Fatty Liver Changes Research Articles

Two-Year Toxicity Study of Doxylamine Succinate in B6C3F1 Mice

Doxylamine succinate, a commonly used antihistamine, was administered as an admixture in the feed to groups of male and female B6C3F1 mice at dosage levels of 0,190,375, and 750 parts per million (ppm) (based on free amine) for 65 weeks (12 per group) or 2 years (48 per group). Survival to terminal sacrifice in the 2-year groups was 85–98% with no significant differences between groups of the same sex. Final body weights of the highest dose group were 3.4% and 8.7% less than controls in males and females, respectively. Doxylamine produced liver lesions in male mice including hepatocellular hypertrophy, atypical hepatocytes, clear cell and mixed cell foci, and necrosis. In females, doxylamine produced liver fatty change, hepatocellular hypertrophy, and necrosis. Doxylamine produced a significant increase in hepatocellular adenomas in the mid- and high-dosage groups of males and in the high-dosage group of females. Thyroid follicular cell hyperplasia and thyroid follicular cell adenomas also were increased in treated mice of both sexes. A treatment-related increase in cytoplasmic alteration of the parotid salivary gland in males and an increased incidence in hyperplasia of the pituitary gland in females were observed.

Rat Liver Is Not Damaged by High Dose Tryptophan Treatment ,

Adult male Sprague-Dawley rats were treated with USP-grade L-tryptophan at a level of 250 mg/kg seven times over 14 d or three times over 3 d by gastric gavage. At autopsy liver specimens were prepared for histological study by stains specific for lipids, for glycoprotein and glycogen, and for fine structure by electron microscopy. Liver lipid did not accumulate as a result of tryptophan treatment. In a series of unfed animals, however, liver lipid had accumulated within 24 h of food withdrawal. Tryptophan has been implicated in fatty liver development by several reports that cite each other, but, in all cases but one, unfed animals were used, and the data show that liver lipid was already present in the unfed animals at the beginning of the experiment. Tryptophan has also been cited as causing abnormal liver morphology, but our evidence suggests that such observations are the result of artifact induced by frozen section preparation and not the result of tryptophan treatment. Our experiments indicate that tryptophan administered to rats at dosages in excess of those recommended for humans does not induce fatty liver or other morphological changes detectable by the methods described.

Hepatic Steatosis and Morbid Obesity.

One hundred and twenty-seven consecutive morbidly obese patients who presented for bariatric surgery underwent open wedge liver biopsy at the completion of their gastric restrictive procedure. All hepatic specimens were graded histologically for degrees of steatosis. Three-quarters of the patients had histological evidence of hepatic steatosis and in one-fifth this was severe and diffuse. No patient had histological evidence of fatty hepatitis, portal fibrosis, or cirrhosis. There was no significant correlation between the degree of obesity (measured as percentage over ideal weight), age, sex, or preoperative liver function tests and the degree of fatty change observed. Insufficient data were available to Implicate alcohol and poor protein nutrition in the etiology of the observed fatty liver change. Other factors such as diabetes mellitus or drugs were not etiologic factors in this series of patients.

A Study Relating to Progressive or Regresive Changes of Fatty Liver over Years and its Mediating Factors

A Study Relating to Progressive or Regresive Changes of Fatty Liver over Years and its Mediating Factors

Hepatoprotective effect of BPC 157, A 15-aminoacid peptide, on liver lesions induced by either restraint stress or bile duct and hepatic artery ligation or CCl 4 administration. A comparative study with dopamine agonists and somatostatin

The hepatoprotective effects of a newly synthesized 15 amino acid fragment code named BPC 157 was evaluated in comparison with the reference standards (bromocriptine, amantadine and somatostatin) in various experimental models of liver injury in rats: 24 h-bile duct + hepatic artery ligation 48 h-restraint stress and CCl 4 administration. BPC 157 administered either intragastrically or intraperitoneally, significantly prevented the development of liver necrosis or fatty changes in rats subjected to 24 h bile duct + hepatic artery ligation, 48 h-restraint stress, CCl 4 treatment (1 ml/kg i.p., sacrifice 48 h thereafter). The other reference drugs had either little or no protective actions in these models. Noteworthy, the laboratory test results for bilirubin, SGOT, SGPT fully correlated with the macro/microscopical findings. Thus, on the basis of consistent protective eefect of BPC 157, possible clinical application in liver diseases is now warranted.

