Protein hepatic synthesis

Alcoholism leads to fat accumulation in the liver, hyperlipidemia, and ultimately cirrhosis. The exact mechanism of action of ethanol in the long term is stiU uncertain. Ethanol consumption over a long period leads to the accumulation of fatty acids in the liver that are derived from endogenous synthesis rather than from increased mobilization from adipose tissue. There is no impairment of hepatic synthesis of protein after ethanol ingestion. Oxidation of ethanol by alcohol dehydrogenase leads to excess production of NADH. 

It has been well documented that the anaemia of chronic disease, ACD, results in a lowering of various haematological parameters. Several mediators are involved, among them histamine, serotonin, bradykinin, prostaglandins and, as found more recently, cytokines and nitric oxide. ACD is a parameter of systemic autoimmune disorders. The severe inflammatory stimuli lead to several systemic changes, mediated by inflammation-associated cytokines, e.g. IL-6, IL-1 TNFa, TGF beta that regulate hepatic synthesis of the acute phase proteins. 

Activators and inhibitors regulate not the amount of enzyme protein but the activity ( efficiency ) of that which is present. Two principal mechanisms of control are (i) competitive and (ii) allosteric. Competitive control (inhibition) occurs when a compound which is structurally similar to the true substrate binds to the active site of the enzyme. This is how a number of drugs and poisons bring about their effect. For example, a group of therapeutic drugs called statins are used to treat heart disease because by inhibiting a key enzyme called HMGCoA reductase, they reduce the hepatic synthesis of cholesterol and therefore the plasma concentration of that lipid. 

Pharmacology Vitamin K promotes the hepatic synthesis of active prothrombin (factor II), proconvertin (factor VII), plasma thromboplastin component (factor IX), and Stuart factor (factor X). The mechanism by which vitamin K promotes formation of these clotting factors involves the hepatic post-translational carboxylation of specific glutamate residues to gamma-carboxylglutamate residues in proteins involved in coagulation, thus leading to their activation. 

Baseline levels of urea and creatinine can be highly variable. Plasma urea reflects hepatic synthesis rate and will be elevated with increased protein catabolism (increased dietary protein intake, gastrointestinal hemorrhage, fever, severe bums, corticosteroid administration, sustained exercise or muscle wasting),... 

Rates of hepatic synthesis of many plasma proteins are affected by a patient s endocrine status. The effects of some steroid hormones on individual plasma protein levels are given in Table 20-5. The plasma protein levels characteristic of a specific disease may therefore be complicated by the steroid status of a patient and by an inflammatory acute phase reaction. The abnormal steroid status may be the result of an intrinsic hormonal disorder or of treatment with steroid hormones, as in inflammation. 

Albumin is synthesized primarily by the hepatic parenchymal cells except in early fetal life, when it is synthesized largely by the yolk sac. The synthetic reserve of the liver is enormous in nephrotic syndrome, it may be 300% or more of normal. The synthetic rate is controlled primarily by colloidal osmotic pressure (COP) and secondarily by protein intake. Synthesis is decreased by inflammatory cytokines, and release (but not synthesis) is decreased by hypokalemia. Catabolism occurs primarily by pinocytosis by aU tissue, with lysosomal catabolism of the protein and use of the resulting free amino acids for synthesis of cellular proteins. The rate of pinocytosis is proportional to the local tissue metaboHc rate. Small amounts (10% to 20% of the total catabolized) are also lost into the gastrointestinal tract... 

In clinical practice, only a few laboratory tests are of value in tlie assessment of protein-energy status It is particularly important to recognize that serum protein concentrations are not helpful in sick patients with any form of inflammatory process (see Chapter 20). Although serum albumin is often measured and reported as an indicator of protein-energy status, factors such as increased transcapillary escape and reduced hepatic synthesis malce it of little value as a nutritional marker. Serum albumin is, however, a valuable prognostic marker and is frequently used as part of prognostic indices. Short half-life proteins, such as transthyretin (prealbumin) also may be of some limited value in patients with no inflammatory response. 

For hospital patients with infections, and after accidental injury or postsurgery, the systemic inflammatory response wiU affect the concentration of essential elements in circulating blood independently of nutritional status. For example, the APR causes increased permeability of capillaries and transfer of certain plasma carrier proteins and their trace metals into interstitial space. Hepatic synthesis of some plasma proteins, the so-called acute phase proteins, is also induced, so that these proteins increase in concentration in plasma, together with any metals that they carry (e.g., ceruloplasmin and copper). Moreover, there are marked changes in the kinetics of elements, with altered rates of transfer to and from the tissue. Knowledge of the effect of disease on metal kinetics and distribution is therefore essential. ... 

