Signs Of Cholestasis Research Articles

The spectrum of autoantibodies in IPEX syndrome is broad and includes anti-mitochondrial autoantibodies

IPEX syndrome is a congenital disorder of immune regulation caused by mutations in the FOXP3 gene, which is required for the suppressive function of naturally arising CD4 + CD25 + regulatory T cells. In this case series we evaluated serum samples from 12 patients with IPEX syndrome for the presence of common autoantibodies associated with a broad range of autoimmune disorders. We note that 75% of patients (9/12) had 1 or more autoantibodies, an incidence far above the cumulative rate observed in the general population. The range of autoantibodies differed between patients and there was no predominant autoantibody or pattern of autoantibodies present in this cohort. Surprisingly, one patient had high-titer anti-mitochondrial antibodies (AMA) typically associated with primary biliary cirrhosis (PBC) although the patient had no signs of cholestasis. PBC is a well-characterized autoimmune disease that occurs primarily in women and includes the serological hallmarks of serum AMA and elevated IgM which were both present in this patient. PBC is virtually absent in children with the exception of one reported child with interleukin 2 receptor α (CD25) deficiency which is associated with an IPEX-like regulatory T cell dysfunction. Based on the present data and the available literature we suggest a direct role for CD4 + CD25 + regulatory T cells in restraining B cell autoantibody production and that defects in regulatory T cells may be crucial to the development of PBC.

Treatment with anti-CD137 mAbs causes intense accumulations of liver T cells without selective antitumor immunotherapeutic effects in this organ.

Cancer therapy with agonist anti-CD137 mAbs has been shown to induce immune-mediated tumor rejections in mice, and equivalent agents of this kind are currently being tested in cancer patients. Previous reports indicated that CD137 stimulation induced polyclonal infiltrates of T lymphocytes in the liver. This study characterizes the liver infiltrates and the target dependency of the phenomena and addresses the question of whether tumors nested in the liver are a more favorable target for CD137-based immunotherapy. Liver infiltrates were studied with conventional histology and multiple color flow cytometry of total liver leukocytes. CD137(-/-) mice, mice with a single rearrangement of the TCR (OT-1 mice) and Rag(-/-) mice were used to clarify molecular requirements. Mice implanted with MC38 colon carcinomas either subcutaneously or inside the liver were used for comparative studies under treatment with agonist anti-CD137 mAbs. CD137 treatment caused mononuclear inflammation in the portal spaces of the liver, which gave rise to moderate increases in transaminases without signs of cholestasis. Marked increases in the numbers of CD8+ T cells were observed, including CD8+ T lymphocytes co-expressing CD11c. Infiltrates were absent in CD137(-/-) mice and mitigated in mice harboring a single transgenic TCR on their CD8 T cells. Despite the tumor-independent accumulation of T cells in the liver, immunotherapeutic effects were not more prominent against tumors located in this organ. Target-dependent effects of CD137 stimulation lead to liver infiltration with T cells, but lymphocyte enrichment in this organ does not privilege this site for immunotherapeutic effects against transplanted tumors.

Hepatotoxic effects of low dose oral administration of monosodium glutamate in male albino rats

The present study is aimed at investigating the potentials of low concentration administration of monosodium glutamate in inducing hepatotoxic effects in male albino rats. Thus, monosodium glutamate at a dose of 5 mg/kg of body weight was administered to adult male albino rats by oral intubation. Treatment was daily for 28 days. The monosodium glutamate treatment significantly (p decreased the serum alkaline phosphatase activity by 71.97% but increased (p monosodium glutamate at a low concentration (5 mg/kg of body weight) could be hepatotoxic without significant cholestasis or pathologies of the bone.

