Mechanical Cholestasis Research Articles

PB1832 MATRIX CHEMOTHERAPY FOR PRIMARY CNS LYMHPOMA COMPLICATED WITH HCV INFECTION AND SUCCESSFUL ERADICATION OF BOTH DISEASES

Background:There is a well‐known connection between Hepatitis C virus (HCV) infection and B‐cell lymphomas (BCL). HCV infected patients have an increased risk of developing BCL. Hypothetically, lymphomagenesis can be induced by chronic antigen stimulation (analogous to Helicobacter pylori associated gastric marginal zone lymphoma) and/or a direct pro‐oncogenic effect of intracellular HCV proteins. Several studies have demonstrated that antiviral therapy may induce remission and improve prognosis of HCV‐associated lymphomas. On the other hand, HCV infection can cause sever complication during the immunochemotherapy and stem cell transplantation. These patients are at risk for HCV reactivation, accelerated liver disease progression, drug‐induced liver toxicity. Thus, HCV‐infected patients often suffer treatment delays, reduced dose intensity, and many times are excluded from bone marrow transplantation. Accordingly, there is some evidence of negative prognostic impact of HCV infection on survival.Aims:To draw attention to the HCV caused complications during lymphoma treatment.Methods:Here we present the case of a HCV‐infected patient with primary central nervous system (CNS) lymphoma complicated with HCV infection and review the relevant literature.Results:A 56‐year old woman with CNS lymphoma was treated with MATRIX (methotrexate, cytarabine, thiotepa, and rituximab). Initial serum serology showed reactivity to HBcAg and HCV. Polymerase chain reaction (PCR) detected no hepatits B virus DNA, however the copy number for hepatitis C virus (HCV) RNA was 104 850 000 IU/ml. She received HBV prophylaxis with lamivudine and subsequently entecavir against reactivation of HBV. After the 2nd cycle of chemotherapy her liver function tests became severely abnormal (AST: 514 U/L ALT: 264 U/L, ALP: 145 U/L, GGT: 1328 U/L, total Bi: 74.6 umol/L, conjugated Bi: 63.5 umol/L). The patient was asymptomatic regarding the lymphoma and in complete remission according to MRI scans. Further systemic chemotherapy had to be halted. The HBV DNA was still undetectable by PCR. Drug induced or mechanical cholestasis and the role of ongoing HCV infection was contemplated. The biliary tracts were not dilated on ultrasound scans. She had an ERCP with sphincterotomy and sofosbuvir plus ledipasvir plus ribavirin treatment for HCV was started. Meanwhile, intrathecal methotrexate therapy was administered 3‐weekly to bridge till next chemotherapy. The antiviral therapy was completed without any side effects and at 3 months, her HCV RNA PCR was negative with entirely normal liver function. The patient achieved sustained virological response. Two more cycles of MATRIX was delivered and an autologous stem cell transplantation with BCNU and thiothepa conditioning. Liver function remained normal ever since.Summary/Conclusion:This is a rare case where the role of HCV infection in liver damage during systemic chemotherapy is highly possible. We would like to draw attention to the liver vulnerability caused by chronic HCV infection. Nowadays HCV eradication is feasible with novel direct acting antiviral therapies, HCV‐infection should not contraindicate the adequate chemotherapy.

S07 * NONINVASIVE SCREENING TOOLS FOR LIVER CIRRHOSIS IN ADDICTED PATIENTS

S07 * NONINVASIVE SCREENING TOOLS FOR LIVER CIRRHOSIS IN ADDICTED PATIENTS

Liver stiffness: a novel parameter for the diagnosis of liver disease

The noninvasive quantitation of liver stiffness (LS) by ultrasound based transient elastography using FibroScan® has revolutionized the diagnosis of liver diseases, namely liver cirrhosis. Alternative techniques such as acoustic radiation impulse frequency imaging or magnetic resonance elastography are currently under investigation. LS is an excellent surrogate marker of advanced fibrosis (F3) and cirrhosis (F4) outscoring all previous noninvasive approaches to detect cirrhosis. LS values below 6 kPa are considered as normal and exclude ongoing liver disease. LS of 8 and 12.5 kPa represent generally accepted cut-off values for F3 and F4 fibrosis. LS highly correlates with portal pressure, and esophageal varices are likely at values >20 kPa. Many other factors may also increase LS such as hepatic infiltration with tumor cells, mast cells (mastocytosis), inflammatory cells (all forms of hepatitis) or amyloidosis. In addition, LS is directly correlated with the venous pressure (eg, during liver congestion) and is increased during mechanic cholestasis. Thus, LS should always be interpreted in the context of clinical, imaging and laboratory findings. Finally, LS has helped to better understand the molecular mechanisms underlying liver fibrosis. The novel pressure-stiffness-fibrosis sequence hypothesis is introduced.

