Serum Proteins in Hepatic Disease

HENRY A. TELOH, M.D.

Holy Cross Hospital, Ft. Lauderdale, FL 33307

ABSTRACT

The serum protein changes occurring in liver disease associated with parenchymal damage are characteristically decreased in serum albumin and increased in gamma globulin levels. Beta-gamma bridging in the elec- trophoretogram is highly characteristic of hepatic cirrhosis. Variation of alpha 1, alpha 2 and beta fractions is inconstant and is not of great diagnos tic or prognostic value. The increase in gamma fraction is polyclonal in nature and is due first to increase in IgM fraction followed by an increase in IgG fraction. Elevation of IgA fraction is not as constant or prominent.

The role of the liver in metabolism of m en ts.6 In a clinical setting, these body proteins is abundantly illustrated changes are slow and do not necessarily by many observations of clinical as well immediately reflect acute liver damage. as research nature. This role may be Thus, in a patient with acute viral roughly divided into the following phases: hepatitis, serum albumin levels may be (1) in providing simple precursors from normal in the early stages of the disease the metabolic pool for synthesis of process and may gradually decrease only tissue protein, (2 ) in formation of hepatic after parenchymal compromise has oc proteins, (3) in synthesis of serum pro curred. Conversely, in liver diseases in teins, (4) in storage of proteins, (5) in the which parenchymal involvement is min catabolic process of breaking down pro imal or absent (e.g., biliary obstruction), teins to amino acids, (6) in deamination of serum levels are usually normal. In se amino acids to form urea and (7) addi vere and prolonged viral hepatitis and in tionally in other transformation processes cirrhosis, the serum albumin levels bear a (e.g., transamination) of amino acids. This close relation to the clinical state and are article deals exclusively with the serum helpful prognostically and in following proteins and their changes occurring in results of treatment. diseases of the liver. The importance of the integrity of the hepatic parenchymal cell in the synthesis Serum Albumin of serum albumin is illustrated by the work of Chey et al,1 in which hepatic le Albumin is believed to be synthesized sions similar to those of alcoholic liver solely in the liver. The experimental ob disease in the human were produced by servation of a sudden and precipitous prolonged administration of ethanol to drop of serum albumin after hepatectomy dogs. One of the prominent biochemical is confirmed by the constant clinical ob changes occurring in these experimental servation of decrease of serum albumin animals was a gradual but progressive levels in hepatic diseases associated with decrease in serum albumin despite an destruction or loss of parenchymal ele adequate dietary intake.