Functional Mx Protein Does Not Prevent Experimental Biliary Atresia in Balb/c Mice

Biliary atresia (BA) is a rare cholestatic disease, which manifests itself in the form of inflammation of the liver and bile ducts in newborns, with an unknown etiology and a poor outcome. Mx proteins, which are mediators of innate, antiviral resistance induced by type I interferon, were recently detected in the livers of children with BA. Therefore, the aim of this study was to examine whether the expression of Mx protein could affect the course of experimental BA in mice. A total of 185 newborn Balb/c mice (expressing dysfunctional Mx protein) and Balb/c-Mx+-A2G mice (with functional Mx protein) were intraperitoneally infected with rhesus rotavirus (RRV) or injected with saline solution as controls. They were sacrificed if they showed signs of cholestasis or at three weeks after infection. The expression of hepatic Mx protein was detected by immunostaining (POX) and the hepatic virus load was determined. There was no significant difference in the incidence of cholestasis between wild-type Balb/c mice and Balb/c-Mx+-A2G mice (67 % vs. 65 %). However, Mx protein was highly expressed in Balb/c-Mx+-A2G mice with BA phenotype, but not in wild type Balb/c mice or disease-free Balb/c-Mx+-A2G mice despite RRV infection. The difference in the hepatic virus load was not statistically significant in mice with BA. In conclusion, Mx protein does not prevent newborn Balb/c mice from developing biliary atresia after RRV infection. However, the expression of Mx protein is independent of the hepatic virus load and could be used as a marker of BA in humans, as well as in the RRV model.

Prevalence of gallstones in the neonatal period

To assess the prevalence of gallstones in normal neonates. We used sonography to assess the gallbladder in 3500 unselected infants between 1993 and 1995. Examination was performed during the first four days of life as part of a prospective neonatal screening study evaluating hip and renal abnormalities. We found sludge or gallstones in 19 children (0.5%). In 4 of 11 patients followed for up to 18 months, the gallstones persisted. In 3 of the cases, there was a family history of gallstones. None of the children had signs of cholestasis. Three were treated with ursodesoxycholic acid 15-20 mg/kg (per day): only one responded. About 0.5% of neonates have gallstones or gall bladder sludge; this is a higher percentage than previously thought. In one-third of the patients who were followed, the gallstones remained. Persistence was more likely in those with a positive family history for gallstones.

Endoskopisch-retrograd implantierbare, selbstexpandierende Endoprothese (Stent) bei malignen Choledochusstenosen

Self-expanding, wire-mesh stents, 10 mm in diameter, were implanted retrogradely through the papilla of Vater via an endoscopically introduced catheter system in 14 patients (9 females, 5 males, mean age 70.2 [44-85] years) with stenosis of the common bile duct by malignant tumour. Postimplantation examinations revealed no complications caused by the stent. Two of the patients have since died from their underlying disease, the others have survived an average of 10.8 weeks with markedly reduced clinical symptoms, neither jaundice nor signs of cholestasis having recurred. Serum bilirubin concentration had fallen from a mean of 8.2 mg/dl to 1.7 mg/dl 12 weeks after the procedure. Serum alkaline phosphatase activity had similarly fallen, from 515 to 330 U/l. No increase in serum amylase activity was recorded, either initially or in the course of follow-up.

Patterns of Correlation of Plasma Ceruloplasmin in Sepsis

In sepsis, plasma ceruloplasmin (Cp, mg/L) is known to increase as part of the acute phase response. However, there is poor knowledge of the patterns of increase and correlation with changes in other biochemical variables, and our study has been performed to investigate this aspect. A total of 213 simultaneous measurements of Cp and other acute phase proteins, biochemical variables, and amino acids were performed on nine patients with severe sepsis, and processed by regression analysis. Mean Cp was 478 +/- 119 mg/L (median 488, range 242-784). Significant direct correlations between Cp and C-reactive protein, alpha-1-antitrypsin and alpha-2-macroglobulin (P < 0.001 for all) were all simultaneously influenced by the level of alkaline phosphatase, which was an independent determinant of increased Cp (P < 0.001). Cp increased further with decreasing plasma pH and increasing triglyceride, taurine levels, and distance from the onset of sepsis (P < 0.001 for all). The maximum increases in Cp were associated with the presence of cholestasis, increasing triglyceride levels, and metabolic acidosis. With regard to septic liver dysfunction, while signs of cholestasis were mostly reflected in greater increases in Cp, increasing bilirubin in the presence of normal alkaline phosphatase was mostly correlated with abnormal increases in cyst(e)ine, cystathionine, and tyrosine levels. These data characterize the patterns of correlation of Cp within the biochemical abnormalities of sepsis, and may provide new insights into the pathophysiology of septic hepatobiliary dysfunction.

