Centrilobular Necrosis Of Liver Research Articles

Accidental colchicine poisoning with fatal outcome after ingestion of meadow saffron (Colchicum autumnale L.) - Report of autopsy case

Introduction. Meadow saffron (Colchicum autumnale L.) is a perennial herbaceous plant belonging to the Lily family (Liliacea). It is similar to the edible wild garlic (Allium ursinum L.). Toxic substance in meadow saffron is alkaloid colchicine. Colchicine poisoning is a very dangerous condition which can lead to a fatal outcome. Case report. A 50-yearsold male was addmited to the hospital complaining of weakness, abdominal pain, nausea, vomiting and diarrhea without blood. The day before, the patient ate two plants thinking they were wild garlic and seven hours after ingestion he felt first symptoms. During the course of the hospital stay, he had gastroenterocolitis, acute renal faliure, hepatic lesions and cardiorespiratory insufficiency with a fatal outcome. Post-mortem examination revealed: brain oedema, lung oedema and congestion, heart weighing 700 g with ventricular hypertrophy, myocardial fibrosis, liver congestion and steatosis, spleen congestion, pancreatic fibrosis. Organs sections were taken for histopathological analysis. Body fluids and parts of organs were toxicologically analyzed. Histopathological findings were: brain oedema, diffuse perivascular and interstitial myocardial fibrosis, myocardial haemorrhage, lungs congestion and oedema, microvesicular and macrovesicular liver steatosis, centrilobular liver necrosis, lymphocytic inflammatory infiltrate in liver portions, red pulp congestion of the spleen, kidney congestion and interstitial bleeding, coagulation necrosis of the proximal tubules of the kidney. Toxicological analysis showed colchicine in the blood ? 0.011 mg/L, urine ? 0.051 mg/L, liver with gallbladder ? 0.007 mg/kg, kidney ? 0.008 mg/kg. Conclusion. Ingestion of meadow saffron can lead to poisoning with a fatal outcome due to the presence of the alkaloid colchicine. Colchicine intoxication should be suspected in patients with gastrointestinal symptoms after consuming wild plants.

Clinico-pathological alterations in geriatric dogs

The present study was conducted to evaluate the gross and microscopic changes in the tissues of dogs dying due to geriatric conditions. During the study period, 15 old dogs were taken into consideration as geriatric dogs during clinical presentation and died at different times. History and clinical findings along with haemato-biochemical alterations were studied in all the 15 cases. Systemic postmortem examination of 7 geriatric dogs was conducted and detailed gross lesion in different organ were recorded. Anemia, anemia associated with dirofilariasis, jaundice, hepatitis, nephritis and chronic enteritis were major cause of death during old age. Important gross changes included pale skeletal muscle, enlarged spleen, cardiac dilatation, necrotic liver, nephritic kidney, thickened intestinal wall etc. Significant histopathological findings related to old age were evidenced like glomerular sclerosis, glomerular atrophy in kidney, bile duct hyperplasia and centrilobular necrosis in liver, depletion of the splenic pulp and thickened epidermis of skin at flank region.

Urolithiasis in an Asiatic Lion (Panthera leo persica): A case report

A 17 years old male lion named Viral belonging to Vasona Lion Safari in Vasona, Silvassa, Dadra and Nagar Haveli was reported to be anorectic, unthrifty with hind limb weakness/paralysis for a week resulting in recumbency. Limited haemato-biochemical study revealed neutropenia with relative lymphocytosis, higher level of creatinine and blood urea nitrogen. Necropsy revealed the presence of one urolith each (15×5mm) in the pelvis of both kidneys. Histopathological changes were characterized by glomerulonephritis, interstitial and pyelonepthritis. Additional findings included congestion of cardiac muscle, centrilobular necrosis in liver, congestion and presence of heart failure cells in lungs. The suggestive cause of death was uremia/renal failure due to urolithiasis.

