Normal Hepatic Architecture Research Articles

Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: A histopathological study

Chronic exposure to stress contributes to the etiology of mood disorders, and the liver as a target organ of antidepressant and antipsychotic drug metabolism is vulnerable to drug-induced toxicity. We investigated the effects of chronic administration of fluoxetine (15mg/kg/day) or clozapine (20mg/kg/day) on liver injury via the measurement of liver enzymes, oxidative stress and histopathology in rats exposed to chronic social isolation (21days), an animal model of depression, and controls. The activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the liver content of carbonyl groups, malonyldialdehyde (MDA), reduced glutathione (GSH), cytosolic glutathione S-transferase (GST) and nitric oxide (NO) metabolites were determined. We also characterized nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2) and CuZn-superoxide dismutase (CuZnSOD) protein expression as well as histopathological changes. Increased serum ALT activity in chronically-isolated and control animals treated with both drugs was found while increased AST activity was observed only in fluoxetine-treated rats (chronically-isolated and controls). Increased carbonyl content, MDA, GST activity and decreased GSH levels in drug-treated controls/chronically-isolated animals suggest a link between drugs and hepatic oxidative stress. Increased NO levels associated with NF-κB activation and the concomitant increased COX-2 expression together with compromised CuZnSOD expression in clozapine-treated chronically-isolated rats likely reinforce oxidative stress, observed by increased lipid peroxidation and GSH depletion. In contrast, fluoxetine reduced NO levels in chronically-isolated rats. Isolation induced oxidative stress but histological changes were similar to those observed in vehicle-treated controls. Chronic administration of fluoxetine in both chronically-isolated and control animals resulted in more or less normal hepatic architecture, while clozapine in both groups resulted in liver injury. These data suggest that clozapine appears to have a higher potential to induce liver toxicity than fluoxetine.

Ameliorative effect of vitamin C against 5-fuorouracil-induced hepatotoxicity in mice: A light and electron microscope study

5-Fluorouracil is one of the most widely used chemotherapeutic agents in case of hepatic neoplasms. The object of this study was to determine the effectiveness of vitamin C in alleviating 5-fluorouracil-induced hepatotoxicity in male mice. Thirty male albino mice were divided equally into 3 groups, each of 10 animals; group 1, mice received normal saline solution (control group); group 2, mice received 5-fluorouracil 80mg/kgb.wt./day intraperitoneally for 4weeks (5-fluorouracil group); group 3, mice received 5-fluorouracil 80mg/kgb.wt./day for 4weeks with daily injection of vitamin C (12mg/kgb.wt./day) for 4weeks. Animals of all groups were sacrificed and tissue samples from the liver were taken and processed for both light and electron microscopical examination. Light microscopic observations revealed that administration of 5-fluorouracil causes variable signs of hepatotoxicity which are represented by focal areas of liver cell necrosis with distortion of normal hepatic architecture; the hepatocytes showed vacuolated cytoplasm and pyknotic nuclei together with inflammatory cell infiltration. Dilated, congested hepatic sinusoids with active kupffer cells were also seen. Ultrastructure examination confirmed the light microscopic findings and demonstrated vacuolated hepatocytes cytoplasm, dilated endoplasmic reticulum, increased lysosomes, electron-dense mitochondria and pyknotic nuclei. Treatment with vitamin C with 5-fluorouracil attenuated 5-fluorouracil-induced hepatotoxicity and reverted the abnormal structural changes to near normal. In conclusion, these results suggest that vitamin C has a protective potential in ameliorating 5-fluorouracil-induced hepatotoxicity.