Nephrotic syndrome is characterized by proteinuria greater than 3.5 g/day per 1.73 m, hypoproteinemia, edema, and hyperlipidemia. A hypercoagulable state may also be present in some patients. The syndrome may be the result of primary diseases of the glomerulus, or be associated with systemic diseases such as diabetes mellitus, lupus, amyloidosis, and preeclampsia. Hypoproteinemia, especially hypoal-buminemia, results from increased urinary loss of albumin and an increased rate of catabolism of filtered albumin by proximal tubular cells. The compensatory increase in hepatic synthesis of albumin is insufficient to replenish the protein loss, probably because of malnutrition. 

Prealbumin is the transport protein for thyroxine and a carrier for retinol-binding protein. The body s content of prealbumin is low (10 mg/kg of body weight), and it has a very short biologic half-fife (I to 2 days). Prealbiunin may be reduced in as few as 3 days after calorie and protein intake is significantly decreased, or when hypercatabolism or severe metabolic stress (tramna or bmns) is present. Because of its short half-life, it is most useful in monitoring the shortterm, acute effects of nutrition support. As with ALB and TFN, sermn prealbumin concentrations are depressed in those with liver disease due to decreased hepatic synthesis. Increased serum prealbumin concentrations have been noted in patients with renal disease due to impaired renal excretion. 

The cholinesterases are generally accepted as being synthesized in the liver, and the assay of cholinesterase first became of interest to the clinician and to the clinical chemist as a test of liver function. Low serum cholinesterase activities are found in acute hepatitis, acute cirrhosis, and in liver metastases—that is, in those conditions where the hepatic synthesis of the protein is impaired. The synthesis of several other proteins is also reduced in such conditions, so that cholinesterase assay has been largely superseded as a test of liver function by measurements related to such proteins as albumin and prothrombin. Nevertheless, cholinesterase still has a place in the assessment of hepatic and other diseases, as discussed in Section 5.2. 

Answer C. Warfarin inhibits the hepatic synthesis of factors II (prothrombin), VII, IX, and X. Its onset of anticoagulation activity is slow, and its impact on individual coagulation factors depends on their half-lives. Factor VII and protein C have much shorter half-lives than prothrombin, and so the extrinsic pathway and protein C system are the first to be affected by warfarin. The intrinsic pathway continues to function for 2 to 3 days, causing a state of hypercoagulability with possible vascular thrombosis. 

Fig. 1. Simplified schematic summary of the essential pathways for receptor-mediated human lipoprotein metabolism. The liver is the crossing point between the exogenous pathway (left-hand side), which deals with dietary lipids, and the endogenous pathway (right-hand side) that starts with the hepatic synthesis of VLDL. The endogenous metabolic branch starts with the production of chylomicrons (CM) in the intestine, which are converted to chylomicron remnants (CMR). Very-low-density lipoprotein particles (VLDL) are lipolyzed to LDL particles, which bind to the LDL receptor. IDL, intermediate-density lipoproteins LDL, low-density lipoproteins HDL, high-density lipoproteins LCAT, lecithinxholesterol acyltransferase CETP, cholesteryl ester transfer protein A, LDL receptor-related protein (LRPl) and W, LDL receptor. Lipolysis denotes lipoprotein lipase-catalyzed triacylglycerol lipolysis in the capillary bed.

All of the information obtained on the amounts and patterns of urinary proteins should be interpreted, together with plasma measurements—particularly for evidence of glomerular nitration changes—and altered hepatic protein synthesis. For example, loss of large amounts of urinary albumin may result in hypoalbuminemia, or the hypoalbumineamia may reflect reduced hepatic synthesis with no evidence of marked changes of renal clearance of albumin. 

The estrogenic component of oral contraceptives may increase hepatic synthesis of a number of serum proteins, including CBG, TBG, and SHBG. While physiological feedback mechanisms generally adjust hormone synthesis to maintain normal free hormone levels, these changes can... 

It is important to distinguish between changes in zinc metabolism which occur as a secondary effect of disease, injury, infection and drug therapy and alterations caused by a primary nutritional zinc deficiency. There is confusion in the literature because a number of unrelated causes can temporarily lower the concentration of zinc in plasma, and this is reported uncritically as evidence of nutritional depletion. Since a high proportion of zinc in plasma is albumin bound, any circumstance which lowers plasma albumin wiil also lower plasma zinc. For example, the changes seen in severe liver disease are primarily caused by a failure of hepatic synthesis of plasma proteins such as albumin. This results in problems in the distribution of zinc and eventual tissue depletion. It is questionable whether zinc supplementation of diet is worthwhile without some restoration of hepatocyte function, by effective treatment of the underlying disease (Mills et al., 1983). 

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