Hepatic steatosis

For twenty years localised MRS has been used in medicine and biomedical research to obtain non-invasive biochemical information from living tissue (Koretsky et al. 1992). The spectra obtained possess the very valuable property that the intensity of a given peak is proportional to the number of nuclei contribut- 

MODIFICATION OF THE METHOD Hazle et al. (1991) used MRS to follow the time course of ethanol induced liver steatosis in rats. Spectra were acquired without respiratory triggering and lipid signal was normalised to signal from an external reference sample. Correlation between MRS normalised lipid signal and biochemically determined lipids was moderate (r = 0.52). Ling et al. (1992) used respiratory triggered MRS to examine the same model and were able to show that a 5.5-fold increase in lipid signal on 

Bottomley PA (1987) Spatial localization in NMR spectroscopy in vivo. Annal NY Acad Sci 508 333-348 Brown H, Prescott R (1999) Applied mixed models in medicine. Wiley, Chichester 

Clark JM, Brancati FL, Diehl AM (2002) Nonalcoholic fatty liver disease. Gastroenterology 122 1649-1657 Coatney RW (2001) Ultrasound imaging principles and applications in rodent research. liar Journal 42 233-247 Cockman MD, Hayes DA, Kuzmak BR (1993) Motion suppression improves quantification of rat liver volume in vivo by magnetic resonance imaging. Magnetic Resonance in Medicine 30 355-360 

Collins KA, Korcarz CE, Lang RM (2003) Use of echocardiography for the phenotypic assessment of genetically altered mice. Physiological Genomics 13 227-239 Daubioul C, Rousseau N, Demeure R et al. (2002) Dietary fruc-tans, but not cellulose, decrease triglyceride accumulation in the liver of obese Zucker fa/fa rats. Journal of Nutrition 132 967-973 

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Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Qin Invest 116 1494-1505 Kaul M, Garden GA, Lipton SA (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410 988-994... 

Hepatobiliary disease occurs due to bile duct obstruction from abnormal bile composition and flow. Hepatomegaly, splenomegaly, and cholecystitis may be present. Hepatic steatosis may also be present due to effects of malnutrition. The progression from cholestasis (impaired bile flow) to portal fibrosis and to focal and multilobar cirrhosis, esophageal varices, and portal hypertension takes several years. Many patients are compensated and asymptomatic but maybe susceptible to acute decompensation in the event of extrinsic hepatic insult from viruses, medications, or other factors.7... 

Zalcitabine (ddC) Hivid (anticipated discontinuation of distribution in 2006) 0.375-, 0.75-mg tab 0.75 mg tid CrCI Dose (mL/minute) 10-40 0.75 mg bid less than 10 0.75 mg qday No data on hemodialysis None Peripheral neuropathy stomatitis, lactic acidosis with hepatic steatosis (rare but potentially life-threatening toxicity with use of NRTIs) pancreatitis Renal excretion... 

Dextrose Hyperglycemia, hypertriglyceridemia, hepatic steatosis, hypercapnia hyperglycemia may cause fluid and electrolyte disturbances and increased infection risk... 

Total calories Hepatic steatosis, cholestasis, hypercapnia... 

The incidence of liver complications associated with PN ranges from approximately 7% to 84%, and end-stage liver disease develops in as many as 15% to 40% of adult patients on long-term PN.35 Patients often develop a mild increase in liver enzymes within 1 to 2 weeks of initiating PN, but this generally resolves when PN is discontinued. Severe liver complications include hepatic steatosis (fat deposition in liver), steatohepatitis (a severe form of liver disease characterized by hepatic inflammation that may progress rapidly to liver fibrosis and cirrhosis), cholestasis, and cholelithiasis.35... 

Hepatic steatosis usually is a result of excessive administration of carbohydrates and/or lipids, but deficiencies of carnitine, choline, and essential fatty acids also may contribute. Hepatic steatosis can be minimized or reversed by avoiding overfeeding, especially from dextrose and lipids.35,38 Carnitine is an important amine that transports long-chain triglycerides into the mitochondria for oxidation, but carnitine deficiency in adults is extremely rare and is mostly a problem in premature infants and patients receiving chronic dialysis. Choline is an essential amine required for synthesis of cell membrane components such as phospholipids. Although a true choline deficiency is rare, preliminary studies of choline supplementation to adult patients PN caused reversal of steatosis. 