Somatostatinoma of the Vater's papilla in a patient with von Recklinghausen's disease

Somatostatinomas of the gastrointestinal tract secret hormon somatostatin which can cause "inhibitory syndrom" comprising diabetes mellitus, cholelithiasis and steatorrheic diarrhea. It is also secreted by the D cells of Langerhans's islands of the pancreas as well as endocrine cells of the stomack, small bowel, salivary glands and parafollicular cells of the thiroid gland. Somatostatinomas of the digestive tract appear within the pancreas and duodenum. Patients suffering from von Recklinghausens's disease are paticularly prone to the somatostatinomas of the duodenum. In this paper we presented a 51-year-old female patient with von Recklinghausen's disease in whom, during the investigation for obstructive jaundice, tumor of the Vater's papilla was found. The patient was submitted to Whipple's duodenopancreatectomy. Histology and immunohistochemistry discovered type B glandular carcinoid tumor with strong antisomatostatin and mild antigastrin immunoreactivity. The patient stayed symptom-free more than four years now. Patients with von Recklinghausen's disease should be examined for other tumors, particularly carcinoids of the duodenum and papilla, especially if the signs of cholestasis are present.

A novel pattern of transaminase elevation associated with autologous transplant for neuroblastoma

To determine the pattern and degree of hepatic transaminitis experienced by children undergoing autologous transplantation for neuroblastoma. Sixty-four children with high-risk neuroblastoma received an autologous transplant with cyclophosphamide, etoposide, and carboplatin conditioning. Forty-eight went on to receive a second transplant with M and TBI conditioning. Charts were reviewed for evidence of hepatic regimen-related toxicity. A high rate of transaminitis was observed after both regimens. In each transplant, there was an early period of transaminitis during conditioning, from which patients recovered, followed by a second period of transaminase elevation. The degree of elevation was not associated with age, whether the administered dose was calculated based on a per kg or per M(2) basis or the presence of regimen-related severe mucositis. Elevated transaminases at admission were not associated with maximal hepatotoxicity during the first transplant although there was an association in the second transplant. However, the magnitude of transaminase elevation was less in the second transplant. VOD occurred in one and three patients in transplants 1 and 2, respectively. Both conditioning regimens were associated with an early and late elevation of transaminases without significant cholestasis. This biphasic pattern of transaminitis has not been reported previously. The high prevalence of transaminase elevation at time of both transplants was not associated with an increased incidence of VOD. We conclude that elevated transaminases should not preclude proceeding to a first or second autologous transplant with these regimens.

Cholestasis Induced by Parabolan Successfully Treated with the Molecular Adsorbent Recirculating System

We describe a case of a 21-year-old male bodybuilder who overdosed on Parabolan (trenbolone acetate) because of its anabolic activity. The patient, with no previous medical history, experienced pruritus and yellow discoloration of the skin and sclerae. Basic biochemical laboratory examination revealed signs of cholestasis with a serum bilirubin level of up to 65.5 mg/dl. Because supportive medical treatment was ineffective, the patient was treated with the molecular adsorbent recirculating system (MARS). Five MARS cycles lasting from 8 to 12 hours were performed every second day. The procedure was well tolerated by the patient and resulted in a sustained relief of pruritus. At the 2-month follow-up visit the plasma bilirubin level had decreased to 2 mg/dl.