Rapidly progressing fatal reperfusion syndrome caused by acute critical ischemia of the lower limb

The most severe complication of ischemia-reperfusion injury following lower limb arterial surgery is reperfusion syndrome. Therefore, our aim was to describe the extent of muscle damage and the reperfusion syndrome-related remote organ lesions in detail, through a well-documented case of long-lasting infrarenal aorta thrombosis. After urgent revascularization, several clinical signs of multiple organ dysfunction were detectable, including the circulatory, urinary, respiratory, gastrointestinal, and hemostatic systems. Upon histological examination, intraoperative muscle biopsy showed severe muscle damage. Muscle fiber viability was assessed with a special nitroblue tetrazolium staining-based viability test developed by our team; the obtained results indicated significant degree of muscle damage before this was confirmed by conventional histological methods. Thorough postmortem examination confirmed the presence of remote organ damage. The pathological findings included acute tubular necrosis, myocardial and jejunal infarctions, ischemic pancreatitis, and diffuse alveolar damage with hyaline membrane formation in the lungs and focal centrilobular liver necrosis. By using special staining techniques, the presence of myoglobin and lipofuscin deposits was confirmed in the kidney samples. In this paper, we present a patient who developed all major complications following long-lasting arterial occlusion. We also introduce a novel method to assess the degree of ischemic injury, which may be suitable in the near future for the rapid detection of irreversible muscle injury. Therefore, the mortality of the disease might be reduced.

Natural and experimental poisoning of goats with the pyrrolizidine alkaloid–producing plant Crotalaria retusa L.

Crotalaria retusa L. (rattleweed), estimated to contain about 4.96% monocrotaline (MCT) in the seed, was associated with a natural poisoning outbreak in goats. The poisoning was experimentally reproduced by the administration of C. retusa seeds containing approximately 4.49% of MCT. Thus, 1 of 3 goats given a single dose of 5 g/kg bodyweight (bw) of seeds (248 mg MCT/kg bw) and 2 goats given a single dose of 347 mg MCT/kg bw showed acute clinical signs and were euthanized 10-11 days after dosing. Clinical signs and gross and histologic lesions were characteristic of acute centrilobular liver necrosis.

Pulmonary and hepatic lesions caused by the dehydropyrrolizidine alkaloid-producing plants Crotalaria juncea and Crotalaria retusa in donkeys

The effects and susceptibility of donkeys to Crotalaria juncea and Crotalaria retusa poisoning were determined at high and low doses. Seeds of C. juncea containing 0.074% of dehydropyrrolizidine alkaloids (DHPAs) (isohemijunceines 0.05%, trichodesmine 0.016%, and junceine 0.008%) were administered to three donkeys at 0.3, 0.6 and 1 g/kg body weight (g/kg) daily for 365 days. No clinical signs were observed and, on liver and lung biopsies, the only lesion was a mild liver megalocytosis in the donkeys ingesting 0.6 and 1 g/kg/day. Two other donkeys that received daily doses of 3 and 5 g seed/kg showed initial respiratory signs 70 and 40 days after the start of the administration, respectively. The donkeys were euthanized following severe respiratory signs and the main lung lesions were proliferation of Clara cells and interstitial fibrosis. Three donkeys ingested seeds of C. retusa containing 5.99% of monocrotaline at daily doses of 0.025, 0.05 and 0.1 g/kg for 365 days. No clinical signs were observed and, on liver and lung biopsies, the only lesion was moderate liver megalocytosis in each of the three donkeys. One donkey that received a single dose of 5 g/kg of C. retusa seeds and another that received 1 g/kg daily for 7 days both showed severe clinical signs and died with diffuse centrilobular liver necrosis. No lung lesions were observed. Another donkey that received a single dose of 2.5 g/kg of C. retusa seeds showed no clinical signs. The hepatic and pneumotoxic effects observed are consistent with an etiology involving DHPAs. Furthermore, the occurrence of lung or liver lesions correlates with the type of DHPAs contained in the seeds. Similarly as has been reported for horses, the data herein suggest that in donkeys some DHPAs are metabolized in the liver causing liver disease, whereas others are metabolized in the lung by Clara cells causing lung disease.