Clusterin expression in cholestasis, hepatocellular carcinoma and liver fibrosis

Clusterin shares functional properties with small heat shock proteins. In contrast to other heat shock proteins, it is present in the extracellular space. Its expression is altered in various diseases. The aim was to evaluate the presence and distribution of clusterin in liver diseases associated with cholestasis, in fibrosis and in hepatocellular carcinoma. Tissue microarrays and biopsy materials were used to evaluate immunohistochemically the expression of clusterin in hepatocellular carcinoma, primary sclerosing cholangitis, primary biliary cirrhosis, mechanical cholestasis, drug-induced cholestasis, liver fibrosis and cirrhosis. The presence of clusterin in human bile was assessed by Western blotting. Furthermore, real-time reverse transcriptase-polymerase chain reaction was performed on liver tissue with mechanical cholestasis. Clusterin colocalized with elastic fibres, but not with collagen, hepatocytes or bile duct epithelia. It was detected in bile plugs in cholestasis and hepatocellular carcinomas with pseudoglandular features within the lumina. Clusterin was demonstrated in bile by Western blotting and its mRNA was expressed in normal and cholestatic livers. Clusterin may protect bile duct epithelium against offensive biliary components or inhibit precipitation of biliary proteins. The association of clusterin with elastic fibres could reflect an extracellular chaperone function by either protecting elastic fibres or shielding abnormal elastic material.

Cholestatische Hepatitis bei Situs inversus abdominalis

A 75 year old patient was admitted to hospital due to painless jaundice and fatigue. Patient's history was not remarkable for chronic viral hepatitis, autoimmune hepatitis, hereditary metabolic disorders or a hepatotoxic damage. Laboratory tests revealed significant elevation of the parameters of cholestasis and aminotransferase activity, a significantly elevated titer of both antinuclear (ANA) and antimitochondrial (AMA) antibodies. Abdominal ultrasound and computertomography showed no mechanic cholestasis nor tumorous process but a situs inversus abdominalis of the abdominal parenchymatous organs. Portal and periportal inflammation, consistent with autoimmune hepatitis, was diagnosed histologically after performing laparoscopic liver biopsy. Regarding the significantly elevated cholestatic parameters and the positive AMA-autoantibodies AIH-PBC overlap syndrome was highly probable so medical treatment including both ursodeoxycholic acid and immunosuppressive therapy with corticosteroids and azathioprine was started resulting in a continous downward tendency of liver enzymes and an improvement of the patient's clinical condition. Finding the correct diagnosis and therapy of autoimmune liver disease is not always easy and unproblematic. Regarding its sometimes fatal progression and good response towards medical treatment prompt diagnosis and institution of autoimmune hepatitis--alone or combined as PBC/AIH overlap syndrome--should not be deferred. Laparoscopic liver biopsy should be the method of choice in patients's with situs inversus abdominalis regading the variable anatomy.

Choledochoduodenal fistula after liver transplantation

Endoscopic procedures are the treatment of choice;however, surgery is often required for refractory dis-ease.Here, we present the case report of a liver transplantrecipient with a bile leak forming a choledochoduodenalfistula, which was treated successfully by endoscopicstenting. A 67-year-old man underwent orthotopic livertransplantation for end-stage liver disease due to hep-atitis C virus infection. Biliary reconstruction was per-formed with end-to-end choledochocholedochostomywithout intraoperative complications. The patient wasdischarged from the hospital 16 days after transplan-tation.He was readmitted 10 days later because of painlessjaundice and elevation of liver function tests. Abdomi-nal ultrasound gave no evidence for mechanical cho-lestasis. Histologic analysis as well as serological testsrevealed hepatitis C reinfection.However, 3 weeks later abdominal ultrasonographyshowed intrahepatic bile ducts being dilated up to 4mm in diameter. Endoscopic retrograde cholangiogra-phy revealed biliary leakage at the level of the anasto-mosis without communication to other organs; conse-quently, a stent was placed within the common bileduct which resulted in timely abrogation of jaundice.Ten weeks later, the patient presented at our institu-tion again because of itching, jaundice, and elevatedcholestatic parameters. Magnetic resonance cholangio-pancreatography (MRCP) was performed, and it showeda signal-enhancing structure dorsal to the common bileduct leading to the small intestine (Fig. 1).After endoscopic examination, absence of the biliarystent was noticed. Retrograde endoscopic cholangiog-raphy showed a pearl necklace–like contrasted fistula-tion originating from the bile duct anastomosis andleading to the duodenum (Fig. 2). To localize the mouthof the fistula, 0.1% methylene-blue solution was in-jected into the distal choledochus (Fig. 3). Remarkably,the mouth of the fistula could be localized proximal tothe papilla vateri in the wall of the duodenum. Closingof the fistula was obtained by placing a 11.5-Frenchplastic endoprosthesis into the right hepatic duct. Thepatient recovered from jaundice after this procedure,without further events or complications.