HEPATOPROTECTIVE EFFECT OF AQUEOUS AND N-HEXANE EXTRACT OF NIGELLA SATIVA IN PARACETAMOL (ACETAMINOPHEN) INDUCED LIVER DISEASES OF RATS: A HISTOPATHOLOGICAL EVALUATION

Acute o ver dose of p aracetam ol (acetaminophen) causes serious hepatic necrosis. So, this study was conducted to observe the h epatoprotective activity of aqueous and n - hexane extract of Nigella sativa in paracetamol induced hepatotoxicity in rats in Dhaka , Bangladesh from 2008 to 2010 . Single dose of parac etamol was administered on day one and rats were sacrificed on day three . Liver damage was evaluated by hepa t ic histology. A queous and n - hexane extract of Nigella sativa was administered orally into two other rat groups through intra - gastric tube for 28 days in wh ich paracetamol was administered orally on day 28 and were sacrificed on day 30. L iver of all rats were excised and processed for light microscopy with a view to histopathological evaluation . The histological examination of th e liver tissues in vehicle treated group and paracetamol - control group of rats showed normal hepatic architecture , centrilobular necrosis, polymorph (neutrophils) infiltration and pyknosis of the hepatocytes respectively . The hepatic architecture of rats p re - treated with aqueous extract of Nigella sativa showed improvement of necrosis with very few pyknotic nuclei when compared to the paracetamol - control group. The hepatic architecture of rats pre - treated with aqueous extract as well as w ith the n - hexane ex tract of Nigella sativa did not show pyknotic nuclei and polymorph infiltration while apparently regenerating hepatocytes , visible under the microscope . Aqueous extract and n - hexane extract of Nigella sativa extended hepatoprotection by reducing oxidative stress in experimental liver damage in ra ts. Furthermore, the protection afforded by the n - hexane extract of Nigella sativa pre - treated group was superior to the aqueous extract of Nigella sativa pre - treated group .

겨우살이 Lectin이 흰쥐의 혈청지질 및 간조직에 미치는 영향

본 연구에서 국내산 겨우살이 lectin이 흰쥐 간의 지방형성에 미치는 영향을 알아보기 위해 혈청 내 지질 함량을 측정하였고, 이를 확인하고자 간조직의 지방형성 변화를 조사하였다. 렉틴의 분리는 sephadex G-150로 여과 및 sepharose 4B affinity chromatography 로 정제하였다. <TEX>$CCl_4$</TEX>를 복강 내에 투여시 72시간 경과 후 혈청 총cholesterol 및 triglyceride는 정상군 및 olive oil 투여군에 비해 유의하게 증가하였으며, lectin과 <TEX>$CCl_4$</TEX>를 동시 투여 하였을 때는 유의한 감소를 나타내였다. 흰쥐 간의 조직학적 관찰은 <TEX>$CCl_4$</TEX>투여군은 정상군 및 olive oil 투여군에 비해 지방변화 및 간세포 내에 많은 대소의 cytoplasmic vacuole가 보였으나, <TEX>$CCl_4$</TEX>와 lectin을 동시 투여시는 <TEX>$CCl_4$</TEX> 투여군에 비해 cytoplasmic vacuole은 현저히 감소하였고, 이에 비례하여 혈청 cholesterol 및 triglyceride 측정치가 현저히 감소하는 결과를 나타내었다. 이상의 결과를 볼때 흰쥐에서 lectin이 혈청 지질을 감소시키거나 또는 조직학적 관찰에서 간조직의 지질형성을 억제시키는 효과가 있는 것으로 확인되었다. This study was carried out to investigate effect of serum lipid and liver tissue in lectin from Viscum album on rats. The lectin was purified by sepharose 4B affinity chromatography and gel filtration using sephadex G-150 with plant material from Viscum album. After 72 h of <TEX>$CCl_4$</TEX> injection, there was a significant increase in serum total cholesterol and triglycerige levels relative to the control group. However, treatment of both Viscum album and purified lectin were significantly decreased lipid parameters against the <TEX>$CCl_4$</TEX>-induced. Histological observation of the liver section of rats challenged with <TEX>$CCl_4$</TEX> produced a marked increase of cytoplasmic vacuoles in number, while rats administered olive oil alone did not alter the normal hepatic architecture. Histological observation of the liver section in rats treated 72 h with either Viscum album purified lectin or <TEX>$CCl_4$</TEX>-induced liver lipogenesis showed decreased numbers of cytoplasmic vaculoes and necrotic cells. These results suggest that Viscum album lectin has a significantly decreased lipid in serum or histological observation of the liver section decreased in lipogenesis in rats.

