Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with cirrhosis of the liver require an increased amount of protein to achieve N balance. However, the utilization of protein with increased protein intake, i.e. the slope from regression analysis of N balance v. intake, is highly efficient (Nielsen et al. 1995). In the present study, protein requirement and protein utilization were investigated further by measuring protein synthesis and degradation. In two separate studies, five or six patients with cirrhosis of the liver were refed on a balanced diet for an average of 2 or 4 weeks. Protein and energy intakes were doubled in both studies. Initial and final whole-body protein metabolism was measured in the fed state by primed continuous [15N]glycine infusion. Refeeding caused a statistically significant increase of about 30% in protein synthesis in both studies while protein degradation was only slightly affected. The increase in protein synthesis was associated with significant increases in plasma concentrations of total amino acids (25%), leucine (58%), isoleucine (82%), valine (72%), proline (48%) and triiodothyronine (27%) while insulin, growth hormone, insulin-like growth factor (IGF)-I and IGF-binding protein-3 were not changed significantly. The results indicate that the efficient protein utilization is due to increased protein synthesis, rather than decreased protein degradation, and suggest that increases in plasma amino acids may be responsible for the increased protein synthesis. A comparison of the patients who had a normal protein requirement with the patients who had an increased protein requirement suggests that the increased protein requirement is due to a primary increase in protein degradation. It is speculated that this is due to low levels of IGF-I secondary to impaired liver function, since initial plasma concentration of IGF-I was about 25% of control values and remained low during refeeding.
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PMID:Effect of long-term refeeding on protein metabolism in patients with cirrhosis of the liver. 913 67

Structural and functional changes during liver regeneration have been studied extensively in experimental animals following partial hepatectomy or hepatic injury induced by noxious substances. These observations have been extended to evaluate abnormalities of liver regeneration which contribute to chronic hepatitis, cirrhosis and/or liver cancer in man. This is facilitated by the simultaneous perfusion of flash frozen percutaneous biopsies or explanted liver in an acrylic chamber with tritiated thymidine and proline to evaluate DNA and collagen synthesis, respectively. Such investigations indicate that chronic liver damage is associated with replication of mesenchymal, ductular and parenchymal cells, accompanied by increased fibrogenesis. The regenerative response of the liver after noxious injury in experimental animals and man is associated with the release of cytokines, increase of growth response genes and change in telomerase activity. The ability to monitor morphological, genetic and biochemical parameters provides new information on the kinetics of the reparative process in hepatobiliary disease. Abnormal liver regeneration and its untoward effects including tumorigenesis may be modified by altering nutrients, blocking antigens or receptors, and inhibiting metabolites which regulate cell replication and collagen deposition.
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PMID:Abnormalities of liver regeneration: a review. 957 74

We analyzed basal energy metabolism in 20 healthy volunteers and 41 cirrhotic patients by indirect calorimetry. Subjects were then given either glucose, branched-chain amino acids (BCAA) or fatty acids as an energy substrate. Resting energy expenditure (REE), nonprotein respiratory quotient (npRQ), and oxidation rates of glucose (% CHO), protein (% PRO) and fat (% FAT) were analyzed. REE and %FAT were significantly higher and % CHO and %PRO were significantly lower in cirrhosis than in controls. These changes correlated with disease severity. Glucose and BCAA were utilized efficiently as energy substrates and reduced %FAT in cirrhosis. Energy efficacy (increased energy expenditure/energy equivalent of the supplemented nutrient) was significantly higher in BCAA (96 +/- 16%) than in glucose (41 +/- 8%) (p<0.01) and fatty acids (27 +/- 13%) (p<0.05). Patients with cirrhosis have an increased energy requirement. BCAA seems to be the preferred substrate to meet this demand, because its energy efficacy is higher than glucose or fatty acids in cirrhosis.
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PMID:Preferential use of branched-chain amino acids as an energy substrate in patients with liver cirrhosis. 965 95

Fibrosis and cirrhosis of the liver are often the result of chronic liver damage by a variety of different agents. Pathological accumulation of collagen, disruption of the lobular structure, and impaired hepatocellular function frequently lead to systemic involvement and fatal complications. Drugs inhibiting collagen hydroxylation and accumulation are expected to improve this situation, making prolyl 4-hydroxylase (P4H), the key enzyme of intracellular collagen processing, a rational target for pharmacological intervention. S 4682, a novel inhibitor of purified P4H (Ki = 155 nmol/L), reduced hydroxyproline (Hyp) synthesis in chicken embryo calvaria (IC50 = 8.2 micromol/L) and in cultured hepatic stellate cells (HSC) (IC50 = 39 micromol/L). S 4682 inhibited hepatic collagen hydroxylation in vivo after metabolic labeling with [14C]proline. In the CCl4 model of chronic hepatic injury, characterized by histologically and biochemically evident fibrosis and highly elevated levels of serum procollagen type III N-peptide, S 4682 reduced hepatic collagen accumulation, decreased prevalence of ascites, and lowered serum procollagen type III N-peptide (PIIINP) levels. The hepatic Hyp content of drug-treated animals was closely correlated with serum levels of PIIINP S 4682 had no influence on Hyp content of heart, lung, and kidney.
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PMID:Selective inhibition of hepatic collagen accumulation in experimental liver fibrosis in rats by a new prolyl 4-hydroxylase inhibitor. 969 4