Renal elimination of p-aminohippurate (PAH) in response to three days of biliary obstruction in the rat. The role of OAT1 and OAT3

Pharmacokinetic studies of the drugs administered to subjects with mechanical cholestasis are scarce. The purpose of the present study was to examine the effects of bile duct ligation of 3 days (peak of elevation of serum bile acids and bilirubin) on the systemic and renal PAH clearance and on the expression of cortical renal OAT1 and OAT3 in a rat model. PAH is the prototypical substrate of the renal organic anion transport system. Male Wistar rats underwent a bile duct ligation (BDL rats). Pair-fed sham-operated rats served as controls. BDL rats displayed a significantly lower systemic PAH clearance. Renal studies revealed a reduction in the renal clearance and in the excreted and secreted load of PAH in BDL rats. The OAT1 protein expression in kidney homogenates was not modified, but it decreased in the basolateral membranes from BDL rats. In contrast, OAT3 abundance in both kidney cortex homogenates and in basolateral membranes increased by 3 days after the ligation. Immunocytochemical studies (light microscopic and confocal immunofluorescence microscopic analyses) confirmed the changes in the renal expression of these transport proteins. The present study demonstrates the key role of OAT1 expression in the impaired elimination of PAH after 3 days of obstructive cholestasis.

Schwere intrahepatische Cholestase bei einem 66-jährigen Patienten mit medikamentös behandeltem Vorhofflimmern

A 66-year-old male was admitted to hospital due to painless jaundice. Because of ischemic cardiomyopathy with paroxysmal atrial fibrillation as well as recurrent ventricular tachycardias and fibrillation he was treated with phenprocoumon and amiodarone (200 mg per day) for 2 years. Laboratory tests revealed significant elevation of the parameters of cholestasis and aminotransferase activity. Serological tests excluded infectious, autoimmune or metabolic liver diseases. Abdominal ultrasound and ERCP showed no mechanic cholestasis nor tumor of the pancreas. Cardiac congestive disease was also excluded. Severe intrahepatic cholestasis, consistent with drug-induced hepatotoxic damage, was diagnosed histologically. After discontinuing phenprocoumon the liver enzymes further increased. When amiodarone was stopped, however, laboratory parameters showed a continuous downward tendency. For prevention of malignant cardiac arrhythmia the patient received an atrioventricular defibrillator. Intrahepatic cholestasis is a rare presentation of amiodarone-induced hepatic toxicity. Liver damage can even occur after the drug has been taken for prolonged periods without any problems.

Abdomineller Ultraschall zum Therapiemonitoring nach endoskopischer oder perkutaner Stent- und Drainageimplantation

Stents and prostheses in the hepatobiliary system are visible by ultrasound examination and can be checked for their function. The reappearance of mechanical cholestasis, stent dislocation or formation of sludge on the stent tip is signs of stent dysfunction. Graduation of the biliary obstruction can help to find the best time for changing the stent. After intervention hematoma, abscess, intraabdominal fluid or gas may occur and can be diagnosed by ultrasound. Tumor stenosis in the gastrointestinal tract can be treated by self expandable metallic stents. Ultrasound helps to localize the stent in the correct position and to observe the reduction of occlusive ileus. Percutaneous and gastrointestinal drainage of pancreatic cysts, necrosis and abscesses are often controlled by ultrasound to evaluate size, echogenicity and localized pain. Many procedures and interventions in gastroenterology can be monitored by an experienced ultrasound examiner in an effective and inexpensive manner.