Acute left hemispheric syndrome with cortical lesions in a patient with secondary porphyrinuria

Sirs: Oberndorfer et al. report a patient with the full clinical picture of a hereditary acute hepatic porphyria whose brain MRI was normal [1]. They conclude that a secondary abnormality of porphyrin metabolism should be the origin of their patient’s symptoms although secondary alterations of porphyrin metabolism are reported not to produce any porphyria-like symptoms [2]. We here present the case of another patient in whom we presume a secondary porphyrinuria was the cause of a neurological disorder mimicking the clinical and neuroradiological picture of a hereditary porphyria [3–5]. A 45 year old female was admitted to our neurological intensive care unit with an acute right-sided hemiparesis combined with aphasia. Cardiovascular risk factors could not be determined, her medical history included a series of generalized epileptic seizures before her admission to our hospital and an alcohol-dependency. Further medical history was not known as the patient was living alone. On admission, cerebral CT showed no abnormalities, especially no signs of a cerebral ischemia. On cerebral MRI in proton density and diffusion-weighted images a diffuse signal change was found bifrontally, in the left-hemispheric cortex and thalamus as well as in the right cerebellar cortex, FLAIR sequences showed corresponding changes. MR-Angiography was not tolerated by the patient as she was in an agitated state. Correlating with MRI findings, cerebral perfusion of the left hemisphere and the rightsided cerebellar hemisphere was diminished as shown on perfusion-SPECT while EEG showed diffuse slowing with a left frontotemporal theta-delta-focus without epileptic discharges. Cardiovascular investigations (Ultrasound-examination of cervical vessels, echocardiography, and ECG) showed no specific abnormalities; transcranial Doppler sonography could not be performed owing to the thickness of the temporal bone squama. Cerebrospinal fluid was normal as well, whereas liver-enzymes were elevated (Bili. tot. 13.53 mg/dl [0.00–1.10], Bili. dir. 11.87 mg/dl [0.00–0.25]; ASAT/GOT 348 U/l [10–50]; ALAT/GPT 295 U/l [10–50]; AP 386 U/l [40–129]; GGT 610 U/l [0–66]; LDH 647 U/l [135–225]; CK 1025 U/l [0–174], CK-MB 30 U/l [0–24]; normal values for creatinine.) As the patient was known to be an alcoholic and presented with seizures, elevated liver enzymes and dark urines, we checked for porphyrin abnormalities. During these investigations elevated urinary uroand coproporphyrins and total porphyrins were found (coproporphyrin 415 μg/d (< 120), uroporphyrin 113 μg/d (< 33), heptacarboxyporphyrin 17 μg/d (< 10), calculated total porphyrins 551 μg/d (< 170), normal values for hexacarboxyporphyrin and pentacarboxyporphyrin. In the course we found normal values for liver enzymes in 24h-urine for deltaaminolaevulic-acid, porphobilinogen, total porphyrins, porphobilinogen deaminase). We interpreted these laboratory findings as signs of cholestasis and the porphyrins as secondary coproporphyrinuria with a disturbed decarboxylation during cholestasis. Abdominal ultrasound showed an intrahepatic biliary obstruction causative for cholestasis. During her stay on our intenLETTER TO THE EDITORS

Intraluminal brachytherapy without stenting in intrahepatic papillary cholangiocarcinoma: A case report

A 46-year-old female patient, with mild cholestasis by a large papillary cholangiocarcinoma involving the left hepatic duct, received intraluminal brachytherapy (50 Gy at 1 cm from the source axis) with the aim to relieve biliary obstruction without stent positioning. The patient presented with haemobilia and vegetant lesions in the left main biliary duct, and thus she had a high risk of early stent obstruction. Eighteen months after the treatment the patient presented tumour progression in the controlateral hepatic lobe, but had a patent left hepatic duct, without signs of cholestasis and/or cholangitis. Based on this and other published reports, intraluminal brachytherapy may be tested in a setting different from standard setting with the aim to safely palliate jaundice in patients with intraductal tumour growth in the biliary tract.