1 2 7 1 2 8 TELOH

Serum Globulins creased in viral hepatitis along with gradual decrease of albumin. Diminution Alpha globulins, including alpha 1 an of alpha 2 globulin to low levels may be a titrypsin, glycoprotein, alpha 2 lipopro poor prognostic sign. The gamma globu teins, alpha 2 macroglobulins, haptoglo lin returns to normal late in convale- bin and ceruloplasmin are synthesized in sence. Failure to return to normal should the liver. Some of the beta globulins, in raise a suspicion of delayed recovery or cluding beta lipoproteins, transferrin, chronic active hepatitis. In cholangiolitic hemopexin, are likewise synthesized in hepatitis, there is an increase in beta glob the liver. Alpha 1 globulins tend to be ulin which may reach very high levels in low in hepato-cellular disease falling in chronic progressive disease. parallel with the serum albumin. Alpha 2 and beta globulins contain lipoproteins Hepatic Cirrhosis which may be markedly increased in cholestatic lesions of the liver. In choles Sunderman and Sunderman7'8 p re tasis, the increase in alpha 2 and beta sented data from 95 patients with Laen- globulin components correlates with the nec’s cirrhosis and 18 patients with viral height of serum lipid values and may be a hepatitis. In cirrhosis there was a sig useful point in distinguishing between nificant diminution in the mean concen biliary obstructive lesions and other tration of albumin and an increase in the non-obstructive types of jaundice. mean concentration of gamma globulin Gamma globulins are commonly mark while the mean concentration of alpha edly increased in chronic hepatic disease and beta globulins were normal. They and are not formed in the liver primarily also pointed out the characteristic feature but in the cells of the immunoblastic sys of the electrophoretic pattern in hepatic tem. The liver assumes only a minor role cirrhosis of beta-gamma bridging, i.e., a in this process only to the extent of its lack of demarcation between the peaks of content of elements of the reticulo beta and gamma globulins. They indi endothelial system (lining sinusoidal cated that beta-gamma bridging almost cells and Kupffer cells). always denotes hepatic cirrhosis. Havens2 presented a study of the pro Powell et al5 studied a series of400 un teins in hepatic diseases. Except for selected patients with hepatic cirrhosis gamma globulin, the liver produces most admitted to two large hospitals in Au of the plasma proteins including albu stralia. Prominent in the biochemical ab min, enzymes, coagulation factors, lipo normalities were abnormal serum elec proteins and glycoproteins. Gamma globu trophoretic patterns in 78.2 percent of pa lin is produced by the reticuloendothelial tients with alcoholic cirrhosis, 86 percent cells. Although these reticuloendothelial of patients with cryptogenic cirrhosis, elements occur in the liver, evidence in 96.3 percent with active chronic hepatitis dicates that in this site their participation and 56 percent of patients with hemo in the production of gamma globulin is chromatosis. In over 40 percent of pa insignificant under normal conditions. tients with alcoholic cirrhosis, there was There is evidence that in certain hepa an abnormal protein band between the tic diseases gamma globulin may be pro beta and gamma globulins (beta-gamma duced in increasing amounts by the hepa bridging). Serum immunoglobulin levels tic reticuloendothelial cells. However, were measured in 56 patients. Elevated the classic pattern of changes in various IgG levels were present in about 50 per liver diseases includes increase in cent of those tested in each type of cir gamma and/or beta globulins with or rhosis except hemochromatosis. Twelve without diminution of albumin. Alpha 1, of 20 alcoholic patients showed elevated alpha 2 and beta globulin are slightly de IgG and IgA levels. IgM levels were in SERUM PROTEINS IN HEPATIC DISEASE 129 creased in 14. The frequency of increased process. They did not consider these tests levels of IgG, IgA and IgM in patients of sufficient discriminative value as to be with alcoholic cirrhosis did not differ sig reliable in diagnosis. nificantly from that of patients in other groups. Summary Murray-Lyon et al3 studied the In summary, the serum protein changes occuring in 10 serum proteins by changes occurring in liver disease asso quantitative IEP in 42 patients with inac ciated with parenchymal damage charac tive cryptogenic cirrhosis, alcoholic cir teristically are decreased in serum rhosis and active chronic hepatitis. Alpha albumin and increased in gamma globulin 2 macroglobulins were significantly in levels. Beta-gamma bridging in the elec- creased in each group of patients. Alpha 2 trophoretogram is highly characteristic of glycoproteins, ceruloplasmin and trans hepatic cirrhosis. Variation of alpha 1, ferrin were elevated in patients with ac alpha 2 and beta fractions is inconstant tive chronic hepatitis while ceruloplas and is not of great diagnostic or prognos min was raised in patients with alcoholic tic value. The increase in gamma fraction cirrhosis. The only proteins to be signifi is polyclonal in nature and is due first to cantly reduced were transferrin in al- increase in IgM fraction followed by an cholic cirrhosis and haptoglobin in active increase in IgG fraction. Elevation of IgA chronic hepatitis. Other proteins of the fraction is not as constant or prominent. alp h a 1, alpha 2 an d b eta 1 groups showed no significant variation from References normal. These authors indicated that al though there do appear to be distinct dif 1. C h e y , W . Y., Ko s a y , S., S i p l e t , H., and L o r b e r , S. H.: Observations on hepatic histol ferences in the patterns of abnormality ogy and function in alcoholic dogs. Digest. Dis. found, the correlation between changes 16:825-838, 1971. in protein concentration of clinical or 2. H a v e n s , W . P.: Serum proteins in hepatic disease. Serum Proteins and the Dyspro- biochemical assessment of the severity of teinemias. Sunderman, F. W., and Sunderman, the disease was poor and not of particular F. W., Jr., eds. Philadelphia, J. B. Lippincott prognostic value. Co., 1964, pp. 346-350. 3. M u r r a y -L y o n , I. M ., M in c h in C l a r k e , H. G., M c P h e r s o n , K., and W il l ia m s , R.: Quan Viral Hepatitis titative immunoelectrophoresis of serum pro teins in cryptogenic cirrhosis, alcoholic cir Peters and Ashcaval4 studied the im rhosis and active chronic hepatitis. Clin. Chim. munoglobulin levels in the detection of Acta 39:215-220, 1972. viral hepatitis in order to determine the 4. P e t e r s , R. L. and A s h c a v a l , M.: Immuno globulin levels in detection of viral hepatitis. usefulness of serum immunoglobulin Amer. J. Clin. Path. 54:102-109, 1970. quantitation in screening for occult viral 5. P o w e l l , L. W., M o r t im e r , R., and H a r r is , hepatitis, evaluating the course of viral O. D.: Cirrhosis of the liver: A comparative study of the four major aetiological groups. hepatitis and for distinguishing serum Med. J. Australia. 1:941-950, 1971. hepatitis from infectious hepatitis. Of the 6. S h e r l o c k , S .: Diseases of the Liver and patients studied throughout the course of Biliary System. Oxford, pp. 30-35, 1975. 7. Su n d e r m a n , F. W. and Su n d e r m a n , F. W., viral hepatitis, there was a fairly charac Jr.: Clinical applications of the fractionation of teristic immunoglobulin response charac serum proteins by paper electrophoresis. terized by an initial elevation of IgM Amer. J. Clin. Path. 27:125-128, 1957. 8. S u n d e r m a n , F. W., Jr.: Recent advances in level followed by an elevation of IgG clinical interpretation of electrophoretic frac levels. However, Peters and Ashcaval tionations of the serum proteins. Serum Pro considered this response a non-specific teins and the Dysproteinemias. Sunderman, F. W., and Sunderman, F. W., Jr., eds. Philadel response, reflecting only the patient’s phia, J. B. Lippincott Company, 1964, pp. immunologic reaction to an inflammatory 323-345.