Clinical Pathology Approaches to Hepatic Injury

Abstract

Testing the blood for evidence of hepatic damage and dysfunction frequently involves measuring several blood constituents simultaneously to screen for disease. While useful, this approach occasionally leads to apparent disparities between the blood test results, and the results of other diagnostic tests such as histology. In part, these perceived discrepancies may stem from a lack of appreciation for tissue, cellular, and molecular factors that affect the appearance of hepatic disease biomarkers in the blood. Further confusing the matter is that in some instances the mechanisms responsible for the appearance of diagnostic compounds in blood are only partially understood. Many of the known factors that affect hepatic biomarkers are similar to those affecting other tissue markers, while others are unique to the liver, such as those involved with cholestasis. Disease conditions can also cause misleading results by affecting tissue concentrations of test compounds, hepatic mass, and the clearance rate of compounds from the blood. Knowledge of the factors affecting the blood concentrations of biomarkers, as well as investigations into the mechanisms behind changes to hepatic biomarker concentrations, may allow for a better interpretation of blood test results and fewer inconsistencies between diagnostic results.

Effects of Hepatic Drug-metabolizing Enzyme Induction on Clinical Pathology Parameters in Animals and Man

“…Distinguishing among these conditions is generally not possible based on circulating ALT activity alone. However, reversible or less extensive injury is generally associated with changes of smaller magnitude than irreversible or widespread cellular injury (Lassen 2004;Solter 2005). Increases in serum ALT activity are not liver specific, as increased serum ALT has been reported following strenuous exercise or severe muscle necrosis in dogs and restraint in cynomolgus monkeys (Center 2007;Landi et al 1990;Solter 2005;Valentine et al 1990).…”

Liver Hypertrophy

“…Based on the recommendations of regulatory authorities, (EMEA 2010;FDA 2009;HED 2002) increases in ALT activity of two-to threefold should be considered as indicative of hepatocellular damage. Distinguishing irreversible and reversible liver injury is pragmatically dealt with by assessing the magnitude of the transaminase elevation where minimal and reversible hepatic injury is commonly accompanied by small increases in transaminase levels of less than twofold (Kramer et al 2003;Lassen 2004;Peterson et al 2004;Satoh et al 1982;Solter 2005). However, considerably larger ALT increases in humans (30-to 100-fold of the upper limit of normal) can also be accompanied by full recovery of hepatic function (Koch et al 1997).…”

The Correlation of Serum Transaminase Values with Fibrosis Staging and Necroinflammatory Activity Scores in Chronic Hepatitis

“…In cre a sed se rum ALT le vel has the hig hest sen si ti vity (80 % to 100 %) for inf lamma ti on, nec ro sis, va cu o lar he pa to pathy and primary ne op la si a. 19 Com pa red with ALT, AST is mo re sen si ti ve but less spe ci fic for de tec ti on of he pa tic di se a se. AST is nor mally fo und in a di ver sity of tis su es inc lu ding liver, he art, musc le, kid ney, and bra in.…”

“…Thus, whi le ad van cing fib ro sis in ju res the si nu so i dal cells, it may re sult in an ad di ti o nal AST in cre a se. [19][20][21][22] The mec ha nism of in cre a se in AST le vels du e to he pa tocy te in jury is par ti ally un ders to od. Most of the AST in he pa tocy tes is lo ca ted in mi toc hondri a, whe re as ALT is exc lu si vely lo ca ted in cytop - AST is re le a sed from the he pa tocy te mi tochon dri al AST com part ments as a con se qu en ce of mo re se ve re he pa to cel lu lar da ma ge.…”

“…For examp le, it was shown in rat li ver that, isc he mic cells with mini mal loss of in teg rity, re sul ting in the for ma ti on of mem bra ne blebs only, do not lo se mitochondrial AST. 19 In fact, isc he mic li ver do es not lo se mi tochon dri al AST (mAST) un til al most all cyto so lic AST (cAST) is lost. Mar ked ele va ti ons in AST ac ti vity are sug ges ti ve of mo re se ve re he pa to cel lu ler da ma ge and ir re ver sib le he pa tocy te in jury with re le a se of mAST sto res.…”