Fatty Livers

The role that fatty liver plays in liver injury is not clearly understood, and fatty liver in itself does not necessarily mean liver dysfunction. The onset of lipid accumulation in the liver is accompanied by changes in blood biochemistry, and for this reason blood chemistry analysis can be a useful diagnostic tool. 

Carbon tetrachloride Necrosis and fatty liver Dimethylnitrosamine Phosphorous 

Chlorpromazine Cholestasis (drug-induced) Imipramine Carbarsone 

Iproniazid Hepatitis (drug-induced) Methoxyflurane Halothane 

Aflatoxin B1 Carcinogenesis (experimental animals) Dimethylbenzanthracene Acetylaminofluorene 

Intrahepatic events contributing to increased fatty acid availability include enhanced de novo synthesis and impaired p-oxidation, whereas increased esterification would lead to triglyceride accumulation. Each of these processes is sensitive to 

Hepatic fibrosis is seen with chronic exposure to hepatoxicants that cause increasing damage to hepatocytes and is part of the wound healing response. Chronic fibrosis leads to severe disruption of the liver architecture by the deposition of extracellular matrix (ECM). Advanced fibrosis disrupts the proper blood flow and results in scarring of the liver that can lead to irreversible liver damage known as cirrhosis. Chronic exposure to the hepatoxins CCI4, monocrotaline, and alcohol are examples of compounds that cause excessive fibrosis. 

---

Treem WR et al Acute fatty liver of pregnancy and long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Hepatology 1994 19 339. 

Imbalance in the Rate of Triacylglycerol Formation Export Causes Fatty Liver... 

The second type of fatty liver is usually due to a metabolic block in the production of plasma lipoproteins, thus allowing triacylglycerol to accumulate. Theoretically, the lesion may be due to (1) a block in apolipoprotein synthesis, (2) a block in the synthesis of the lipoprotein from lipid and apolipoprotein, (3) a failure in provision of phospholipids that are found in lipoproteins, or (4) a failure in the secretory mechanism itself. 

One type of fatty liver that has been smdied extensively in rats is due to a deficiency of choline, which has therefore been called a lipotropic factor. The antibiotic puromycin, ethionine (a-amino-y-mercaptobu-tyric acid), carbon tetrachloride, chloroform, phosphorus, lead, and arsenic all cause fatty liver and a marked reduction in concentration of VLDL in rats. Choline will not protect the organism against these agents but appears to aid in recovery. The action of carbon tetrachloride probably involves formation of free radicals... 

Figure 25-6. The synthesis of very low density lipoprotein (VLDL) in the liver and the possible loci of action of factors causing accumulation of triacylglycerol and a fatty liver. (EFA, essential fatty acids FFA, free fatty acids ...

Eaton S et al Multiple biochemical effects in the pathogenesis of fatty liver. EurJ Clin Invest 1997 27 719. 

Phytochemicals have little nutritional value and do not get absorbed in the body, but they seem to turn on certain switches in the biochemical mechanisms, which signal the beneficial pathways to maintain health, and to turn off the switches which proceed to adverse biochemical pathways. Rice bran products have demonstrated significant benefits as nutritional therapies in diabetes, hyperlipidemia, cancer, fatty liver, hypercalcuria and heart disease. There is experimental and clinical evidence for the beneficial health effects of the following bioactives of rice bran ... 

Progression of alcoholic liver disease moves through several distinct phases from development of fatty liver to the development of alcoholic hepatitis and cirrhosis. Fatty liver and alcoholic hepatitis may be reversible with cessation of alcohol intake, but cirrhosis itself is irreversible. Although the scarring of cirrhosis is permanent, maintaining abstinence from alcohol can still decrease complications and slow development to end-stage liver disease.22 Continuing to imbibe speeds the advancement of liver dysfunction and its complications. 

Non-alcoholic fatty liver disease begins with asymptomatic fatty liver but may progress to cirrhosis. This is a disease of exclusion elimination of any possible viral, genetic, or environmental causes must be made prior to making this diagnosis. Non-alcoholic fatty liver disease is related to numerous metabolic abnormalities. Risk factors include diabetes mellitus, dyslipidemia, obesity, and other conditions associated with increased hepatic fat.26... 

Fatty liver of pregnancy Placental abruption Preeclampsia/eclampsia Retained fetus syndrome Pulmonary syndrome syndrome Empyema Hyaline membrane disease... 

In adults, a study of 75 autopsies of persons who had resided in a soft-water, leached soil region of North Carolina found a positive correlation between lead level in the aorta and death from heart-related disease (Voors et al. 1982). The association persisted after adjustment for the effect of age. A similar correlation was found between cadmium levels in the liver and death from heart-related disease. (Aortic lead and liver cadmium levels were considered to be suitable indices of exposure.) The effects of the two metals appeared to be additive. Potential confounding variables other than age were not included in the analysis. The investigators stated that fatty liver (indicative of alcohol consumption) and cigarette smoking did not account for the correlations between lead, cadmium and heart-disease death. 

Metabolic liver disease Hemochromatosis Wilson s disease < 1-Antitrypsin deficiency Nonalcoholic steatohepatitis ("fatty liver")... 

Approximately 11% of patients with ulcerative colitis have hepatobiliary complications including fatty liver, pericholangitis, chronic active hepatitis, cirrhosis, sclerosing cholangitis, cholangiocarcinoma, and gallstones. 

Fatty liver, nonalcoholic fatty liver disease (NAFLD) Rat liver from Male (resistant to NAFLD), Female (sensitive to NAFLD) Fish oil, dextrose Comparison of liver response to high fat diet in male and female suggest pathways contributing to NAFLD [15]... 

The physiologic sequelae of biotin deficiency are almost unexplored. Severe skin lesions, especially seborrheic dermatitis and Leiner s disease (Erythroderma desquamativum or exfoliative dermatitis), were increased in young infants bom of mothers on a restricted diet low in eggs, livers, and other biotin-rich foods. After biotin administration the lesions healed. There are claims that excess biotin produces a fatty liver characterized by heightened cholesterol content. Choline has no effect in the prevention of biotin-fatty livers (G2, M2). In mice with transplanted tumors, both the tumors and the blood levels of biotin are below normal (R8). More recent studies established a protection with avidin, the biotin-binding fraction of egg white, against tumor formation (K4). More data along these lines are still needed for confirmation. 

In the present compilation of the distribution and pharmacokinetic data of a dozen xenobiotics studied in the dogfish shark, this species yielded excellent data consistent with what we know from similar studies on terrestrial mammals. The data from the shark occasionaly provided information not available in other animals. Major transport parameters in this fish were shown to be similar to those found in mammals. This aquatic organism handles lipid-soluble pollutants by sequestering them in its fatty liver. Together with a previous summary (23) we have now studied about three dozen xenobiotics in this species. Because of its ease of handling, low cost, abundance, predictive value of transport mechanisms, and well-developed pharmacokinetics, the dogfish shark is an ideal fish species to use as a model to study aquatic pollutants. 

---