Hypoechoic lesions in fatty liver: Quantitative study by histomorphometry

Ten patients with fatty liver changes were subjected to liver biopsies. In seven, ultrasonography showed focal hypoechogenicity within a “bright” liver, generally interpreted as focal sparing. Three patients had hyperechoic areas surrounded by “normal” parenchyma usually felt to represent local fat accumulation without diffuse involvement. Morphometric analysis was used to determine the total area occupied by fat (area density) and the number of lipid droplets (numerical density) per microscopic field in lesional and perilesional specimens. Compared with respective perilesional values, hypoechoic lesional numerical densities were significantly lower in 6 of 7 patients; the three hyperechoic samples had significantly higher values. In most cases, lesional and perilesional area densities were not significantly different. These hypoechoic focal lesions are believed to be merely areas in which a similar quantity of fat is contained in fewer droplets, and focal hyperechogenicity is believed to result from a larger number of fat-filled vacuoles with respect to that of the surrounding parenchyma. Variation in the number of solid-liquid interfaces causes the ultrasonic contrast between these lesions and the similarly fatty liver parenchyma surrounding them.

Regenerating nodules-are they premalignant lesions?

In the period 1985-1988, 62 focal liver lesions in 58 cirrhotic patients were studied by ultrasonography; 12 of these focal lesions were documented to be regenerating lesions by echo-guided fine-needle biopsy. During an average follow-up period of 10.2 months (range 3-22 months), hepatocellular carcinoma was subsequently found in 10 of the cases of regenerating nodules, whereas the initial diagnosis of regenerating nodule was confirmed in the remaining two cases. Based upon this finding, it is suggested that every focal mass visualized by ultrasonography in a cirrhotic liver should either considered to be a neoplastic lesion or at least a preneoplastic lesion if the possibility of either a metastatic or benign lesion (eg hemangiomas, focal fatty liver change areas) can be excluded. Therefore either fine-needle aspiration or biopsy of all ultrasonographically revealed mass lesions within a cirrhotic liver is advised, such that early appropriate treatment for hepatocellular carcinoma can be instituted.

REMNANT-LIKE PARTICLES IN VARIOUS LIVER DISEASES

Remnant-like particles (RLP) are the lipoproteins that do not bind to an immunoaffinity gel mixture made of anti-apo A-I and anti-apo B-100 monoclonal antibodies. It was previously shown that RLP could provide a useful index for potentially atherogenic chylomicron and very low density lipoprotein-like remnants.Liver is the most important organ for lipid metabolism. Thus we studied changes in cholesterol and triglyceride values of RLP [RLP (Ch) and RLP (TG)] in 364 patients with various liver diseases.There were no significant differences in RLP (Ch), RLP (TG), RLP (Ch) /RLP (TG) [ratio of RLP (Ch) to RLP (TG)] in patients with chronic hepatitis or compensated liver cirrhosis when compared with the control group. However, RLP (TG) and RLP (TG) /T-TG [ratio of RLP (TG) to total triglyceride of serum] were significantly lower, RLP (Ch) /RLP (TG) was higher in patients with decompensated liver cirrhosis or hepatocellular carcinoma than in controls (P<0.01).Good correlations between ICG 15min., serum choline esterase, serum albmin and RLP (TG), RLP (TG) RLP (TG) / RLP (TG) were obtained. These results suggest that RLP (TG), RLP (TG) /T-TG and RLP (Ch) /RLP (TG) are useful indexes of severe liver dysfunction and poor lipid metabolism.Patients with fatty liver and alcoholic liver injury with fatty change of liver also showed significantly higher RLP (Ch) and RLP (TG) values.

Impaired lipopolysaccharide-inducible tumor necrosis factor production in vitro by peripheral blood monocytes of patients with viral hepatitis