Orthotopic Liver Transplantation for Biliary Atresia Complicated by Incidental Cholangiocarcinoma

Orthotopic Liver Transplantation for Biliary Atresia Complicated by Incidental Cholangiocarcinoma

Evaluation of Hepatoprotective Activities of &lt;i&gt;Satureja punctata&lt;/i&gt; Benth Briq and &lt;i&gt;Solanecio angulatus&lt;/i&gt; Vahl Jeffrey in Ferric Nitrillotriacetate Induced Hepatotoxicity in Rats

Satureja punctata Benth. Briq (Lamiaceae) and Solanecio angulatus Vahl Jeffrey (Asteraceae) are among the plants widely used in Ethiopian traditional medicine for the treatment of liver diseases. The study aimed at evaluating the hepatoprotective activity of the crude extracts and solvent fractions of these medicinal plants. Hepatoprotective activity was evaluated by measuring levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (AP) as well as by morphologic pathology and antioxidant assay against ferric nitrilotriacetate induced hepatotoxicity in rats. Crude aqueous extract of S. punctata at 250 and 500 mg/kg suppressed plasma levels of AST and ALT (p&lt;0.01), and AP (p&lt;0.01 and p&lt;0.001). S. angulatus at 400 mg/kg decreased AP (p&lt;0.05), whilst 200 mg/kg reduced AST and AP (P&lt;0.01), without affecting ALT. The methanol fraction of S. punctata (500 mg/kg) showed maximum hepatoprotective activity comparable to silymarin (p&lt;0.001, in all cases). Likewise, the chloroform fraction (250 mg/kg) reduced to a similar extent (p&lt;0.01 in all cases). The aqueous fraction (250 mg/kg) showed significant reduction in AST and ALT (p&lt;0.001) and AP (p&lt;0.05), but 500 mg/kg failed to affect levels of AP. The methanol fraction was able to return the normal hepatic architecture of hepatocytes and scavenge free radicals in 1,1-diphenylpicrylhydrazyl (DPPH) assay. S. punctata is endowed with hepatoprotective activity, probably mediated via its antioxidant activity. Thus, S. punctata can be taken as one candidate&#160; for development of hepatoprotective agents as it was also showed good safety profile.Keywords: Satureja punctata, Solanecio angulatus, hepatoprotective, ferric nitrilotriacetate, antioxidant

Lymphoid Leucosis and Coligranoluma in a Budgerigar (Melopsittacus undulatus)

An adult female budgerigar (Melopsittacus undulatus) presented with abdominal enlargement. The condition of the bird deteriorated after needle aspiration for cytological examination. The budgerigar was euthanatized and a complete necropsy was performed. Microscopic sections were prepared and stained with hematoxylin and eosin, Gram staining, periodic acid-Schiff (PAS) and acid-fast staining. Escherichia coli was isolated in pure culture. Necropsy revealed the pres­ence of granulo­matous lesions of varying sizes at different locations and hepatomegaly, oviduct impaction and oophoritis. Histopathologically, typical granuloma with a central area of coagulation necrosis and bacterial colonies surrounded by lymphocytes, macrophages and multinucleated giant cells were found. These granulomas were present in the liver, oviduct and intestinal tract. A sheet of neoplastic cells and disruption of the normal hepatic architecture was seen. The diagnosis was lymphoid leucosis and coligranuloma.

Healing of Blunt Liver Injury After Non-Operative Management: Role of Ultrasonography Follow-Up.