DGAT2- - mice suffer from severe hypolipidemia and do not survive postnatally [44]. However, this may be only a developmental phenomenon, since adult obese mice treated with DGAT2 antisense oligonucleotides were viable and showed improved hepatic steatosis along with improved insulin sensitivity [45]. 

Treating mice with 23 led to the inhibition of atherosclerotic progression, whereas macrophage-specific knockout of LXR exacerbates atherosclerosis [111]. In vivo activation of LXR leads to increased fatty acid synthesis, accumulation of TG and the development of hepatic steatosis [109]. Successful LXR agonists will show desirable HDL elevation without these side effects [112]. 

Studies in rats have shown that acute doses of hydrazine cause hepatic steatosis accompanied by depletion of ATP and reduced glutathione (GSH) and hepatic accumulation of triglycerides. Biochemical effects from repeated exposure, however, included depletion of triglycerides and induction of nitrophe-nol hydroxylase activity in addition to changes in other microsomal enzymes. ... 

Aragno M, Danni 0, Ugazio G. 1989. In vivo studies on halogen compound interactions. II. Effects of carbon tetrachloride plus 1,2-dibromomethane on relative liver weight and hepatic steatosis. Res Comm Chem Pathol Pharmacol 66 105-116. 

As a class effect NRTIs are associated with lactic acidosis and hepatic steatosis, conditions which may occur more frequently in pregnant women. The individual NRTIs have their own adverse reactions. Pancreatitis is seen with lamivudine, stavudine, di-danosine and rarely with zalcitabine while the latter three agents can also induce peripheral neuropathy. 

A. The NRTIs can produce a potentially fatal syndrome of lactic acidosis and severe hepatomegaly with hepatic steatosis. Risk factors associated with the development of this syndrome include female sex, obesity, alcoholism, and prolonged exposure to NRTIs. Peripheral neuropathy is a common side effect of some NRTIs (e.g., stavudine., didanosine, and zalcitabine) but not associated with these risk factors. Stevens-Johnson syndrome is rarely associated with NNRTIs, such as nevirapine, and not with these risk factors. Hyperuricemia is not associated with these risk factors. Hypersensitivity reaction may oc-... 

Adverse gastrointestinal symptoms (nausea, vomiting, anorexia, metallic taste, abdominal discomfort, and diarrhea) occur in up to 20% of individuals taking metformin this can be minimized by starting at a low dose and slowly titrating the dose upward with food. Like phenformin, metformin can cause lactic acidosis, but its occurrence is rare except when renal failure, hypoxemia, or severe congestive heart failure is present or when coadministered with alcohol. Metformin is also contraindicated in persons with hepatic dysfunction, but it appears to be safe for use in the hepatic steatosis that often occurs with fatty infiltration of the liver in poorly controlled type II diabetics. 

Lecithin 7 Hepatic steatosis, dennatitis. Gallbladder disease. 

All NRTI agents, as well as tenofovir, carry the risk of lactic acidosis with hepatic steatosis as a potential adverse event. 

All NRTIs may be associated with mitochondrial toxicity, probably owing to inhibition of mitochondrial DNA polymerase gamma. Less commonly, lactic acidosis with hepatic steatosis may occur, which can be fatal. NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of unknown cause. The thymidine analogues zidovudine and stavudine may be particularly associated with dyslipidemia and insulin resistance. Also,... 

Adefovir dipivoxil is well tolerated. A dose-dependent nephrotoxicity has been observed in clinical trials, manifested by increased serum creatinine with decreased serum phosphorous and more common in patients with baseline renal insufficiency and those receiving high doses (60 mg/d). Other potential adverse effects are headache, diarrhea, asthenia, and abdominal pain. As with other NRTI agents, lactic acidosis and hepatic steatosis are considered a risk owing to mitochondrial dysfunction. No clinically important drug-drug interactions have been recognized to date. Pivalic acid, a by-product of adefovir dipivoxil metabolism, can esterify free carnitine and result in decreased carnitine levels. However, it is not felt necessary to administer carnitine supplementation with the low doses used to treat patients with HBV (10 mg/d). 

Diuron Cellumen CLM hepatic steatosis (24 h) Hepatic steatosis Expression 171.50 13.01... 