The prevention of cirrhosis in alcohol-fed baboons by the administration of a soybean extract-43% to 50% of which was dilinoleoyl-phosphatidylcholine (DLPC) and 24% of which was 1,palmitoyl 2,linoleoyl-phosphatidylcholine (PLPC)-was associated with a significant reduction in the number of stellate cells transformed to myofibroblast-like cells. To study whether these two major phospholipids affect the similar transformation that occurs by culturing stellate cells on uncoated plastic, we assessed their effects on proliferation (by (methyl-3H)-thymidine incorporation into DNA), expression of alpha-smooth muscle actin and type I procollagen (by densitometry of Western blots), and collagen synthesis (by incorporation of tritiated proline into collagenase-digestible proteins). These manifestations of stellate cell activation were decreased by 10 micromol/L DLPC but not by 10 micromol/L PLPC when compared with controls incubated either with 17 mmol/L ethanol (used as solvent for the phospholipids) or without addition. These agents did not affect cell viability, contamination with other cells, or the capacity of stellate cells to synthesize protein. Thus DLPC specifically decreases the in vitro activation of stellate cells, as judged by the decreases in proliferative activity, alpha-smooth muscle actin and procollagen I expressions, and collagen synthesis, whereas PLPC did not show such effects. alpha-Procollagen (type I) mRNA was not affected by DLPC, suggesting a post-translational effect. The reduction in the activation of hepatic stellate cells by DLPC may be responsible for, or at least contribute to, the prevention of fibrosis by the polyenylphosphatidylcholine mixture administered in vivo.
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PMID:Dilinoleoylphosphatidylcholine decreases hepatic stellate cell activation. 1021 64

The intestine is an important target organ for insulin-like growth factor-I (IGF-I), an anabolic hormone synthesized in the liver upon growth hormone (GH) stimulation. Levels of IGF-I are reduced in cirrhosis, and altered GH/IGF-I axis may contribute to malnutrition in cirrhotic patients. Our aim was to study Na(+)-dependent jejunal transport of amino acids (L-leucine, L-proline, L-glutamic acid, and L-cysteine) in cirrhotic rats and to analyze the effect of IGF-I on this function. IGF-I or saline was administered for 2 wk to rats with CCl(4)-induced cirrhosis and saline was administered to healthy control rats. Transport of amino acids was assessed in brush-border membrane vesicles (BBMV) using (14)C- or (35)S-labeled amino acids, and the kinetic constants V(max) and K(t) were determined. Na(+)-independent uptake of L-leucine, L-proline, L-glutamic acid, and L-cysteine by BBMV was similar in all groups. Na(+)-dependent uptake of all four amino acids was significantly diminished in cirrhotic rats compared with both controls and IGF-I-treated cirrhotic rats. The latter two groups exhibited similar V(max) and K(t), whereas untreated cirrhotic rats had reduced V(max) and increased K(t) compared with normal controls and IGF-I-treated cirrhotic animals. In conclusion, the transport of all four tested amino acids by BBMV is impaired in cirrhotic rats, and low doses of IGF-I can correct this defect.
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PMID:Altered intestinal transport of amino acids in cirrhotic rats: the effect of insulin-like growth factor-I. 1091 40

The effects of different doses of Interferon alpha 2b (IFN alpha 2b), alone and in combination with praziquantel (PZQ), on hepatic schistosomiasis were tested. An experimental murine model of hepatic schistosomiasis was used. Four parameters were assessed; hepatic fibrosis by estimation of OH-proline content/g dry weight liver, hepatocyte proliferative activity by the PCNA/LI, schistosomal egg load by digesting parts of the liver by KOH and hepatocyte function by measuring parenchymal liver enzyme levels. IFN alpha 2b was found to increase hepatic fibrosis in a dose dependent manner both alone and in combination with PZQ. An augmentation of the regenerative activity of the liver was observed. A reduction in the number of the granulomas and egg counts was observed only when PZQ was added. However, no effect on the size of the granulomas was observed apart from the normal process of modulation. Caution should be exercised when treating patients with concomitant hepatic schistosomiasis and hepatitis with IFN alpha 2b as it increases both hepatocyte regenerative activity and hepatic fibrosis; two main components of cirrhosis.
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PMID:Parasitological, pathological and functional studies on the effects of IFN alpha 2b in murine hepatic schistosomiasis. 1141 37

