New Characteristics of Liver Gvhd: Kinetics, and the Serum Levels of Enzymes Linked to Cholestasis

Acute GVHD is usually reported by stages or grades based on the extent of organ(s) involvement. For liver GVHD, the classical parameter is bilirubin. Recently, so called hepatitic variant was described, characterized by elevations of serum aminotransferases levels (ALT or AST >10 of upper normal limit, UNL). However, liver GVHD has its onset and dynamics of evolution before reaching the diagnostic values and these parameters have not been studied in details. Moreover, crucial histological feature of liver GVHD is damage of small bile ducts, which may increase plasma levels of other two easily measurable liver enzymes, gamma glutamyl transferase (GGT) and alkaline phosphatase (ALP). Surprisingly, also this has not been systematically studied.

Methods. We identified the cases of liver GVHD (based on bilirubin and/or aminotransferases levels) and carefully selected only those, where the diagnosis was definite and there were no other potential reasons for elevations of bilirubin or liver enzymes. GVHD episode was defined as the number of days from the time of fulfilling the laboratory diagnostic criteria for GVHD (bilirubin, and/or ALT and/or AST) to the decrease to the values <2 UNL. For all tests (bilirubin, ALT, AST, GGT or ALP), we also selected the day, from which there was a continuous increase in that particular parameter, and measured the time interval: start of increase - definite GVHD. For hospitalized patients, the laboratory parameters were usually measured daily or every other day. Moreover, for every GVHD episode, 5 areas under the curves (AUC) were calculated, each considering one laboratory parameter. Integral mean (AUC divided by the duration of GVHD episode) then characterizes the average increase in a particular parameter during the GVHD episode. We also measured the GGT and ALP values at the end of GVHD episode.

Results. There were 47 GVHD episodes in 26 patients. Usually, the episode started and ended with the same parameter(s) (e.g. bilirubin-bilirubin, ALT, ALT), however, in 2 episodes, the starting and ending parameter was different, and in 4 cases, the identification of the episode end was impossible for continuous increase in that particular parameter. Some combined patterns were also seen (e.g. start: ALT, AST, bilirubin; stop: bilirubin). The minimal, maximal, and median length of GVHD episodes were: total length: (2, 415, 24), for bilirubin only: (0, 415, 10), for ALT: (0, 157, 13), and for AST: (0, 54, 0). Integral means for bilirubin, ALT, AST, GGT, and ALP were (medians) 1.7, 4.4, 1.6, 8, and 1.1, respectively (expressed as xUNL), which shows, that GGT is the most sensitive marker of liver damage. The number of GVHD episodes, where the systematic increase in laboratory parameters was seen before reaching the GVHD values, and the minimum, maximum, and median length of that increase, were as follows: bilirubin (39; 0, 70, 1), ALT (28; 0, 71, 12), AST (9; 0, 72, 12), GGT (34; 0, 70, 9), and ALP (13; 0, 57, 14). At the end of GVHD episode, GGT was 5.6xUNL (median) and ALP 0.7xUNL (median).

Conclusion. Liver GVHD is not a static process. It can develop extremely quickly, however, on the other hand, also very slowly over about 2 months. Continuous increase in bilirubin or liver enzymes is the sign of imminent liver GVHD. GGT seems to be the most sensitive and dynamic marker of liver involvement. In significant proportion of patients, GGT is not normal at the end of GVHD episode and probably signifies residual disease activity. Several questions arise from this study:

1. Early intervention before reaching the GVHD criteria?

2. Is there different treatment response, or a necessity of different treatment strategies for fulminate or smoldering GVHD?

3. Importance of subclinical liver GVHD?