Dendritic cell depletion exacerbates acetaminophen hepatotoxicity

Acetaminophen (APAP) overdose is one of the most frequent causes of acute liver failure in the United States and is primarily mediated by toxic metabolites that accumulate in the liver upon depletion of glutathione stores. However, cells of the innate immune system, including natural killer (NK) cells, neutrophils, and Kupffer cells, have also been implicated in the centrilobular liver necrosis associated with APAP. We have recently shown that dendritic cells (DCs) regulate intrahepatic inflammation in chronic liver disease and, therefore, postulated that DC may also modulate the hepatotoxic effects of APAP. We found that DC immune-phenotype was markedly altered after APAP challenge. In particular, liver DC expressed higher MHC II, costimulatory molecules, and Toll-like receptors, and produced higher interleukin (IL)-6, macrophage chemoattractant protein-1 (MCP-1), and tumor necrosis factor alpha (TNF-α). Conversely, spleen DC were unaltered. However, APAP-induced centrilobular necrosis, and its associated mortality, was markedly exacerbated upon DC depletion. Conversely, endogenous DC expansion using FMS-like tyrosine kinase 3 ligand (Flt3L) protected mice from APAP injury. Our mechanistic studies showed that APAP liver DC had the particular capacity to prevent NK cell activation and induced neutrophil apoptosis. Nevertheless, the exacerbated hepatic injury in DC-depleted mice challenged with APAP was independent of NK cells and neutrophils or numerous immune modulatory cytokines and chemokines. Taken together, these data indicate that liver DC protect against APAP toxicity, whereas their depletion is associated with exacerbated hepatotoxicity.

Urinary Micrornas as Noninvasive Biomarkers for Acetaminophen- Induced Liver Injury

Several recent studies measured elevated levels of circulating plasma microRNAs (miRNAs) after toxicant-induced liver injury, most likely due to leakage from damaged hepatocytes. miRNAs have also been detected in urine with some of them being derived from organs outside of the urinary system, opening up their potential use as noninvasive biomarkers of disease or injury. Despite this potential, changes in urine miRNA profiles have not been investigated as biomarkers for drug-induced liver injury. In this study, urine miRNA profiles were assessed from rats treated with a single oral dose of acetaminophen (APAP: 100 or 1250 mg/kg). The low dose did not cause any clinical pathology or histopathological changes indicative of liver injury. In contrast, the high dose increased clinical pathology and histopathological indices of liver injury at 24 hours; however, there was a high inter-animal variability in these endpoints. No evidence of kidney injury was noted at either APAP dose. Urinary miRNA levels correlated best with the degree of liver centrilobular glycogen depletion. In contrast to the high inter-animal variability noted for serum alanine and aspartate aminotransferases and centrilobular liver necrosis, urinary miRNA levels were consistently elevated in all high dose animals. Alterations in the urinary miRNA profiles were also noted in the low dose animals, albeit fewer in number. These results suggest that specific miRNAs in the urine could reflect the severity of APAP-induced liver injury and therefore have the potential to be used as noninvasive preclinical and clinical biomarkers.

Role of cytochrome P450 2E1 in protein nitration and ubiquitin-mediated degradation during acetaminophen toxicity

It is well established that following a toxic dose of acetaminophen (APAP), nitrotyrosine protein adducts (3-NT), a hallmark of peroxynitrite production, were colocalized with necrotic hepatic centrilobular regions where cytochrome P450 2E1 (CYP2E1) is highly expressed, suggesting that 3-NT formation may be essential in APAP-mediated toxicity. This study was aimed at investigating the relationship between CYP2E1 and nitration (3-NT formation) followed by ubiquitin-mediated degradation of proteins in wild-type and Cyp2e1-null mice exposed to APAP (200 and 400mg/kg) for 4 and 24h. Markedly increased centrilobular liver necrosis and 3-NT formation were only observed in APAP-exposed wild-type mice in a dose- and time-dependent manner, confirming an important role for CYP2E1 in APAP biotransformation and toxicity. However, the pattern of 3-NT protein adducts, not accompanied by concurrent activation of nitric oxide synthase (NOS), was similar to that of protein ubiquitination. Immunoblot analysis further revealed that immunoprecipitated nitrated proteins were ubiquitinated in APAP-exposed wild-type mice, confirming the fact that nitrated proteins are more susceptible than the native proteins for ubiquitin-dependent degradation, resulting in shorter half-lives. For instance, cytosolic superoxide dismutase (SOD1) levels were clearly decreased and immunoprecipitated SOD1 was nitrated and ubiquitinated, likely leading to its accelerated degradation in APAP-exposed wild-type mice. These data suggest that CYP2E1 appears to play a key role in 3-NT formation, protein degradation, and liver damage, which is independent of NOS, and that decreased levels of many proteins in the wild-type mice (compared with Cyp2e1-null mice) likely contribute to APAP-related toxicity.

