Malnourished patients are usually repleted with elemental diets which provide 2-4 x RDA of all essential nutrients. Our studies show that alcoholic cirrhotic patients, administered these enteral or parenteral formula, develop plasma deficiencies (i.e., levels 2SD below normal average) of cysteine and choline, nutrients considered nonessential and deficient in the elemental formulae. Both nutrients are normally synthesized in liver from methionine via transsulfuration pathway. We and others have shown that in alcoholic cirrhosis the hepatic conversion of methionine to S-adenosylmethionine (SAM) is blocked because their SAM synthetase is about 1/4 of that in the normal. Interestingly, the hepatic SAM concentration is reportedly either subnormal or normal. SAM is not only an intermediate in the conversion of methionine to cysteine but is also a substrate in the hepatic formation of choline by the hepatic methyltransferase reaction. The pathophysiologic and metabolic consequences of cysteine and choline deficiencies in man have not been examined. Pilot studies here indicate that these patients remain in negative N balance, develop hepatic steatosis, and have abnormal serum profile of bilirubin and hepatic enzymes. Furthermore, oral bolus of cysteine and choline corrects these abnormalities. These observations are in line with data from animal studies. The key issues addressed in this proposal are: (a) Incidence of hypocysteinemia and hypocholinemia in malnourished cirrhotic subjects on enteral elemental formula. (b) Whether hypocysteinemic patients have negative N balance and abnormal nutritional indices and whether hypocholinemic patients have abnormal PC/PE ratio, abnormal hepatic functions, hepatic injury, and dysautonomia. (c) Whether oral supplements of choline and cysteine correct the plasma deficiencies and related abnormalities. And (d) whether hepatic content of SAM in these patients is subnormal. We will study 18 patients with clinically stable cirrhosis per year in a three phase protocol. During phase I (5 days), patients will eat regular hospital diets; during phase II (2 weeks) patients will receive enteral elemental formula and during phase III (2 weeks) the patients will receive the enteral formula along with oral supplement of cysteine/choline. During each phase, patients will undergo tests for their clinical, nutritional, hepatic, and neurologic status. Patients will also undergo galactose clearance and antipyrine clearance tests, and computerized tomography scan of their liver and their biochemical package-fasting plasma levels of choline, PC, PE, methionine, cyst(e)ine, and SAM-will also be analyzed. SAM content of biopsied of liver tissue (~20 mg) will also be determined. A large number of malnourished alcoholic cirrhotics routinely receive elemental formula for nutritional support but do not respond to the therapy. This may be partly due to cysteine and choline deficiencies identified by us. In addition, these patients may be at a greater risk to develop hepatomas since choline deficient diets by themselves act as carcinogens.
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| Chawla, R K; Watson, W H; Eastin, C E et al. (1998) S-adenosylmethionine deficiency and TNF-alpha in lipopolysaccharide-induced hepatic injury. Am J Physiol 275:G125-9 |
| Chawla, R K; Watson, W H; Jones, D P (1996) Effect of hypoxia on hepatic DNA methylation and tRNA methyltransferase in rat: similarities to effects of methyl-deficient diets. J Cell Biochem 61:72-80 |
| Chawla, R K; Jones, D P (1994) Abnormal metabolism of S-adenosyl-L-methionine in hypoxic rat liver. Similarities to its abnormal metabolism in alcoholic cirrhosis. Biochim Biophys Acta 1199:45-51 |
| Chawla, R K; Lawson, D H; Ahmad, M et al. (1992) Cancer-related urinary proteinase inhibitor, EDC1: a new method for its isolation and evidence for multiple forms. J Cell Biochem 50:227-36 |
