Blankenhorn first reported the icterus index to assess liver function in 1917.38,39 For the icterus index, the amount of bile pigment in serum was estimated on the basis of color change compared with an arbitrary color standard in a microcolorimeter. Normal icterus index scores ranged from 4 to 6, scores between 6 and 15 indicated latent jaundice, and scores above 15 indicated clinical icterus. In 1921 van den Bergh40 reported a method to qualitatively and quantitatively assess bilirubin in blood. In 1925 Wallace and Diamond41 developed a satisfactory quantitative method for estimating the amount of urobilinogen. Increased amounts of urobilinogen in urine were indicative of an advanced disease state and an increased amount of urobilinogen was the single most reliable identifier of advanced liver disease.42 Pioneers in the study of liver disease include Mann, Magath, Whipple, Greene, Boilman, Hooper, Van Den Bergh, Rous, McMasters, Ellmann, Graham, and Cole. These investigators have written illuminating chapters on experimental hepatic physiologic research.39

In 1927 Epstein et al.43 reported the rose bengal test (a dye clearance test) to assess liver function in disease states. By 1930 the role of the liver in normal metabolic functions and its regenerative ability had been established. In a consensus report, three tests were shown to be of clinical value in assessing liver function in liver disease patients: (1) the bromsulphalein dye test (a modified version of the rose bengal test); (2) the estimation of serum bilirubin levels (i.e., the icterus index and quantitative van den Bergh test); and (3) the estimation of urobilinogenuria. Bromsulphalein retention provided valuable confirmatory evidence of liver dysfunction and had been used in cases of liver disease not associated with jaundice, especially cirrhosis.39

In 1944 Higgins et al.44 investigated a cohort of 71 patients with liver disease of variable severity and validated the diagnostic and prognostic value of a liver function panel comprising serum bilirubin, albumin, protein, globulin, and phosphatase levels in distinguishing liver dysfunction from control and other disease states. The panel also included hippuric acid and laevulose tolerance tests. Changes in plasma protein levels were significant for liver disease.

In cases of hepatitis with jaundice, strong correlations between the time of jaundice presentation, changes in the albumin-to-globulin ratio, and prognosis were observed. Jaundice for more than 2 months and a plasma albumin level of less than 2 g/dL (plasma globulin level is commonly greater than 4 g/dL) were correlated with irreparable liver damage.45 A quantitative method for measuring serum alkaline phosphate was developed in 1934, although its first association with liver disease (obstructive jaundice) was described in 1939.46,47

Histochemical techniques to identify the source of this enzyme were first reported in 1942.48 ALT was first reported as an indicator of liver injury in 1960.49 Prolonged prothrombin time (PT) and hippuric acid were reported as markers of liver injury in patients with hepatosplenomegaly and hepatic amebiasis in an Egyptian patient population in 1947.50 In 1953 PT was recognized as a marker of hepatic insufficiency.51

Child and Turcotte52 first described a classification for hepatic function reserve in patients with cirrhosis in 1964; in 1981 this classification was shown to be a prognostic tool for portal hypertension in patients undergoing shunt surgery.53 This system comprises albumin, bilirubin, ascites, encephalopathy, and nutritional status. In 1973 nutritional status was replaced with PT by Pugh et al.54 Another model, the Model for End-Stage Liver Disease (MELD), was designed in 2000 on the basis of bilirubin level, international normalized ratio, and serum creatinine level to more objectively predict mortality in patients with cirrhosis and portal hypertension undergoing transjugular portosystemic shunt.55 Subsequently, this model was extensively validated in multiple cohorts of cirrhosis patients to predict mortality and was implemented as a tool to prioritize patients for liver transplantation in February 2002.56,57

In the last decade several noninvasive biochemical panels, models, and scores have been developed based on LFTs (AST, ALT, AP, albumin, and international normalized ratio) in conjunction with other parameters to assess hepatic fibrosis with a very high degree of certainty (discussed later in this chapter). Currently, with the availability of a wide array of tests, in addition to LFTs, clinicians can use to establish a precise etiologic diagnosis, disease stage, and prognosis in chronic liver disease patients with greater precision.

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