We investigated lipopolysaccharide-induced tumor necrosis factor production in vitro by peripheral blood monocytes from patients with various liver diseases. Tumor necrosis factor production was found to be significantly reduced in patients with chronic hepatitis B (n = 17; 135 +/- 30 pg tumor necrosis factor/ml; mean +/- S.E.M.) and patients with chronic non-A, non-B hepatitis (n = 15; 212 +/- 22 pg tumor necrosis factor/ml) compared with healthy control individuals (n = 47; 411 +/- 40 pg tumor necrosis factor/ml; p less than 0.0005 and p less than 0.01, respectively). This reduced tumor necrosis factor production was not only seen with an optimal stimulating concentration of lipopolysaccharide (100 ng/ml) but also with suboptimal concentrations (0.1 ng/ml). In contrast to patients with chronic viral hepatitis, monocytes from patients with alcohol-induced cirrhosis (n = 26; 444 +/- 49 pg tumor necrosis factor/ml), primary biliary cirrhosis (n = 7; 412 +/- 81 pg tumor necrosis factor/ml) and alcohol-induced fatty liver changes (n = 5; 401 +/- 62 pg tumor necrosis factor/ml) produced normal amounts of tumor necrosis factor when stimulated with an optimal concentration of lipopolysaccharide. Lipopolysaccharide (0.1 ng lipopolysaccharide/ml)-stimulated peripheral blood monocytes of patients with chronic hepatitis B (n = 15; 102 +/- 32 pg/ml) or non-A, non-B hepatitis (n = 13; 97+/- 16 pg/ml) could not be induced to produce more tumor necrosis factor either when prestimulated with gamma-interferon (170 +/- 45 pg/ml and 149 +/- 32 pg/ml, respectively), a lymphokine known to activate monocytes, or with the cyclooxygenase inhibitor indomethacin to reduce the suppressive effect of prostaglandin E2 (148 +/- 40 pg/ml and 153 +/- 45 pg/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and chronic toxicity of cyclosporine A in genetic hydroxylation-deficient dark Agouti rats

Since oxidation plays a key role in the metabolism of cyclosporine A (CsA), the pharmacokinetics and the toxicity of CsA was investigated in female dark Agouti rats exhibiting a deficiency for debrisoquine hydroxylation and for dextromethorphan demethylation. When compared with Wistar rats (n = 10), dark Agouti rats (n = 10) had a higher mean clearance (4.8 ml/min per kg vs. 3.3 ml/min per kg) and a lower mean residence time (606 min vs. 1361 min) after intravenous dosing of CsA. The systemic availability of subcutaneous CsA was close to 100%. The steady state CsA concentrations assessed by HPLC in whole blood after subcutaneous dosing of 20 mg/kg per day for 23 days (n = 10) were about 1000 ng/ml in dark Agouti rats. When compared with dark Agouti rats treated with cremophore (n = 10) or not treated at all (n = 12), dark Agouti rats on chronic subcutaneous CsA plus cremophore for 23 days (n = 10) had no difference in kidney histology but had slightly increased liver fatty changes. Rats on CsA and/or cremophore had a decreased uric acid clearance and evidence of hypoaldosteronism. The urinary ratio of debrisoquine/4-hydroxydebrisoquine decreased in rats on CsA, whereas the O-demethylation and N-demethylation of liver obtained from rats on cremophore was impaired. Thus, dark Agouti rats show no difference in the metabolism of CsA and when given CsA for 23 days show drug-induced functional but no relevant structural light microscopic changes in the kidney, and functional and slight structural changes in the liver.

Fatty Liver Change as a Result of Hepatic Artery Infusion Chemotherapy

Direct hepatic arterial infusion of floxuridine (FUDR) (Roche Laboratories, Division of Hoffman-LaRoche Inc., Nutley, NJ, U.S.A.) has been used extensively in the treatment of metastases of colorectal tumors to the liver. The effectiveness of infusion and tolerance of the chemotherapy has been improved utilizing a totally implantable infusion pump delivery system. However, unequal distribution of drug infusion may occur to different parts of the liver parenchyma as demonstrated by hepatic arterial infusion scintigraphy (HAPS). We present a case of such unequal perfusion in which fatty metamorphosis of the liver occurred in the overperfused liver segment after FUDR therapy. The liver parenchymal changes were followed by serial computerized tomography scans and proven by biopsy during a minilaparotomy. Serial HAPS examinations show redirection of subsequent infusion to the opposite liver lobe due to parenchymal damage and vascular sclerosis. The importance of uniform liver perfusion and a rare dose-related effect of FUDR on liver parenchyma are thereby demonstrated.

Focal ultrasound lesions in liver cirrhosis diagnosed as regenerating nodules by fine-needle biopsy

In the period 1985-1988, 62 focal liver lesions in 58 cirrhotic patients were studied by ultrasonography; 12 of these focal lesions were documented to be regenerating lesions by echo-guided fine-needle biopsy. During an average follow-up period of 10.2 months (range 3-22 months), hepatocellular carcinoma was subsequently found in 10 of the cases of regenerating nodules, whereas the initial diagnosis of regenerating nodule was confirmed in the remaining two cases. Based upon this finding, it is suggested that every focal mass visualized by ultrasonography in a cirrhotic liver should either be considered to be a neoplastic lesion or at least a preneoplastic lesion if the possibility of either a metastatic or benign lesion (eg, hemangiomas, focal fatty liver change areas) can be excluded. Therefore either fine-needle aspiration or biopsy of all ultrasonographically revealed mass lesions within a cirrhotic liver is advised, such that early appropriate treatment for hepatocellular carcinoma can be instituted.