Unusual hyperbilirubinemia associated with bacterial pneumonia and acute myeloid leukemia

A 77-year-old man with pneumonia associated with acute myeloid leukemia was introduced to the hepatology unit at our hospital for hyperbilirubinemia. He had been suffering from a high fever because of pneumonia. He was icteric and his serum concentrations of total and direct bilirubin were 13.1 and 7.9 mg/dl, respectively. However, the other standard biochemical examinations for hepatic function, such as serum concentrations of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase and alkaline phosphatase were normal except for lactate dehydrogenase. Lactate dehydrogenase isoenzyme analysis revealed that the high concentration was derived from leukemia cells. Ultrasonography of the abdomen revealed no abnormality in the liver or biliary tract. Administration of antibiotics for pneumonia decreased the serum bilirubin concentration, however, he died because of respiratory failure caused by the progression of pneumonia at 33 days after the admission. It was suggested that a disturbance in the bilirubin metabolism without hepatocyte necrosis or mechanical cholestasis might be involved in the pathogenesis of hyperbilirubinemia in patients with infectious diseases.

Serologic assay for secretory component distinguishes mechanical from hepatocellular cholestasis in humans.

In rats, serum secretory component (SC) is elevated in mechanical but not hepatocellular cholestasis. To determine if serum SC might distinguish cholestatic syndromes in humans, serum samples were obtained from control subjects and patients with mechanical and hepatocellular cholestasis. Equal volumes of serum were assayed for SC by immunoblotting with an antibody specific for human SC. Quantitative densitometry of these immunoblots showed that in mechanically obstructed patients serum SC was reversibly elevated to a level approximately 10-fold higher than that of patients with hepatocellular cholestasis (P < 0.001). When comparing the two cholestatic groups, levels of serum alkaline phosphatase, but not bilirubin and alanine aminotransferase, were significantly higher in the group with mechanical cholestasis (P < 0.01). When comparing individual patients, serum SC was more reliable than alkaline phosphatase in distinguishing the two cholestatic syndromes (P < 0.05). Thus, serum SC may distinguish mechanical from hepatocellular cholestasis in humans.

The endoplasmic reticulum of the rat liver cell in experimental mechanical cholestasis. Correlated biochemical and ultrastructural-morphometric studies on structure and enzyme composition

The structure and enzyme composition of the endoplasmic reticulum (ER) and smooth (SER) and rough (RER) microsomal subfractions derived from choledochusligated rat livers were studied using biochemical and ultrastructural-morphometric methods. Mechanical cholestasis resulted in an increase in ER per total liver but affected neither the protein/phospholipid nor the SER RER ratios of the microsomal membranes. ER in cholestasis was poor in cytochrome P-450, the P-450 loss being more pronounced in the RER than in the SER. The decrease in cytochrome b 5 was less pronounced. Microsomal UDP-glucuronyl transferase activity (per milligram of microsomal protein) remained unchanged; total activity in the liver was elevated in proportion to the increase in total microsomal protein. Glucose-6-phosphatase activity was significantly decreased in SER and RER. Benzpyrene hydroxylase activity of liver microsomes in vitro was greatly impaired in cholestasis (20% of the controls). In contrast to aminopyrine- N-demethylase, the benzpyrene hydroxylase activity did not correlate with P-450 loss or loss of P-450 reductase. This may be due to a predominant alteration of the P-450 species specifically engaged in benzpyrene metabolism. Cholestasis had no effect on microsomal lipid peroxidation and fatty acid desaturation in vitro. Selective ligation of the middle lobe of the liver was not accompanied by an increase in the weight of the obstructed lobe nor by inhibition of microsomal aminopyrine- N-demethylation. However, an increase in microsomal protein as well as a decrease in the specific microsomal content in P-450 and b 5 and in glucose-6-phosphatase activity was observed, similar to the situation seen in complete cholestasis.

Turnover of hepatic cytochrome P-450 in experimental cholestasis

In mechanical experimental chllestasis, hypertrophy of smooth microsomal membranes was observed. In contrast to typical induction, the membranes were deficient in cytochrome P-450. The total cytochrome P-450 content of the liver, however, as determined in the liver homogenate remained unchanged. To clarify the mechanism of the development of cytochrome P-450 deficient membranes in cholestasis, the half life of the heme portion of cytochrome P-450, and the initial rate of synthesis of cytochrome P-450 and b 5 hemes were compared in bile duct ligated rats and in control animals after labeling the heme by injection of the precursor δ-[4- 14C]aminolevulinic acid. The half lives were not significantly different, which eliminates the possibility that selective destruction of cytochrome P-450 has occurred. Depression of cytochromal heme synthesis was not observed. During mechanical cholestasis, the relative cytochrome P-450 deficiency is probably caused by proliferation of components of the endoplasmic reticulum other than the hemoprotein.