Liver Dysfunction after a Left Ventricular Assist Device: A Comparison between Pulsatile and Non-Pulsatile Pumps

Background: The relationship between the heart and the liver is well established. Hyperbilirubinemia, a common complication associated with left ventricular assist device (LVAD) implantation, appears as a result of liver dysfunction and can turn into a life-threatening problem. Previous studies have related these events to intrahepatic cholestasis and centrilobular liver necrosis. In this study we want to observe if there is any difference between the type of pump used and the presence of liver dysfunction.

Heinz body anaemia associated with onion (Allium cepa) toxicosis in a flock of sheep

Onion (Allium cepa) toxicosis was diagnosed in a flock of local breed sheep, which had grazed daily on onion fields for 1 month. Two ewes died, four aborted and many showed clinical signs of toxicosis including pale mucous membranes, weakness and poor appetite. Haematology of 12 ewes revealed low PCV, erythrocyte number and haemoglobin, Heinz bodies in erythrocytes, polychromasia and mild leukocytosis. In those animals that died, there was haemoglobinuric nephrosis with haemosiderin deposition in tubular cells and centrilobular necrosis of liver. Onion feeding was discontinued and haematinics were used for treatment of the affected animals.

Selective blockade of mGlu5 metabotropic glutamate receptors is protective against acetaminophen hepatotoxicity in mice

Background/Aims: mGlu5 metabotropic glutamate receptor antagonists protect rat hepatocytes against hypoxic death. Here, we have examined whether mGlu5 receptor antagonists are protective against liver damage induced by oxidative stress.Methods: Toxicity of isolated hepatocytes was induced by tert-butylhydroperoxide (t-BuOOH) after pretreatment with the mGlu5 receptor antagonists, MPEP, SIB-1757 and SIB-1893. The effect of these drugs was also examined in mice challenged with toxic doses of acetaminophen.Results: Addition of tBuOOH (0.5 mM) to isolated hepatocytes induced cell death (70±5% at 3 h). Addition of MPEP or SIB-1893 to hepatocytes reduced both the production of reactive oxygen species (ROS) and cell toxicity induced by t-BuOOH (tBuOOH=70±5%; tBuOOH+MPEP=57±6%; tBuOOH+SIB-1893=40±4%). In mice, a single injection of acetaminophen (300 mg/kg, i.p.) induced centrilobular liver necrosis, which was detectable after 24 h. MPEP (20 mg/kg, i.p.) substantially reduced liver necrosis and the production of ROS, although it did not affect the conversion of acetaminophen into the toxic metabolite, N-acetylbenzoquinoneimine. MPEP, SIB-1893 and SIB-1757 (all at 20 mg/kg, i.p.) also reduced the increased expression and activity of liver iNOS induced by acetaminophen.Conclusions: We conclude that pharmacological blockade of mGlu5 receptors might represent a novel target for the treatment of drug-induced liver damage.

Liver Necrosis Induced by Thyroid Hormone Administration in Rats Fed Ethanol

Recently it was observed that the hypothyroid state induced by propylthiouracil treatment reduced the elimination rate of ethanol. This was based on the fact that hypothyroid rats could only tolerate 10 g/kg/day of ethanol infusion over 24 h. Euthyroid rats tolerate 13 to 14 g/kg/day of ethanol infusion. In the present report it was postulated that thyroid supplements would increase the daily dose of ethanol that the treated rats could tolerate. Daily thyroid supplements, given intraperitoneally or orally, did, in fact, result in an increase in the elimination rate of ethanol. Death from ethanol overdose did not occur until the amount of ethanol given reached 16 to 19 g/kg/day. In addition, thyroxine supplements blunted or completely inhibited the urinary ethanol cycle. Submassive centrilobular liver necrosis was present in 9 of 10 rats given thyroid hormone and fed ethanol. Periportal duct metaplasia and fibrosis were also observed. Thus, thyroid supplements probably enhanced central hypoxia caused by ethanol to the point where ischemic necrosis developed. The latter healed by scar formation. Thyroid treatment completely prevented ethanol-induced steatohepatitis, indicating that the fatty change is responsive to the metabolic rate.