Cirrhosis is one of the most common causes of mortality worldwide, because hepatic dysfunction constitutes a potentially lethal condition. Having demonstrated the hepatoprotective effect of adenosine against CCl(4)-induced cirrhosis, the present study was aimed at assessing adenosine's effect on an already-established micronodular cirrhosis. Chronic administration of CCl(4) (10 weeks) induced a cirrhotic state, characterized by increased liver fibronectin and collagen types I and III content, enhanced expression of alpha-1 (I) collagen mRNA, portal hypertension, and liver dysfunction. After CCl(4) discontinuation (5 weeks), increased persitance of alpha-1 (I) collagen mRNA expression and deposition, enhanced proline incorporation into collagen and prolyl hydroxylase activity evidenced active fibrogenesis. Several weeks after CCl(4) withdrawal, deposited collagen showed an enhanced type I/III ratio, which was associated with deficient collagenolytic activity in cirrhotic livers. Liver expression of some metalloproteinases (MMPs) and of tissue inhibitors of MMPs (TIMPs) also indicated decreased collagen breakdown in cirrhotic livers. Parameters indicative of oxidative stress (mainly protein oxidation) were persistently augmented. These events were coincident with diminished regenerative capacity of the cirrhotic liver. Intraperitoneal adenosine administration to CCl(4)-induced cirrhotic rats blocked active fibrogenesis and increased the collagen degradation (most probably by decreasing liver TIMPs levels), normalizing collagen-type ratios. In addition, the nucleoside promoted an effective hepatocyte's proliferation in the cirrhotic liver and accelerated normalization of parameters indicative of liver function and oxidative stress. Thus, adenosine readily reversed an experimental cirrhosis through stimulating liver collagenolytic and proliferative capacities, as well as by accelerating functional recovery.
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PMID:Adenosine reverses a preestablished CCl4-induced micronodular cirrhosis through enhancing collagenolytic activity and stimulating hepatocyte cell proliferation in rats. 1158 63

Branched-chain amino acids (BCAA: leucine, isoleucine and valine) are not just structural constituents of proteins, but have ''pharmacologic'' properties, known for several years: BCAA are catabolized mainly in muscle; can be oxidized with energy production, being nitrogen donors for other amino acids; regulate protein synthesis and degradation; modulate metabolism of neuroactive mediators. These properties make the clinical use of BCAA particularly suitable in critical conditions such as liver cirrhosis, sepsis, surgical or nonsurgical trauma, acute renal failure, acute pancreatitis, cancer, in which energy production from conventional substrates is altered and, at the same time, reduction of protein catabolism and enhancement of synthetic processes is advisable. Recently, the changes of plasma aminoacidograms induced by the administration of high-dose BCAA in sepsis have been better detailed: 1) a tendency to normalization of high levels of proline and of other amino acids transported intracellularly by transport system ''A''; 2) less relevant reduction of the levels of other amino acids; 3) increase of the levels of taurine, glutamate and aspartate; more complex interactions with specific amino acids. These changes, and changes of other variables, reconfirm in part some well-known properties of BCAA, and are also objective indicators of an improvement of the metabolic abnormalities of sepsis induced by BCAA administration. In sepsis and in other stress conditions it is recommended to administer, within balanced parenteral nutritional regimens, AA solutions with a 35-50% BCAA concentration.
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PMID:[The branched-chain amino acids]. 1650 46

The stable-isotopic composition of nitrogen (delta15N) or carbon (delta13C) of body tissues depends on the isotopic composition of food sources and on shifts due to isotopic fractionation during metabolism. As little is known about the effects of pathophysiological conditions we measured delta15N and delta13C values in hair and hair amino acids of patients with cirrhosis (n = 21) and compared the results with those of healthy subjects (n = 100) randomly selected from the 1987-1988 VERA German nutrition survey population. Cirrhosis was reflected in lower hair 15N abundances (6.7 vs. 9.9 per thousand delta15N; P < 0.001) whereas hair 13C abundances did not differ from healthy subjects (-19.4 vs. -19.6 per thousand 13C). Distinct patterns of delta15N and delta13C values were measured in hair amino acids. The delta15N values of phenylalanine were significantly higher in cirrhotics (P < 0.001). With the exception of isoleucine, threonine, and proline all other measured amino acids showed lower delta15N values than healthy subjects (P < 0.001). Lower hair delta15N values were associated with cirrhotic liver disease which suggests that under this condition the altered liver amino acid metabolism affects the nitrogen isotopic composition of the amino acids used for hair protein synthesis. It remains to be determined in controlled studies whether the altered nitrogen isotopic composition directly reflects the pathophysiological condition or is related to differences in dietary protein intake from plant or animal food sources.
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PMID:Nitrogen isotopic composition in hair protein is different in liver cirrhotic patients. 1695 36


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