Non-operative management of patients with blunt liver trauma has become the standard of care. Usually after initial computed tomography (CT) evaluation and a short-term intra-hospital instrumental and clinical monitoring, no other imaging assessment is routinely requested. A restriction of physical activities for a few (unfixed number of) months is the most common recommendation. A few studies investigated the re-establishment of normal hepatic parenchymal architecture, but there is no evidence of the correct length of time for a certain resumption to normal life. To understand the progression of traumatic liver damage and the time course of healing, and to indicate the correct spontaneous recovery time, a long-term sonographic followup was done. Forty-four patients with blunt non-operatively managed hepatic injury were selected by a retrospective review of a prospectively collected database. At admission, in accordance with the American Association for the Surgery of Trauma (AAST), all lesions were evaluated by CT and graded by the Organ Injury Scale (OIS). The progression of liver repair was followed by ultrasonographic (US) controls on days 3, 5, 10, 15, 30, and 60, and monthly up to a complete clinical recovery and sonographic disappearance of lesions. One OIS grade I, 20 grade II, 13 grade III, eight grade IV, and two grade V hepatic injuries were included in the study. Forty patients were monitored until liver normalization by 218 US examinations. The median time for liver repair in OIS grades II, III, IV, and V was 30, 63, 62, and 118 days, respectively, and 75% of the patients recovered in 60, 80, and 98 days in the II, III, and IV classes, respectively. In our experience, a long time variability for spontaneous liver repair after blunt trauma and non-operative treatment was found, but a parenchymal US normalization was evidenced in a median time shorter than that usually reported in the literature.

Liver architecture, cell function, and disease

The liver is an organ consisting of the largest reticulo-endothelial cell network in the body and playing an important role in host defense against invading microorganisms. The organ is comprised of parenchymal cells and many different types of non-parenchymal cells, all of which play a significant role. Even biliary epithelial cells are not only the target in autoimmune liver diseases but also have central role in orchestrating several immune cells involved in both innate and acquired immunity. Tissue damage caused by various agents results in inflammation, necrosis, fibrosis, and, eventually, distortion of normal hepatic architecture, cirrhosis, and functional deterioration.

Effect of all-trans retinoic acid on liver fibrosis induced by common bile duct ligation in rats

The aim of this study was to investigate the effect and possible mechanism of all-trans retinoic acid (ATRA) on liver fibrosis induced by common bile duct ligation (CBDL) in rats. Fifty-three female Wistar rats were randomly divided into 5 groups: sham operation group (group J, 5 animals) and groups A, B, C and D (12 animals in each group). The rats in groups A, B, C and D were subjected to CBDL to induce liver fibrosis, while those in group J to sham operation. From the 3rd week the rats in groups B, C and D respectively received daily administration of ATRA via gastric tube at three different doses [0.1, 1.5 and 7.5 mg/kg body weight (BW)]. Animals were sacrificed at 6th week. Rats' liver tissues were observed for pathologic changes under a light microscope. The protein levels of type I collagen (COL I), matrix metalloproteinase-2 (MMP2), MMP13 and tissue inhibitors of metalloproteinase-1 (TIMP-1) in liver tissues were determined by immunohistochemical techniques. The expression levels of TGF-beta1 and CTGF mRNA in liver tissues were detected by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). The results showed that loss of normal hepatic architecture and formation of obvious fibrosis were observed in group A, while ATRA treatment for 4 weeks notably alleviated the pathological changes of hepatocytes. The expression of COL I and TIMP-1 proteins in group A was increased, while decreased in ATRA-treated CBDL groups (P<0.05). ATRA (1.5 and 7.5 mg/kg BW) reduced the expression levels of COL I protein more greatly than that of 0.1 mg/kg BW (P<0.05). ATRA treatment increased the protein levels of MMP2 and MMP13. The expression levels of TGF-beta1 and CTGF mRNA in group A were increased. In comparison with group A, the mRNA levels of TGF-beta1 and CTGF in ATRA-treated CBDL groups were significantly decreased (P<0.05). It was concluded that ATRA could inhibit CBDL-induced liver fibrosis in rats by suppressing the expression of TGF-beta1 and CTGF so as to diminish the inhibition of TIMP-1 on MMP2 and MMP13 and increase the activity of MMP2 and MMP13.