Hepatic Copper in Patients Receiving Long-term Total Parenteral Nutrition

To assess the possibility of iatrogenic hepatic copper overload in adult patients on long-term total parenteral nutrition (TPN). TPN predisposes to hepatic copper accumulation through disturbances of the enterohepatic bile acid pool, but iatrogenic copper overload through TPN solutions may occur as well. Quantitative hepatic copper and multiple clinical, biochemical, and histopathologic parameters were compared between patients with long-term TPN associated liver disease (n = 28) and patients with drug-induced cholestatic liver disease (n = 10). Eighty-nine percent of TPN patients and all controls had mildly elevated hepatic tissue copper, but 29% of TPN patients had levels above the diagnostic threshold for Wilson's disease. Quantitative hepatic copper correlated positively with serum aspartate aminotransferase (P = 0.001, r = 0.59), total bilirubin (P < 0.001, r = 0.65), and direct bilirubin (P < 0.001, r = 0.63) in TPN patients, but not in controls. The amount of hepatic copper did not correlate with the duration of TPN (median, 1.9 years; range, 0.3-18.0 years) or serum copper levels. TPN patients with significant cholestasis accumulated more copper than patients with no or only minimal cholestasis (P = 0.002). Significant hepatic copper overload in TPN patients occurs through chronic cholestasis in TPN-associated liver disease and is independent from the total duration of TPN. Iatrogenic copper overload through trace elements in TPN solutions does not seem to be a significant factor.

Cholestasis in children with portal vein obstruction

We describe cholestasis as a result of bile duct abnormalities in 8 children with portal vein obstruction. In a clinical, biochemical and radiological investigation of 121 children with cavernous transformation of the portal vein seen between 1986 and 2000, 8 presented with jaundice, pruritus, and/or raised serum aminotransferases and/or gamma glutamyl transpeptidase (gamma GT) activities. Each displayed dilation and narrowing of intra- and/or extrahepatic bile ducts. Surgical decompression of the portal system (portal-systemic or Rex anastomosis) resulted in the regression of the signs of cholestasis in all children. We conclude that children with portal vein obstruction may exhibit clinically significant cholestasis as a result of external compression of the bile duct by the cavernoma.

HETEROTOPICALLY TRANSPLANTED HEPATOCYTES PRODUCE LIVER NEO-TISSUE WITH PROLIFERATIVE ACTIVITY AND EXPRESSION OF A MATURE BILE CANALICULI NETWORK

P1218 Aims: As previously reported, we performed flow culture of hepatocytes on a biodegradable polymer matrix and observed formation of spheroids, which in vitro created a bile canaliculi network. We were now interested in their in vivo behavior. Therefore we designed a long term implantation study and compared hepatocyte transplantation without pre-culture with pre-cultured hepatocyte spheroid transplantation in a heterotopic matrix based transplantation model. Methods: Primary hepatocytes were isolated from male Lewis rats using a two step collagenase digestion method. Highly porous poly(L-lactic acid) (PLLA) sponges were seeded with 4 x 106 hepatocytes. They were transplanted onto the mesentery of Lewis rats either immediately after cell seeding, or after 3 days of culture. For hepatotrophic stimulation a porto-caval shunt operation was performed 2 weeks before hepatocyte transplantation. After 1 week, 1, 3, or 6 months the specimens were harvested and underwent histological, immunohistochemical, immunofluorescent and morphometric analysis. For statistical analysis the nonparametric Kruskal-Wallis test was used, assuming p< 0,1 as statistically significant. Results: Newly formed liver tissue could be found in all implants and was positive for PAS, Hepar 1, and Cytokeratin 18. Phaloidin immunofluorescent studies showed expression of a liver like bile canaliculi network in the spheroid group after 1 week in vivo. The non pre-cultured group expressed only some bile canaliculi at that time point. After 1 month no difference in expression between the two groups could be observed. The HE staining showed no sign of intracellular cholestasis throughout the observation period of 6 months after transplantation. Proliferation activity of the hepatocytes was demonstrated in both groups by PCNA stain and morphometric analysis, which showed an increase of the total heterotropic hepatocyte area. With p=0,023 (pre-cultured spheroids) and p=0,051 (non pre-cultured) for the monte-carlo-significance a statistically significant difference was shown with increasing rank order over the incubation time. After 6 months, the transplantation efficiency was twice as high in the spheroid group (90 ± 39%) compared to the non pre-cultured group (40 ± 25%). Conclusions: Matrix based heterotopic hepatocyte and hepatocyte spheroid transplantation led to liver neo-tissue with in vivo formation of a bile canaliculi network and long term proliferation activity. As there are no signs of cholestasis within the heterotopically formed liver neo-tissue even after 6 months in vivo, a removal of bile must be assumed. Transplantation of pre-cultured hepatocyte spheroids led to a higher efficiency and proliferation, compared to non pre-cultured hepatocyte transplantation. Pre-implantation tissue assembly, including the formation of a bile canaliculi network could possibly explain this advantage.