ACUTE TOXICITY OF STREPTOZOTOCIN IN SYRIAN HAMSTERS OF THE APA STRAIN

Acute toxicity of Streptozotocin (SZ) was examined in 3-month-old APA hamsters at dose levels of 0 (C). 20 (T1), 40 (T2), and 60mg/kg b.w. (T3-group). In T3-group, depression of body weight gain was recorded and a death occurred to one male 3 days after administration. Changes in blood chemical and urinary parameters suggestive of the existence of functional disorders in the liver and kidney were observed in male of T2-and T3-groups and in females of T3-group. In these groups, prominent elevation of blood glucose level was also recorded. Histopathological changes were mainly observed in the liver (fatty change and decrease of glycogen granules in hepatocytes). pancreas (atrophy and degeneration of beta cells with decrease of insulin granules). lymphoid organs (depression of lymphocytes), and kidney (fatty change in proximal tubule epithelium and necrosis in distal tubule epithelium). Most of these changes were detected in males of T2-and T3-groups and in females of T3group, but renal lesions were found only in T3-group. On the other hand, similar but far less severe changes were noticed in males of T3-group of Std: golden hamsters employed as a control strain.

Animal model of margosa oil ingestion with Reye-like syndrome. Pathogenesis of microvesicular fatty liver.

The aetiology and pathogenesis of Reye's syndrome (RS) are incompletely understood. A number of environmental toxins and biological agents, including viruses, have been postulated to cause RS, either acting alone or synergistically. Most investigations have suggested that the primary insult is in the liver mitochondria, leading to a complex biochemical catastrophe, with death from encephalopathy. Margosa oil (MO), a long-chain fatty acid compound, has been shown to cause a Reye-like syndrome with death from hepatoencephalopathy, in children in Malaysia and India. The present time-course study performed in MO-administered mice showed the development of hepatic lesions with many features of RS. MO acts rapidly, within 30 min, on the nuclei of hepatocytes inducing mitoses and binucleated cells. This is followed by mitochondrial injury, with swelling, rarefaction of matrix, loss of dense bodies, pleomorphism, and loss of ribosomes starting at 60 min. There is loss of liver glycogen, and proliferation and hypertrophy of the endoplasmic reticulum (ER), followed by the presence of lipid droplets in the hyaloplasm, and globules within dilated cisterns of the ER. Additional fatty acids from lipolysis of body adipocytes, and fat globules from intestinal MO ingestion further aggravate the liver fatty change. There is evidence of fat globule ingestion by endocytosis into hepatocytes at the level of the sinusoids. The development of microvesicular liver steatosis and glycogen depletion due to involvement of liver cell organelles occur rapidly as in RS.

脂肪肝の進展過程における腹腔鏡下肝表面被膜下血管像の意義 実験的脂肪肝の肝内微小血管構築所見との対比検討

アルコール性,過栄養性,代謝性その他の成因による脂肪肝の進展過程における腹腔鏡下の肝被膜下血管構築像の変化の意義を,生検肝の組織学的変化及び実験的脂肪肝における肝内微小血管構築改変像とを対比しつつ検討した.その結果,脂肪肝においては肝被膜内の門脈枝が早期から明瞭に観察できる頻度が増加し,病変の進展につれてその拡張と蛇行が顕著となった.動脈枝の出現は炎症状態を反映するが,肝線維化への進展と共に門脈枝より優位になり,間質の走行から更に増大した偽小葉結節上に認められるに至った.コリン欠乏食惹起性ラット脂肪肝においても早期に肉眼上門脈枝が観察されたが,微小血管構築像上門脈系の擾乱が強く認められ,病変の進行に従って動脈系に異常像が波及した.以上,腹腔鏡下肝被膜下血管構築像は肝内血管の変化を反映しており,病変を把握する上で有用であるが,これは他面病変進展における肝内微小循環系の意義を呈示するものである.

The repeated dose toxicity of a zinc oxide/hexachloroethane smoke.