Patterns of liver infiltration in lymphoproliferative disease

Liver involvement is a common finding in patients suffering from lymphoproliferative disease, and histopathological patterns of infiltration vary according to lymphoma subtype. Data correlating the form of liver involvement with distinct lymphoma subtypes is, however, scarce. The aim was to review 89 liver biopsies diagnosed with lymphoma infiltration and evaluate the infiltration patterns. In equivocal cases, additional immunohistochemical and molecular pathology analyses were performed to differentiate between neoplastic and reactive cell infiltrates and to classify the lymphoma subtypes. Diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukaemia (CLL), Hodgkin's lymphoma (HL) and Burkitt lymphoma (BL) were the most prevalent subtypes in our series, which included 14 different lymphoma entities in total. Whereas DLBCL and BL predominantly demonstrated tumour nodules deranging the normal hepatic architecture, CLL and HL mostly showed infiltration of the portal fields. Interestingly, distinct lymphoma entities, particularly marginal zone B-cell lymphomas (MZL) and HL, commonly revealed lympho-epithelial lesions of bile ducts, which were observed in 10% of all investigated cases. Four cases, initially interpreted as T-cell lymphomas, proved to be reactive T-cell lesions. Distinct lymphoma subtypes show characteristic patterns of liver infiltration. Additional molecular analyses can support diagnosis by verification of clonality or detection of characteristic genetic aberrations.

The Adventures of Sonic Hedgehog in Development and Repair. II. Sonic hedgehog and liver development, inflammation, and cancer

Hedgehog (Hh) signaling modulates tissue remodeling by controlling the fate of Hh-responsive cells. Healthy adult livers exhibit little Hh activity. However, cells involved in adult liver repair, including myofibroblasts and progenitors, are capable of producing and responding to Hh ligands. During adult liver injury, Hh ligand production increases and populations of Hh-responsive cells expand. This process is accompanied by fibrosis. Ligand production and Hh-responsive cells diminish as fibrosis resolves and normal hepatic architecture is restored, but Hh signaling persists in hepatocellular carcinomas. These findings suggest that the Hh pathway mediates remodeling responses that are triggered by adult liver damage.

Hepatoprotective activity of &lt;i&gt; Vitex trifolia&lt;/i&gt; against carbon tetrachloride-induced hepatic damage

Aqueous and ethanol extracts of leaf of Vitex trifolia was investigated for hepatoprotective activity against carbon tetrachloride induced liver damage. To assess the hepatoprotective activity of the extracts, various biochemical parameters viz., total bilirubin, total protein, alanine transaminase, aspartate transaminase and alkaline phosphatase activities were determined. Results of the serum biochemical estimations revealed significant reduction in total bilirubin and serum marker enzymes and increase in total protein in the animals treated with ethanol and aqueous extracts. However significant rise in these serum enzymes and decrease in total protein level was noticed in CCl4 treated group indicating the hepatic damage. The hepatoprotective activity is also supported by histological studies of liver tissue. Histology of the liver tissue treated with ethanol and aqueous extracts showed normal hepatic architecture with few fatty lobules. Hence the present study revealed that Vitex trifolia could afford significant protection against CCl4 induced hepatocellular injury.

Protective effect of Rumex patientia (English Spinach) roots on ferric nitrilotriacetate (Fe-NTA) induced hepatic oxidative stress and tumor promotion response

In this communication, we document the antioxidant potential of ethanolic extract of Rumex patientia L. (Polygonaceae) roots and its chemopreventive effects against Fe-NTA mediated hepatic oxidative stress, hepatotoxicity and tumor promotion response. The extract exhibited high polyphenolic content, potent reducing power and significantly scavenged free radicals (including several reactive oxygen species (ROS) and reactive nitrogen species (RNS)). The extract also significantly and dose dependently protected against oxidative damage to lipids and DNA. These results indicated R. patientia root extract to exert a potent antioxidant activity in vitro. The efficacy of extract was also evaluated in vivo and it was found to exert a potent protective affect in acute oxidative tissue injury animal model: ferric nitrilotriacetate (Fe-NTA) induced hepatotoxicity in mice. Administration of Fe-NTA (9 mg/kg body weight, i.p.) to mice led to a significant oxidative stress and allied damage in liver tissues and induced hyperproliferation. A significant depletion was observed in GSH content and enzymes implicated in its metabolism. Attenuation also occurred in activities of other hepatic antioxidant enzymes including SOD, CAT, and GPX. Fe-NTA also incited hyperproliferation response elevating ornithine decarboxylase activity and [ 3H]-thymidine incorporation into DNA. Histopathological investigations and liver function tests (LFT) indicated Fe-NTA to cause extensive hepatic damage. However, prophylactic treatment with R. patientia root extract at a dose regimen of 100–200 mg/kg body weight for a week not only restored hepatic antioxidant armory close to normal, but also significantly precluded oxidative damage restoring normal hepatic architecture and levels of hepatic damage markers. The data obtained in the present study illustrates R. patientia roots to possess potent antioxidant and free radical scavenging activities and thwart oxidative damage and hyperproliferation in hepatic tissues.

