Liver hepatic steatosis

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.]... 

Hepatic Steatosis/Fatty Liver Hepatic steatosis is the accumulation of fat droplets within the hepatocytes. Steatosis is usually a common response noted with a variety of liver toxicants and represents a potentially reversible injury to hepatocytes (Treinen-Moslen, 2001). Grossly, the affected liver will be swollen with rounded edges, friable, and light brown to yellow in color. Compounds that produce prominent steatosis include... 

Although just a few drinks may result in hepatic fat accumulation, chronic consumption of alcohol greatly enhances the development of a fatty liver. Re-esterification of fatty acids into triacylglycerols by fatty acyl CoA transferases in the ER is enhanced (see Fig. 25.6). Because the transferases are microsomal enzymes, they are induced by ethanol consumption just as MEOS is induced. The result is a fatty liver (hepatic steatosis). 

Fatty liver. Hepatic steatosis is a common pathological condition of obesity and DM. 

Additionally, it has been suggested that non-alcoholic fatty liver disease (NAFLD) should be added to the classical components of the metabolic syndrome given its close association to IR as a central feature (Marchesini et al., 2001). NAFLD is defined as a broad spectrum of liver pathology, ranging from fatty liver (hepatic steatosis) without inflammation, to severe inflammatory activity with significant fibrosis or even curhosis (Marchesini et al., 2001). The release of inflammatory mediators, including C-ieactive protein (CRP), tumour necrosis factor (TNF)-a, interleukin (IL)-6 and IL-8, from the liver and adipose tissue are also characteristic of NAIT.D (Hijona et al., 2010). 

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... 

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. 

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. 

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. 

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. 

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. 

Hepato toxicity Liver, bile duct, and gall bladder. The liver is particularly susceptible to xenobiotics due to its large blood supply and its role in metabolism Steatosis (lipid accumulation in hepatocytes) Chemical hepatitis (inflammation of the liver) Hepatic necrosis (death of the hepatocytes) Hepatic cancer (cancer of the liver) Hepatic cirrhosis (chronic fibrosis) Hypersensitivity (immune reaction resulting in hepatic necrosis)... 

Herbal medicines are becoming more and more popular, and indeed some herbal products may be considered to benefit people with liver disease, e.g. Silybum marianum (milk thistle), Picrorhiza kurroa, Phyllanthus, etc. Herbal hepatotoxicity is increasingly being recognised, for example, with kava kava, black cohosh, and many traditional Chinese remedies. The range of liver injury includes minor transaminase elevations, acute and chronic hepatitis, steatosis, cholestasis, zonal or diffuse hepatic necrosis, veno-occlusive disease and acute liver failure. In addition to the potential for hepatotoxicity, herb-drug interactions may affect the safety and efficacy of concurrent medical therapy [15]. 

Enhanced lysosomal storage of phospholipids due to the inhibition of phospholipases is another special form of hepatic steatosis. The hepatocytes are enlarged and exhibit a distinctive foamy lucency of the cytoplasm. Crystalline inclusions and an agglomeration of myelin structures are visible in the lysosomes by electron microscopy. Mallory bodies may also be found. This idiosyncratic metabolic liver damage may even develop into cirrhosis, (s. p. 545) (s. tab. 31.4)... 

Hepatic steatosis with Mallory inclusion bodies has been reported with nifedipine (28). In patients with liver cirrhosis, nifedipine increases portal pressure due to splanchnic vasodilatation (29) whether this increases the risk of variceal bleeding is unknown. 

The lactic acidosis seen with these drugs has ranged from mild and chronic to acute, severe, and fatal [95-106]. The acidosis generally develops after several months of therapy. Patients with NRTl-associated lactic acidosis present with symptoms of nausea, vomiting and abdominal pain. Other features often include elevated liver enzymes, hepatic steatosis, pancreatitis and elevated creatinine kinase with evidence of a myopathy, and liver failure. The lactic acidosis may persist for many weeks despite discontinuation of the NRTl [95-106]. NRTl-related mitochondrial toxicity may also present with rhabdomyolysis and acute kidney failure [110]. Mortality related to NRTl-induced acute lactic acidosis is high, in the range of 50% to 100%, despite drug discontinuation. 

Siegelman E, Rosen M. Imaging of hepatic steatosis. Semin Liver Dis 2001 21 71-80. 

Nakano T, Inoue I, Koyama I et al (2007) Disruption of the murine intestinal alkaline phosphatase gene Akp3 impairs Kpid transcyto-sis and induces visceral fat accumulation and hepatic steatosis. Am J Physiol Gastrointest Liver Physiol 292 G1439-G1449... 

Large doses of Vitamin E (tocopherol) provides partial protection from hepatic steatosis of the liver during intoxifica-tion. More effective than E is another antioxidant, G-50. 

---