Mice, rats and guinea pigs were exposed to the smoke produced by ignition of a zinc oxide/hexachloroethane pyrotechnic composition, 1 h/day, 5 days/week, at three different dose levels, together with controls. The animals received 100 exposures except for the high dose guinea pigs, which underwent 15 exposures, because of high death rate during the first few days of exposure. The test material had very little effect on weight gain, but there was a high rate of early deaths in the top dose of mice. A variety of incidental findings was seen in both decedents and survivors, but organ specific toxicity was, with one exception, confined to the respiratory tract. The most important of these findings was a statistically significant increase in the frequency of alveologenic carcinoma in the high dose group mice (p less than 0.01) and a statistically significant trend in the prevalence of the same tumour over all dose groups and the controls. A variety of inflammatory changes was seen in the lungs of all species and some appeared to be treatment-related. Fatty change in the mouse liver was more common in the middle and high dose groups than the controls. The aetiology of the tumour incidence is discussed and it is pointed out that hexachloroethane and zinc, as well as carbon tetrachloride, which may be present in the smoke, may be animal carcinogens in appropriate circumstances. Carbon tetrachloride is a known human carcinogen.

Reye's syndrome: are adults big children?

Reye’s syndrome (RS) is generally considered a childhood disease. We report our experience with RS in adults in the metropolitan Milwaukee area. Reye’s syndrome was diagnosed in seven 18- to 46-year-old adults. The diagnostic criteria were as follows: viral prodrome followed by vomiting and encephalopathy without focal neurological signs, normal cerebrospinal fluid values, increased levels of serum aminotransferases (transaminase), prolonged prothrombin time, elevated blood ammonia levels, and characteristic microvesicular fatty liver and mitochondrial changes. None of the patients was hypoglycemic. The diagnosis of RS was entertained in 22 but confirmed in only seven patients. In cases of non-Reye’s encephalopathy, drug ingestion presented as one of the most difficult differential diagnostic problems, which also included alcohol abuse, collagen vascular disease, and hepatitis B surface antigenemia. Clinical jaundice, distinctly uncommon in RS, was present in only one patient who presented to us in stage V coma. In adults, RS is more difficult to diagnose and should be suspected more frequently in patients with unexplained altered behavior following a viral illness and vomiting. Liver biopsy can be performed safely and is usually mandatory in adults. Patients with RS diagnosed during stage I or II coma and treated experienced an uneventful recovery.

Reye's Syndrome in Adults

Reye's syndrome (RS) is generally considered a childhood disease. We report our experience with RS in adults in the metropolitan Milwaukee area. Reye's syndrome was diagnosed in seven 18- to 46-year-old adults. The diagnostic criteria were as follows: viral prodrome followed by vomiting and encephalopathy without focal neurological signs, normal cerebrospinal fluid values, increased levels of serum aminotransferases (transaminase), prolonged prothrombin time, elevated blood ammonia levels, and characteristic microvesicular fatty liver and mitochondrial changes. None of the patients was hypoglycemic. The diagnosis of RS was entertained in 22 but confirmed in only seven patients. In cases of non-Reye's encephalopathy, drug ingestion presented as one of the most difficult differential diagnostic problems, which also included alcohol abuse, collagen vascular disease, and hepatitis B surface antigenemia. Clinical jaundice, distinctly uncommon in RS, was present in only one patient who presented to us in stage V coma. In adults, RS is more difficult to diagnose and should be suspected more frequently in patients with unexplained altered behavior following a viral illness and vomiting. Liver biopsy can be performed safely and is usually mandatory in adults. Patients with RS diagnosed during stage I or II coma and treated experienced an uneventful recovery.

Studies on brain structure and neurological function in alcoholic rats controlled by an indian medicinal formula (SKV)

An Indian herbal brew known in Ayurvedic pharmacy as asavam (SKV) was tested for its effectiveness in controlling addiction to ethanol in rats. Rats on SKV therapy with free access to 15% ethanol showed a marked reduction in voluntary ethanol intake. Their performance in simple neurological tests improved and a reversal of ethanol-induced changes in the electroencephalogram and electrocardiogram were also recorded. SKV treatment appeared to correct the fatty changes in liver and the signs of haemorrhage, demyelination and spongiosis seen in the brain of ethanol-fed rats.

Proton chemical shift imaging: an evaluation of its clinical potential using an in vivo fatty liver model.

The potential laboratory and clinical utility of proton chemical shift imaging (PCSI) was evaluated by studying fatty liver change in rats, which offered a simple animal model for tissue lipid buildup. There was excellent correlation between lipid group signal intensities from in vivo PCSI studies and liver triglyceride levels obtained from in vitro measurements (R = 0.97). The in vivo T1 relaxation time measurements in fatty liver tissue demonstrated two distinct populations of nonexchanging protons. We explain the reason for the lack of sensitivity in conventional magnetic resonance (MR) imaging studies of fatty liver change and discuss the implications of our findings for MR imaging studies of other tissues. PCSI promises improved diagnostic sensitivity and specificity in studying a wide range of human pathologic conditions.