Early Central Catheter Infections May Contribute to Hepatic Fibrosis in Children Receiving Long‐term Parenteral Nutrition

Bacterial infections in infants constitute a risk factor for parenteral nutrition (PN)-related cholestasis. The possible role of infections in the development of liver fibrosis, the most severe long-term complication, has yet to be documented. This study retrospectively compares the incidence of sepsis in children with and without severe liver fibrosis. Medical reports of 30 children in prolonged PN programs between March 1985 and March 2000 were reviewed. Starting at birth, the mean PN duration was 65 months (range, 8-150 months). According to the results of liver biopsy (LB), patients were split into 2 groups: group A (n = 16) with severe liver fibrosis (ie, septal fibrosis involving >50% of portal fields or cirrhosis) and group B (n = 14) with normal hepatic architecture or mild fibrosis (<50% of portal fields). Duration of PN at the time of LB was shorter in group A (30.5 months; range, 8-96 months) than in group B (105 months; range, 37-150 months; P < 0.001). In group A the incidence of sepsis was significantly higher than in group B (3.2 +/- 0.3/year vs 1.5 +/- 0.2/year) and the first infection occurred earlier (group A, 1 month [range, 1-2 months]; group B, 4 months [range, 1-19 months]). By contrast, both groups were similar in terms of pregnancy duration, birth weight, age of PN onset, underlying diseases, mode of PN delivery, and number of cholestasis episodes. Incidence and early onset of infections may contribute to the development of liver fibrosis in cases of long-term PN. New strategies are required in prevention and treatment of infections in children receiving PN.

Presumptive Fluphenazine‐induced Hepatitis and Urticaria in a Horse

4-year-old Standardbred gelding (450 kg) was examined because of depression, poor appetite, and suspected liver disease. Eight days before examination, the horse had won a race. The next day, depression, muscle stiffness, and transient pyrexia (39.0uC) were observed. The horse was treated with single doses of flunixin meglumine a (1 mg/kg IV), phenylbutazone b (0.2 mg/kg PO), methocarbamol c (4.4 mg/kg PO), Nacetylcysteine d (6.6 mg/kg PO), and 5 L lactated Ringer’s solution IV. A CBC and serum biochemical profile performed 4 days before presentation revealed neutrophilia and moderate increases in serum concentration of the hepatic enzyme activities (Table 1). Moderate urticaria (hives) was present over the trunk of the horse. On examination, the horse was quiet but alert and was in good body condition. Initial physical examination revealed mild jaundice and mild clinical dehydration. The heart rate (36 bpm), respiratory rate (12 bpm), and rectal temperature (37.6uC) were within normal reference limits. Multiple raised, edematous, nonpruritic nodules (3–5 mm diameter), consistent with urticaria were observed over the trunk and the neck. Auscultation and percussion of the thorax and the abdomen was unremarkable. Neurologic examination was unremarkable. This was the only horse of 19 on the farm affected. Thirty-three days before referral, the horse had been empirically administered a single dose of a long-acting parenteral preparation of fluphenazine decanoate e (0.28 mg/kg IM) as a tranquilizer to control anxious behavior. The gelding had daily access to 2 species of weeds, which were estimated to occupy approximately 20% of the turnout paddock area. No grass was available in the paddock because of overgrazing. Nineteen other horses shared the same turnout paddock and had the same management. All horses had access over a fence to lush grass, which had been sprayed with a surfactant-free glyphosphate product f the week the subject horse was administered fluphenazine. Serum biochemical profiles conducted on the herdmates, 2 days before examination, revealed serum activity of hepatic enzymes and concentration of total bilirubin within reference limits. No other horses in the barn had been administered fluphenazine decanoate. Vaccines administered to the horse included equine influenza, rhinopneumonitis, tetanus toxoid, and West Nile virus. The last dose of which had been administered approximately 8 weeks before referral. Clinicopathologic abnormalities were limited to hyperbilirubinemia, increased serum activity of hepatic enzymes (glutamate dehydrogenase [GLDH], aspartate aminotransferase [AST], gamma-glutamyl transferase [GGT], and alkaline phosphatase [AP]), and increased total bile acids concentration (Table 1). These findings were interpreted as indicative of impaired bile circulation and active hepatocellular damage. No changes compatible with an inflammatory process were identified. Plasma fibrinogen and blood ammonia concentrations were not determined at that time. Transabdominal ultrasound examination revealed normal hepatic architecture. A fecal bacterial culture for Salmonella spp. was negative. The initial therapy consisted of lactated Ringer’s solution (60 mL/kg/d IV), trimethoprim-sulfadioxine g (24 mg/kg IV q12h), and flunixin meglumine (1 mg/kg IV q24h). The diet was restricted to first-cut grass hay to avoid high dietary protein content. Taxonomic classification of the weed plant species reported by the owner revealed that the predominant plant was ‘‘redroot pigweed,’’ Amaranthus retroflexus (80% of weeds in paddock), and the other was ‘‘Lamb’s quarter,’’ Chenopodium album (20% of weeds in paddock). A. retroflexus has been associated with severe renal disease in cattle, 1 and C. album has been associated with nitrate toxicosis in cattle. 2 To the authors’