Evolution of autoimmune hepatitis to primary sclerosing cholangitis: A sequential syndrome

Recently, the autoimmune hepatitis (AIH)/primary sclerosing cholangitis (PSC) overlap syndrome has been reported increasingly. In this syndrome, patients present with features of both AIH and PSC. It has been suggested that the 2 diseases may be sequential in their occurrence, whereby patients have features of AIH and then after a number of years develop features of PSC, but clear confirmation of evolution has not been documented in adults. We describe 6 adult cases in which PSC was diagnosed many years after well-established AIH. Six patients are described in whom AIH definitely was diagnosed at presentation. No evidence of biliary disease was noted on the initial liver biopsy or endoscopic retrograde cholangiography (ERCP). All patients responded well to immunosuppressive therapy. After an average duration of follow-up of 4.6 years they became resistant to immunosuppression, and developed clear features of PSC, which was confirmed by ERCP in all patients. The average age of the patients at first presentation was 31.3 years, 2 were women and 4 were men, and 3 had ulcerative colitis. We found no specific features at presentation that could predict this evolutionary outcome. In conclusion, patients with well-established AIH can, after variable duration of follow-up, develop PSC. In patients with AIH who become resistant to immunosuppression of develop significant cholestasis, PSC should be ruled out by ERCP. (Hepatology2002;36:1393-1399).

Evolution of autoimmune hepatitis to primary sclerosing cholangitis: A sequential syndrome

Recently, the autoimmune hepatitis (AIH)/primary sclerosing cholangitis (PSC) overlap syndrome has been reported increasingly. In this syndrome, patients present with features of both AIH and PSC. It has been suggested that the 2 diseases may be sequential in their occurrence, whereby patients have features of AIH and then after a number of years develop features of PSC, but clear confirmation of evolution has not been documented in adults. We describe 6 adult cases in which PSC was diagnosed many years after well-established AIH. Six patients are described in whom AIH definitely was diagnosed at presentation. No evidence of biliary disease was noted on the initial liver biopsy or endoscopic retrograde cholangiography (ERCP). All patients responded well to immunosuppressive therapy. After an average duration of follow-up of 4.6 years they became resistant to immunosuppression, and developed clear features of PSC, which was confirmed by ERCP in all patients. The average age of the patients at first presentation was 31.3 years, 2 were women and 4 were men, and 3 had ulcerative colitis. We found no specific features at presentation that could predict this evolutionary outcome. In conclusion, patients with well-established AIH can, after variable duration of follow-up, develop PSC. In patients with AIH who become resistant to immunosuppression or develop significant cholestasis, PSC should be ruled out by ERCP. (H EPATOLOGY 2002;36:1393-1399.)

Prevalence and genomic variability of transfusion transmitted virus in Italian cryptogenic chronic liver disease and healthy blood donors.

