da papila, enquanto na...

Suprapapillary needle puncture for common bile duct access: laboratory profile.

BACKGROUND: [corrected] Biliary cannulation to perform endoscopic retrograde cholangiopancreatography may be difficult due to technical reasons and often is necessary to perform papillotomy, where complications as pancreatitis and perforation may occur AIM: To show minimal complications by a new model of biliary access by means of the suprapapillary needle puncture and its laboratory profile. PATIENTS AND METHODS: After the approval of the protocol by the Scientific Ethics Committee of the institution a free and informed consent was signed by all patients participating in the study. From July 2003 to August 2004, fulfilling the inclusion and exclusion criteria, 30 patients were selected for endoscopic retrograde cholangiopancreatography, using the suprapapillary puncture technique. All patients remained hospitalized, fasting and with basal hydroelectrolytic replacement, were clinically followed up and samples for the determination of serum amylase, lipase and C-RP (C-reactive protein) were collected before and 4 h, 12 h and 24 h after the procedure and reevaluated 60 days after the procedure. Laboratory parameters were submitted to statistical study using analysis of variance for repeated measurements. Multiple comparisons were made based on Wald's statistics RESULTS: The technique was successful in 93.4% (28/30) of the patients. No statistically significant difference regarding to the laboratory profile were observed. Complications related to the technique of papillary puncture occurred in 1/28 patients by not using the guide wire and in 1/28 where mild hemorrhage after dilation of the papillary fistula occurred. Regarding complications related to therapeutic procedures, there were 2/28 retroduodenal perforations, with one (1/30) following unsuccessful puncture and another due to the passage of Dormia's basket through the dilated fistula path. All patients submitted to diagnostic puncture and evaluated 60 days after the procedure presented with the major duodenal papilla of normal aspect. The patients with dilation of the suprapapillary fistula showed the fistula continuing to drain clear bile CONCLUSION: Suprapapillary puncture allows investigative and therapeutic procedures without significant increases in amylase, lipase and C-RP. Patients submitted to diagnostic puncture present complete recovery of the papilla, while dilation of the fistula maintains it pervious later on, but without complications.

Compensation increase in organic anion excretion in rats with acute biliary obstruction: role of the renal organic anion transporter 1.

The purpose of the present study was to examine in rats the effects of acute bile duct ligation on the expression of the organic anion transporter 1 in the kidney and the consequences of these effects on the systemic clearance of organic anions, particularly on P-aminohippurate (PAH) clearance, since it has been viewed as the prototypic organic anion. Male Wistar rats underwent bile duct ligation (BDL rats). Pair-fed sham-operated rats served as controls. All studies were carried out 21 h after surgery. Our data revealed that BDL rats had a higher expression of organic transporter 1 protein in kidney cortex homogenates. Accordingly, systemic clearance of PAH and urinary excretion of PAH were both higher in BDL rats. These findings suggest that impairment of the liver function after BDL is followed by a distinct and statistically significant increase in renal excretion of PAH, indicating a possible compensation mechanism.

[Correlation of the clearance of amylase and creatinine in acute pancreatitis and other pathologies]. / Correlación entre los clearance de amilasa y de creatinina en las pancreatitis agudas y otras patologías.

The study of a group of 151 patients confirms the diagnostic value of elevated ACCR in pancreatitis, it was positive in 89.4% of them, of the group, 30 were normal, 19 exhibited acute pancreatitis and 102 had various other pathologies. Serious pancreatitis has shown coincide with a long-lasting rise of ACCR, and its rise in the course of the disease was a sign of a new outburst of progressive necrosis. Total unreliability when abnormal creatinine clearance is present was ascertained. The possible mechanism of increase in ACCR has been considered also in connection with the study of the results obtained on a group of patients exhibiting renal insufficiency, gastrointestinal bleeding, acute colecystitis, vesicular lithiasis and obstructive jaundice.