Effect of Total Enterectomy, Pancreatectomy, and Portal Vein Ligation on Liver Function and Histology: A Case Report

Impaired hepatic function and histology have been observed in experimental models of diversion of the portal vein blood inflow from the liver and among patients with intestinal failure. Survival after total enterectomy, pancreatectomy, and portal vein ligation, and the effect of such a condition on liver function have never been reported in humans. Herein a 32-year-old woman with familial adenomatous polyposis and multiple desmoid tumors involving the mesentery and the retroperitoneum underwent total enterectomy and pancreatectomy followed by en bloc transplantation of the stomach, small bowel, and pancreas. Due to early graft failure, the patient underwent graftectomy, ligation of the portal vein, and external drainage of the common bile duct. Liver function tests were checked daily and a liver biopsy performed 15 days after graftectomy. The patient died of a ruptured mycotic aneurysm of the abdominal aorta at 27 days after the graftectomy. Liver function tests remained normal throughout the postoperative period; liver biopsy showed normal hepatic architecture with mild portal inflammation and cholestasis and spotty necrosis. Total enterectomy with pancreatectomy and ligation of the portal vein are compatible with survival in humans (at least in the short term), allowing normal hepatic function with minimal histological alterations to the liver.

Non-Cirrhotic Portal Fibrosis

Purpose: Non-cirrhotic portal fibrosis (NCPF), or Idiopathic Portal Hypertension, is an important cause of non cirrhotic portal hypertension leading to significant morbidity and mortality. It constitutes nearly 10–15% of all causes of variceal bleed in developing countries. We present the clinical profile of a large series of well characterized patients of NCPF. Methods: A retrospective analysis of all patients with NCPF consecutively seen since 1983 was done. The diagnosis of NCPF was based on the presence of varices, dilated, thickened and patent portal vein and normal liver histology. Their clinical records were retrieved and analyzed. Results: 366 patients were included in the study. The male:female ratio was 1:1, and 98% were from low socio-economic strata of society. The mean age of presentation was 31.6 (±13.8) years. 262/366 (72%) patients had presented with GI bleed. The frequency of bleeders increased with age: ≤12 yrs 50%, 13–24 yrs 66%, 25–36 yrs 72%, 37–48 yrs 73%, 49–60 yrs 78% and >60 yrs 93%. The bleeders had presented with median 1 episode (range 1 to 20) of bleeding prior to presentation. Those who had bled more than once, tolerated the bleeds well and had a median of 3 bleeding episodes in a median span of 6 months (bleeding risk 0.5 episodes/month).The bleeders had required a median of 2 units of blood transfusion for their bleed. 97% patients had esophageal varices with a median grade of 3. 31% had gastric varices, 70% of them GOV1. Median HVPG (N = 53) was 7 mmHg (range 2–15 mmHg), diagnostic of pre-sinusoidal site of resistance in NCPF. History of pain abdomen was found in 27%, transient ascites in 25%, jaundice in 18%, pedal edema in 18%, and lump left abdomen in 12%. Splenomegaly was seen in 74%, the mean spleen size was 8 (±5) cm below costal margin. 