Experimental intoxication by larvae of Perreyia flavipes Konow, 1899 (Hymenoptera: Pergidae) in pigs and some aspects on its biology

Two pigs were dosed with 5 and 10g/kg bw of fresh Perreyiaflavipes larvae collected at the municipality of Pelotas. Two other pigs were dosed with 0.87 and 1.7g/kg of dry P. flavipes (equivalent to 5 and 10g/kg bw of fresh larvae). Another pig was dosed with 0.17g/kg of dry larvae, daily, during 20d. Forty-eight hours after the ingestion, all pigs that ingested single doses showed clinical signs and marked rise in serum aspartate aminotransferase. Alanine aminotransferase and gamma glutamiltransferase were also slightly increased. The pig dosed with 10g/kg of fresh larvae died in 96h. The others recovered in 4–5days after ingestion. No clinical signs were observed in the pigs dosed during 20d with 0.17g/kg of dry larvae. The main lesion observed in the pig dosed whit 10g/kg of fresh larvae was a centrilobular liver necrosis. These results confirmed the toxicity of P. flavipes for swine, demonstrated that the larvae maintain the toxicity after being dried, and suggest no cumulative effect in the larval toxicity. The larvae collected in the field were conditioned in boxes containing swards of native grasses and covered with gauze to prevent the escape of adults on emergence. The larvae pupated from August 11 to September 25. Emergency of adults occurred from February 10 to March 4. Adult females and males live only for 18–36 and 24–48h, respectively. The eggs had an incubation period of 26–33d. The larval period extend from March 1 to August 24.

Interleukin-11 reduces T-cell-dependent experimental liver injury in mice.

Recombinant human interleukin-11 (rhIL-11) is a multifunctional cytokine that can reduce inflammation through the downregulation of multiple pro-inflammatory mediators from activated macrophages. rhIL-11 also inhibits production of several immunostimulatory cytokines such as IL-12 and interferon gamma (IFN-gamma) and has shown biological activity in multiple animal models of inflammatory disease consistent with immunomodulatory effects on macrophages and T cells. To further elucidate the anti-inflammatory activity of rhIL-11 in vivo, the effect of rhIL-11 in a model of Concanavalin A (Con-A)-induced T-cell-mediated hepatotoxicity was examined. Administration of a single dose of rhIL-11 before Con-A administration reduced centrilobular liver necrosis and enhanced survival. A dose-dependent reduction in serum levels of liver enzymes, tumor necrosis factor alpha (TNF-alpha), and IFN-gamma corresponded with this amelioration of liver damage. No significant change in infiltrating lymphocyte populations in the liver was observed following rhIL-11 treatment. Taken together, these results indicate that rhIL-11 ameliorates T-cell-mediated hepatic injury and suggests its therapeutic potential to treat inflammatory liver disease.

Metalloproteinase inhibitor prevents hepatic injury in endotoxemic mice

This study was conducted to examine of [4-( N-hydroxyamino)-2 R-isobutyl-3 S-(phenylthiomethyl)-succinyl]- l-phenylalanine- N-methylamide (GI 129471), a matrix metalloproteinase inhibitor, for its effects on increase of serum pro-inflammatory cytokine levels as well as hepatic injury in d-galactosamine plus lipopolysaccharide-injected mice. In vitro experiments showed that GI 129471 was able to inhibit the elevation of tumor necrosis factor- α (TNF- α) in LPS-stimulated human and mouse whole blood with IC 50 values of 370 nM and 260 nM, respectively. When administrated i.p. at 40 mg/kg, GI 129471 significantly reduced serum TNF- α level but not other pro-inflammatory cytokines in d-galactosamine plus lipopolysaccharide-injected mice. Treatment of mice with GI 129471 also reduced biochemical indices of hepatic injury to the normal level. Histopathological findings indicated that GI 129471 treatment can prevent severe centrilobular necrosis in liver. These results suggest that release of TNF- α from lipopolysaccharide-stimulated cells is the critical step leading to hepatic injury in endotoxemia and that a matrix metalloproteinase inhibitor with an inhibitory action on this step may be a promising drug for the clinical treatment of endotoxemia accompanied by hepatic injury.

The chronic toxicity of inorganic mercury in goats: clinical signs, toxicopathological changes and residual concentrations.