VLDLs are produced in the liver (Figure 18.17). They are composed predominantly of triacylglycerol, and their function is to carry this lipid from the liver to the peripheral tissues. There, the triacylglycerol is degraded by lipoprotein lipase, as discussed for chylomicrons (see p. 226). [Note "Fatty liver" (hepatic steatosis) occurs in conditions in which there is an imbalance between hepatic triacylglycerol synthesis and the secretion of VLDL. Such conditions include obesity, uncontrolled diabetes mellitus, and chronic ethanol ingestion.]... 

In combination with other antiretroviral agents, stavudine has caused fatal lactic acidosis in some patients. It is also associated with motor weakness in which case it should be discontinued. Peripheral neuropathy is the most common toxicity associated with stavudine, which is more prevalent at high doses (4mg/kg per day). Neuropathy in these patients generally is associated with numbness, tingling or pain in feet or hands. Patients treated with the combination of stavudine and didanosine may also exhibit liver function abnormalities (hepatic steatosis) and pancreatitis. It may also be associated with the etiology of HIV lipodystrophy syndrome. 

The frequency and course of hepatic steatosis due to tamoxifen has been studied using CT scans in 76 patients with breast cancer who took tamoxifen for 5 years (57). In all 29 women developed hepatic steatosis during the first 2 years, four to a severe degree. The livenspleen ratio returned to normal within a mean of 1.2 years after the end of treatment in 23 of these women. The authors stressed that hepatic dysfunction can occur with... 

Nishino M, Hayakawa K, Nakamura Y, Morimoto T, Mukaihara S. Effects of tamoxifen on hepatic fat content and the development of hepatic steatosis in patients with breast cancer high frequency of involvement and rapid reversal after completion of tamoxifen therapy. Am J Radiol 2003 180 129-34. 

Nucleoside analogue reverse transcriptase inhibitors can rarely cause lactic acidosis with hepatic steatosis and might potentiate the effect of metformin. 

Jolliet P, Leverve X, Pichard C. Acute hepatic steatosis complicating massive insulin overdose and excessive glucose administration. Intensive Care Med 2001 27(l) 313-6. 

Nicotinic acid can cause hepatic steatosis and clinical hepatic abnormalities that together can simulate the presentation of hepatobiliary neoplasia (36). 

Kristensen T, Olcott EW. Effects of niacin therapy that simulate neoplasia Hepatic steatosis with concurrent hepatic dysfunction. J Comput Assisted Tomogr 1999 23 314-7. 

Antiretroviral nucleoside analogues have been associated with hepatic steatosis and lactic acidosis. These compounds require phosphorylation to active triphosphate derivatives by cellular phosphokinases. The triphosphate nucleotide inhibits the growing proviral DNA chain, but it also inhibits host DNA polymerases, and this can result in compensatory glycolysis and lactic acidosis. Abnormal mitochondrial oxidation of free fatty acids causes the accumulation of neutral fat in liver cells, and this manifests as hepatomegaly with macrovesicular steatosis. Hepatic steatosis and lactic acidosis have been reported previously with zidovudine, didanosine, zalcita-bine, Combivir (zidovudine plus lamivudine), and lamivudine. Of 349 Australian patients studied for 18 months (516 patient-years) taking NRTIs only two had severe lactic acidosis (847). 

Choline deficiency developed in a 41-year-old woman with advanced cervical cancer who underwent prolonged parenteral nutrition (915). Her liver function tests became abnormal and she became jaundiced and complained of nausea and vomiting. The serum choline concentration was 5.77 mmol/1 and there was histological evidence of hepatic steatosis. There was steady improvement with oral choline supplementation, 3 g/ day, and with oral glutamine 15 g/day. There was a 45% improvement in serum choline concentration over baseline. 

Hashimoto T, Cook WS, Qi C, Yeldandi AV, Reddy JK, Rao MS. Defect in peroxisome proliferator-activated receptor alpha-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting. J Biol Chem 2000 275 28918-28928. 

Raju, J. and Bird, R.P. (2006) Alleviation of hepatic steatosis accompanied by modulation of plasma and liver TNF-alpha levels by Trigonella foenum-graecum (fenugreek) seeds in Zucker obese (fa/fa) rats. International Journal of Obesity 30(8), 1298-1307. 

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