41% had Hb ≤ 7 gm/dl, 22% had TLC ≤ 4×103/mm3 and 27% had platelets ≤ 80×103/mm3. Liver function tests were normal in 98%, with median bilirubin of 0.9 mg/dl, AST 39 IU/L, ALT 35 IU/L, alkaline phosphatase 193 IU/L, albumin 3.7 g/dl and prothrombin time within 3 seconds of control. HBsAg was positive in 5.7% and anti-HCV in 2.2%, predominantly due to transfusions. The histology of liver showed normal hepatic architecture, mild kupffer cell hyperplasia and no evidence of chronic hepatitis or cirrhosis. Conclusions: Gastrointestinal hemorrhage is a serious complication of NCPF and it presents predominantly in the young adults. Though the rebleeding risk is high, the bleeds are well tolerated. The liver functions, liver architecture and HVPG remain normal in these patients.

Halofuginone Induces Matrix Metalloproteinases in Rat Hepatic Stellate Cells via Activation of p38 and NFκB

The semisynthetic plant alkaloid halofuginone (HAL) was reported to prevent and partly reverse experimental liver fibrosis. However, its mechanisms of action are poorly understood. We therefore aimed to determine the antifibrotic potential of HAL and to characterize involved signal transduction pathways in hepatic stellate cells (HSCs). Results were compared with its in vivo effects in a rat model of reversal of established liver fibrosis induced by thioacetamide. In vitro HAL inhibited HSC proliferation and migration dose dependently at submicromolar concentrations. HAL (200 nm) up-regulated matrix metalloproteinase (MMP)-3 and MMP-13 expression between 10- and 50-fold, resulting in a 2- to 3-fold increase of interstitial collagenase activity. Procollagen alpha1(I) and MMP-2 transcript levels were suppressed 2- to 3-fold, whereas expression of other profibrogenic mRNAs remained unaffected. p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor kappaB(NFkappaB) pathways were activated by HAL, and specific inhibitors of p38 MAPK and NFkappaB dose dependently inhibited MMP-13 induction. Treatment with HAL did not affect HSC viability, and observed effects were reversible after its removal. In vivo HAL up-regulated MMP-3 and -13 mRNA expression 1.5- and 2-fold, respectively, in cirrhotic rats, whereas tissue inhibitor of metalloproteinase-1 was suppressed by 50%. In conclusion, submicromolar concentrations of HAL inhibit HSC proliferation and migration and up-regulate their expression of fibrolytic MMP-3 and -13 via activation of p38 MAPK and NFkappaB. The remarkable induction of MMP-3 and -13 makes HAL a promising agent for antifibrotic combination therapies.

Liver cirrhosis and hepatic stellate cells

The cirrhosis represents the final stage of several chronic hepatic diseases and it is characterized by the presence of fibrosis and morphologic conversion from the normal hepatic architecture into structurally abnormal nodules. In the evolution of the disease there is loss of the normal vascular relationship and portal hypertension. There are also regenerative hepatocelular alterations that become more prominent with the progression of the disease. The liver transplantation continues to be the only therapeutic option in cases of disease in terminal phase. The hepatic stellate cells (HSC) are perisinusoidal cells that store vitamin A and produce growth factors, citocins, prostaglandins and other bioactive substances. They can suffer an activation process that convert them to cells with a phenotype similar to myofibroblasts. When activated, they present increased capacity of proliferation, mobility, contractility and synthesis of collagen and other components of extracelular matrix. They possess cytoplasmic processes adhered to sinusoids and can affect the sinusoidal blood flow. HSC are important in pathogenesis of fibrosis and portal hypertension.