Cirrhosis, liver serum proteins

Ricketts, W.E., Kirsner, J.B., Palmer, W.L., Sterling, K. Observations on the diagnostic value of liver biopsy, tests of hepatic function, and electrophoretic fractionation of serum proteins in asymptomatic portal cirrhosis. J. Lab. Clin. Med. 1950 35 403-407... 

An older man with severe emphysema is found to have decreased amounts and abnormal mobility of tti antitrypsin (AAT) protein in his serum when analyzed by serum protein electrophoresis. Liver biopsy discloses mild scarring (cirrhosis) and demonstrates microscopic inclusions due to an engorged endoplasmic reticulum (ER). The most likely explanation for these findings is... 

The total concentration of protein may be measured by nitrogen, or by specific gravity or refractive index. The method is generally applicable to sera and to serum protein solutions. Care should be taken to check the possibility of absorption by nonprotein constituents of serum which in some diseases such as cirrhosis of the liver may be considerable. The presence of such substances is shown by a marked fall in absorption of the serum after dialysis. 

Callewaert, N. et al. Noninvasive diagnosis of liver cirrhosis using DNA sequencer-based total serum protein glycomics. Nat Med, 10, 429, 2004. 

Diseases in which the 7-globulin fraction of the serum proteins shows a diffuse increase on electrophoresis due to the greater than normal production of many types of immunoglobulin molecules i,cf a monoclonal gammopathy when only one class and type of immunoglobulin is produced and this is seen as an extra band on serum protein electrophoresis). Chronic infections, liver cirrhosis and inflammatory disorders such as rheumatoid arthritis are examples of polyclonal gammo-pathies. 

The relation of hypoalbuminemia to ascites formation in cirrhosis of the liver has been the subject of much study (1, 93,110, 214, 215, 258, 274, 291, 295, 309, 352). Post and Patek (291) found that the mean serum albumin level of 28 cirrhotic patients without ascites was 3.7 grams per cent, whereas the mean value in 43 cirrhotic patients with ascites was 2.3 grams per cent (with considerable overlapping between the two groups). These relations are about what might be anticipated from the Starling hypothesis of the role of the serum proteins, particularly albumin, in the maintenance of the osmotic pressure of the blood (331)... 

Ammonia (NH3) is just one of the toxins implicated in HE. It is a metabolic by-product of protein catabolism and is also generated by bacteria in the GI tract. In a normally functioning liver, hepatocytes take up ammonia and degrade it to form urea, which is then renally excreted. In patients with cirrhosis, the conversion of ammonia to urea is retarded and ammonia accumulates, resulting in encephalopathy. This decrease in urea formation is manifest on laboratory assessment as decreased blood urea nitrogen (BUN), but BUN levels do not correlate with degree of HE. Patients with HE commonly have elevated serum ammonia concentrations, but the levels do not correlate well with the degree of central nervous system impairment.20... 

The potent antidiuretic hormone AVP orchestrates the regulation of free water absorption, body fluid osmolality, cell contraction, blood volume, and blood pressure through stimulation of three G-protein-coupled receptor subtypes Vi-vascular types a and b, V2-renal, and V3-pituitary. Increased AVP secretion is the trademark of several pathophysiological disorders, including heart failure, impaired renal function, liver cirrhosis, and SIADH. As a consequence, these patients experience excess water retention or inadequate free-water excretion, which results in the dilution of sodium concentrations, frequently manifesting as clinical hyponatremia (serum sodium concentration <135mmol/L). This electrolyte imbalance increases mortality rates by 60-fold. Selective antagonism of the AVP V2 receptor promotes water... 

Hepatic Effects. Carbon tetrachloride has been known for many years to be a powerful hepatotoxic agent in humans and in animals. The principal clinical signs of liver injury in humans who inhale carbon tetrachloride are a swollen and tender liver, elevated levels of hepatic enzyme (aspartate aminotransferase) in the serum, elevated serum bilirubin levels and the appearance of jaundice, and decreased serum levels of proteins such as albumin and fibrinogen (Ashe and Sailer 1942 McGuire 1932 New et al. 1962 Norwood et al. 1950 Straus 1954). In cases of acute lethal exposures, autopsy generally reveals marked liver necrosis with pronounced steatosis (Jennings 1955 Markham 1967 Smetana 1939), and repeated or chronic exposures leads in some cases to fibrosis or cirrhosis (McDermott and Hardy 1963). 