Chronic mercury toxicity was induced in goats by administering mercuric chloride at 100 micrograms/ml in deionized drinking water offered ad libitum for 90 days. Toxic signs of gastrointestinal disturbances and renal dysfunction developed from 43 days onwards without any mortality. The toxicity also induced nephrosis and tubular nephritis; centrilobular necrosis of liver; mild to moderate necrosis in spleen, intestine and lymph node; Zenker's degeneration of cardiac muscles; exudative pneumonia; and pial congestion, oedema and vacuolation in the brain. In addition, hyperaemia, oedema and tissue haemorrhages were evident in most of the organs. The kidneys contained the largest residues of mercury, followed by liver, spleen, intestine, lymph node, skeletal muscles, lungs, heart, brain and the omental fat. The intensity of the cytotoxic changes in the various organs was proportional to the amount of mercury accumulated.

Metallothionein Induction and Hepatoprotection by Echinoside A and Sakuraso-saponin

Metallothionein-inducing activities of 11 saponins were investigated in mice. Of the saponins investigated, echinoside A and sakuraso-saponin were highly effective. Sakuraso-saponin showed dose-dependent and time-dependent induction of hepatic metallothionein. The isoforms of the induced metallothionein in the liver were determined to be metallothionein 1 and 2. Induction of metallothionein was observed specifically in the liver and heart. Echinoside A showed similar effects to sakuraso-saponin except that no induction was observed in the heart. Pretreatment of mice with these saponins blocked CCl4-induced hepatic injury, such as the elevation of plasma transaminase activity and centrilobular necrosis in the liver. CCl4-induced elevation of lipid peroxide level in the liver was also blocked by injection of sakuraso-saponin. The hepatoprotective activities of the saponins found in this study may have been due to their MT-inducing activity. © 1997 by John Wiley & Sons, Ltd.

A large dose of ergocalciferol does not cause deficient blood coagulation but is extremely toxic to rats

Male JcLSD rats were fed vitamin D 2, (ergocalciferol) at levels of 0 (control), 0.39, 0.63 and 1.00% or 0 (control), 0.0195, 0.0315 and 0.050% in the diet for 7 days. All rats of the 0.39–1.00% groups expired on days 2 and 3, while some rats of the 0.0195–0.050% groups died on days 3–6. LD 50 (median lethal 7-day cumulative dose calculated from food intake) is 110.5 mg/kg (0.0354% dietarily). In expired and surviving treated rats, several organs (kidney, heart, etc.) were found to be mineralized; there were also renal tubular injuries and pulmonary bleeding. Centrilobular necrosis of liver was detected only in dead rats. Treatment also caused hypercalcemia but did not decrease blood coagulation factors. These results suggest that vitamin D does not have the effect of impeding blood coagulation but that it is extremely toxic, probably due to the hypercalcemia it causes.

Hepatic mitochondrial glutathione depletion and progression of experimental alcoholic liver disease in rats

Long-term ethanol feeding has been shown to selectively reduce hepatic mitochondrial glutathione content by impairing mitochondrial uptake of this thiol. In this study, we assessed the role of this defect in evolution of alcoholic liver disease by examining the mitochondrial glutathione pool and lipid peroxidation during progression of experimental alcoholic liver disease to centrilobular liver necrosis and fibrosis. Male Wistar rats were intragastrically infused with a high-fat diet plus ethanol for 3, 6 or 16 wk (the duration that resulted in induction of liver steatosis, necrosis and fibrosis, respectively). During this feeding period, the cytosolic pool of glutathione remained unchanged in the ethanol-fed animals compared with that in pair-fed controls. In contrast, the mitochondrial pool of glutathione selectively and progressively decreased in rats infused with ethanol for 3, 6 or 16 wk, by 39%, 61% and 85%, respectively. Renal mitochondrial glutathione level remained unaffected throughout the experiment. Serum ALT levels increased significantly in the ethanol-fed rats at 6 wk and remained elevated at 16 wk. In the mitochondria with severely depleted glutathione levels at 16 wk, enhanced lipid peroxidation was evidenced by increased malondialdehyde levels. Thus a progressive and selective depletion of mitochondrial glutathione is demonstrated in the liver in this experimental model of alcoholic liver disease and associated with mitochondrial lipid peroxidation and progression of liver damage.