Infection with transfusion transmitted virus, a new member of the Parvoviridae family, has been found in patients both with chronic and fulminant post-transfusion cryptogenic hepatitis. To evaluate the prevalence and clinical impact of transfusion transmitted virus infection in Italy. Studies were carried out on 256 patients and control subjects from three centres from Northern, Central and Southern Italy (92 nonA-nonC chronic hepatitis, 10 acute non fulminant cryptogenic hepatitis, 41 hepatitis C virus-related chronic hepatitis and 113 blood donors). Serum transfusion transmitted virus was detected by nested polymerase chain reaction using two overlapping sets of primers. A total of 52 of the 92 patients (54.3%) with chronic cryptogenic liver disease and 17 of the 41 hepatitis C virus chronic hepatitis patients (41.4%) were transfusion transmitted virus-DNA positive. Transfusion transmitted virus co-infection in hepatitis C virus patients was not associated with either a higher severity of liver histology or higher alanine transaminase levels or signs of cholestasis, transfusion transmitted virus was found in 48 out of 113 (42.4%) blood donors. In the majority of samples, transfusion transmitted virus DNA was detected with only one of the two sets of primers used. Genotyping and phylogenetic analysis performed on 21 randomly selected viral isolates showed the presence of both type 1 and type 2 transfusion transmitted virus and allowed identification of two isolates with high homology to genotype 6, described, so far, mostly in Japan. Transfusion transmitted virus type 1 and 2 infection is common among blood donors and patients with liver disease in Italy. The pathogenic potential of transfusion transmitted virus type 1 and 2 in nonA-nonC hepatitis patients is unlikely but further studies are needed to evaluate the epidemiological and clinical impact of other transfusion transmitted virus subtypes.

Cholestasis with altered structure and function of hepatocyte tight junction and decreased expression of canalicular multispecific organic anion transporter in a rat model of colitis.

Cholestasis is frequently associated with inflammatory bowel disease. Because some cholestasis is resulted from altered hepatocyte tight junctions (TJs) or the canalicular multispecific organic anion transporter, we have investigated the following topics in a rat model of inflammatory bowel disease: (1) alterations in hepatocyte TJs and in the canalicular multispecific organic anion transporter, (2) etiologic factors for cholestasis, and (3) effects of antibiotics on cholestasis. Rats with trinitrobenzene sulfonic acid-induced colitis were studied 24 hours after treatment. Hepatocyte TJs and the canalicular multispecific organic anion transporter were evaluated by immunostaining for TJ-associated proteins, 7H6 and ZO-1, and multidrug resistance protein 2 (mrp2). To investigate etiologic factors causing cholestasis, portal endotoxin and proinflammatory cytokines were examined. The effects of polymyxin B, penicillin G, or metronidazole on immunostaining for 7H6, ZO-1, mrp2, and cholestasis were investigated. (1) Immunostaining for 7H6 and ZO-1 colocalized outlining the bile canaliculi and immunostaining for mrp2 localized on the canalicular membrane in controls. Treatment with trinitrobenzene sulfonic acid induced significant cholestasis and caused translocation of immunostaining for 7H6, but not that for ZO-1, to the cytoplasm and diminished immunostaining for mrp2 on the canaliculus membrane. (2) The levels of portal endotoxin, but not proinflammatory cytokines, was increased. (3) Polymyxin B, but not the other antibiotics, prevented alterations in immunostaining for both 7H6 and mrp2, and cholestasis. We described that both hepatocyte TJs and the canalicular multispecific organic anion transporter were altered and that gut-derived endotoxin levels in the portal blood were increased in this rat colitis model.

Nutrition and liver diseases.

Malnutrition and micronutrient deficiencies are common in patients with liver diseases. The pathogenesis of protein-energy malnutrition in cirrhosis involves many factors, including poor oral intake, malabsorption, and metabolic abnormalities similar to stress. Encephalopathy may complicate cirrhosis but is usually not caused by diet. Protein restriction is only necessary in rare patients with refractory encephalopathy. The use of branched-chain amino-acid solutions is not supported by the literature. Chronic liver diseases without cirrhosis are not usually associated with protein-energy malnutrition, but vitamin and mineral deficiencies are common, especially with significant cholestasis. Fatty liver may result from excessive triglyceride uptake and production by the liver or by a secretory defect. Therapy for fatty liver depends on its cause. Chronic total parenteral nutrition may induce fatty liver and inflammation especially in patients with short-bowel syndrome. Deficiency of choline in parenteral nutrition has been proposed as the mechanism for liver disease. Acute liver diseases such as fulminant hepatic failure or alcoholic hepatitis are considered hypercatabolic diseases and thus require prompt nutritional intervention with a high-calorie enteral or parenteral formula. In fulminant hepatic failure, low-protein, fluid-restricted formulas are recommended.