Transferrin A high-affinity serum iron transport protein Transferrin is synthesised in the liver and its levels are diminished in cirrhosis Iron overload i.e haemochromatosis/haemosiderosis may lead to cirrhosis. A transferrin saturation >55% in males (and postmenopausal women) or >50% in premenopausal women requires investigation to exclude a diagnosis of hereditary haemochromatosis... 

Hepatic hydrothorax (C.S. Morrow et al., 1958) is evident during the course of liver cirrhosis with ascites in 0.4-12% of cases. The mean frequency is about 6%, although in two-thirds of the cases, a right-sided effusion (with the author s own patients a bilateral effusion) was ascertained. (66) (s. fig. 16.8) Hepatic hydrothorax is a transudate cell count protein concentration <2.5 g/dl, total protein effusion to serum ratio <0.5, LDH effusion to serum ratio <2.3, serum to pleural fluid albumin gradient >1.1 g/dl. (s. also fig. 16.9) (17, 37, 47, 52 - 54, 66)... 

Polyclonal increases in serum immunoglobulins are the normal response to infections. IgG response predominates in autoimmune responses IgA in skin, gut, respiratory, and renal infections and IgM in primary viral infections and bloodstream parasites, such as malaria. Chronic bacterial infections may cause an increase in serum levels of all immunoglobulins. In such cases, estimations of the individual immunoglobulins seldom provide more information than protein electrophoresis. They are of value, however, in the differential diagnosis of liver disease and of intrauterine infections. In primary biliary cirrhosis, the IgM level is greatly increased in chronic active hepatitis, IgG and sometimes IgM are increased and in portal cirrhosis, IgA and sometimes IgG are increased. In intrauterine infections, production of IgM by the fetus increases, and the IgM level in umbilical cord blood is increased. Estimations of IgE are used in the management of asthma and other allergic conditions, especially in children. 

Consistent wdth a major role of the liver in maintaining normal somatomedin levels in the circulation, low levels of somatomedin-A activity have been found in unextracted plasma of patients with cirrhosis of the liver and chronic hepatitis (S14, T5). Significant correlations were seen between somatomedin-A and albumin, cholinesterase, and other indicators of liver function (T5). The decrease measured in this RRA appears to be due to low levels of both somatomedins and binding protein, since Zapf et al. (Z5) have shown an 89% decrease in immunoreactive IGF-I, a 74% decrease in total IGF by protein binding assay (which preferentially measures IGF-II), and a 57% decrease in specific binding of somatomedin tracer to stripped serum, in patients with cirrhosis. 

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. 

Fig. 11. Analysis of protein (A280) and total cholesterol A55Q) for human serum. Column G5000PW+G3000SW+G3000SW. Sample (A), normal female (B), liver cirrhosis (C), hyperlipidemia. Loaded volume 20 pi of whole serum. Peaks 1, chylomicrons 2, VLDL 3, LDL 4, HDL2 5, HDL3 6, VHDL 7, r-globul1n 8, albumin. Other HPLC conditions as in Fig. 10.

In healthy people the rate of ketogenesis, and therefore the concentration of acetoacetate and 3-hydroxybutyrate in the blood, will decrease after meals, but may increase in mitochondrial disorders [15, 20]. Increased serum ammonia, creatine kinase or CSF protein concentration is not indicative for a mitochondrial disturbance. If found, urea cycle defects, liver cirrhosis, muscle dystrophy or brain necrosis must be considered. Patients with Kearns-Sayre syndrome and Leigh syndrome, however, often have increased protein concentrations in the CSF. 

The sensitivity and specificity of the quantitative precipitin method make it applicable to the identification and estimation of abnormal plasma proteins in certain diseases, particularly when present in concentrations too low to be detected by other methods. Goettsch and her associates (103, 104) and Kendall (181) employed immunochemical techniques in the study of nephrotic sera Kendall (181) also investigated the distribution of his immunologically distinct globulin subfractions in hyperglobulinemia due to lymphogranuloma venereum, cirrhosis of the liver, and rheumatoid arthritis Kabat (261) was able to demonstrate the presence of as little as 0.15 gram per cent Bence-Jones protein in the serum of a patient with multiple myeloma. Many other applications of immunochemical techniques are noted by Kabat (167) and Treffers (358) in recent reviews. 

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