The aim of this report is not to review QLFTs, but to provide a critical appraisal of their extremely selective use. Widespread application of QLFTs as a prognostic tool is controversial. In a recent study, the predictive value of serial evaluations of GEC and MEGX on survival in a cohort of 35 patients was assessed, and secondarily, these tests were compared to Child-Pugh and Model for End Stage Liver Disease (MELD) scores. The end points were patient death or liver transplantation. Statistically significant differences between dead/transplanted patients and survivors were found for basal values of GEC, MEGX, Child-Pugh class and MELD score. Surprisingly, receiver operating characteristic (ROC) curves of Child-Pugh class and MELD score showed a higher prognostic accuracy than GEC and MEGX. On multivariate analysis, neither GEC nor MEGX were independent predictors of survival. Repeated-measures analysis of GEC and MEGX did not increase the prognostic accuracy of these tests, and did not add useful prognostic information on patient outcome during the following 6 mo. These data suggest that neither single nor repeated determinations of GEC and MEGX are superior to Child-Pugh class and MELD score in predicting prognosis of patients with viral cirrhosis[8].

Blood galactose clearance after an intravenous galactose load has been used widely as a QLFT. A novel QLFT, the galactose single point (GSP) method, has been developed to assess residual liver function in various diseases[9]. The goal of that study was to evaluate the influence of non-hepatic factors such as hyperglycemia on GSP and GEC in rats. Four groups of animal studies were carried out, i.e. normal control (NC), streptozotocin-induced diabetes mellitus (DM), CCl_4-induced hepatotoxicity (CCl₄), and streptozotocin-induced diabetes with CCl₄-induced hepatotoxicity (DM + CCl₄). The serum glucose levels in the diabetic groups (DM and DM + CCl₄) were significantly increased compared with those in the NC and CCl₄ groups. A significant increase of aspartate aminotransferase and alanine aminotransferase was observed in the CCl₄-treated groups (CCl₄ and DM + CCl₄) compared with those in the NC and DM groups. In comparison with the NC group, the values of GSP and GEC in the diabetic groups (DM and DM + CCl₄) were significantly reduced and increased, respectively. GSP had highly significant correlations with GEC. These results suggest that galactose metabolism tests should be interpreted with caution under conditions of significant hyperglycemia[9].

The unique ability of the liver to regenerate quickly after resection makes living donor liver transplantation (LDLT) possible. However, the quality and course of this regeneration process in humans are still unexplored. In a recent study, GEC, ICG and lidocaine half-life as markers for the quality of liver regeneration in the first 3 mo after LDLT were investigated. Twenty-two consecutive living liver donors and their corresponding recipients were analyzed at baseline and at 10 and 90 d after LDLT. Six recipients lost their grafts during the study period. We compared donors and recipients at the different time points. After LDLT, GEC decreased (-42.6%) and ICG increased (+50.6%) significantly in donors. ICG and GEC remained significantly altered over 3 mo in donors with an improvement between days 10 and 90. ICG and GEC improved significantly in recipients between days 10 and 90. The lidocaine half-life showed no significant changes. The donors had better test results and recovered faster than the recipients. In conclusion, after LDLT, the parameters for liver capacity and flow remain altered in donors and recipients despite rapid volume growth[10].

The key point of the whole problem is not how to test residual liver function but when. The ¹³C-methacetin (13C-M) breath test enables the quantitative evaluation of cytochrome-P450-dependent liver function. 13C-M is metabolized in the liver by O-demethylation to ¹³CO₂ and acetaminophen. The aim of a previous study was to evaluate the 13C-M breath test in comparison to the Child-Pugh class and other QLFTs (MEGX and ICG). 13C-M (2 mg/kg) was given orally to 31 patients with histologically proven liver cirrhosis of different etiology and severity (nine Child-Pugh class A, 13 class B, and nine class C). The increase of exhaled ¹³CO₂ was expressed as delta over baseline (DOB; delta/1000). All breath test parameters analyzed provided an excellent discrimination between cirrhotic and non-cirrhotic individuals. The DOB value at 20 min showed a superior correlation with the Child-Pugh class than did MEGX or ICG clearance results. With a cut-off value of ≤ 25 delta/1000 at 20 min, sensitivity and specificity to discriminate between cirrhotic and non-cirrhotic individuals was 93.5% and 95%, respectively[11].

To find out whether this breath test is sensitive in non-cirrhotic patients who also have chronic hepatitis C in the early stages of fibrosis, the following study was carried out. Eighty-one patients with chronic hepatitis C underwent a 13C-M breath test. In all patients, a liver biopsy was performed. The liver histology was classified according to the histology activity index-Knodell score. Patients with early fibrosis did not differ in DOB values from patients at 15 min (23.2 ± 7.9 per thousand vs 22.6 ± 7.2 per thousand; P = 0.61), or cumulative recovery (13.6% ± 3.7% vs 13.2% ± 3.8%; P = 0.45) from patients with more advanced fibrosis. Conclusively, the noninvasive 13C-M breath test fails to detect early stages of fibrosis in patients with chronic hepatitis C[12].

The 13C-caffeine (13C-C) breath test is a noninvasive, QLFT that is considered to be a valid tool by many authorities. The utility of the 13C-C breath test was measured in 48 patients with chronic hepatitis B and 24 controls, along with its ability to monitor response to lamivudine. In 28 patients on lamivudine, 13C-C breath tests were performed at 1 wk and 1 year after therapy. Patients with Metavir F0-1 fibrosis had a 13C-C breath test similar to the controls. However, patients with F2-3 fibrosis and cirrhosis patients had a decreased 13C-C breath test. Fibrosis correlated best with the 13C-C breath test. The 13C-C breath test independently predicted significant (F ≥ 2) and advanced (F ≥ 3) fibrosis and yielded the greatest area under the ROC curve (0.91 ± 0.04) for predicting advanced fibrosis. The 13C-C breath test was unaltered by 1 wk of lamivudine but improved by 61% (P < 0.001) in responders to long-term lamivudine, whereas in those with viremia and elevated alanine aminotransferase, values remained stable or deteriorated. The 13C-C breath test distinguishes chronic hepatitis-B-virus-related fibrosis and detects improvement in liver function in response to long-term lamivudine[13].

Caffeine clearance (CCl) has been suggested as a more exact method than those commonly used. The aim of the following study was to assess the usefulness of CCl in survival prediction of patients with liver cirrhosis. Thirty-four patients with cirrhosis of varying etiology were included: 19 were Child-Pugh class A or B and 15 were class C. CCl was determined from saliva samples. The mean length of follow-up was 33.8 mo. A bivariant survival analysis was carried out following the Kaplan-Meier method, together with a multivariate analysis using the Cox proportional hazards model. Twelve patients died during follow-up. CCl values < 0.24 mL/kg per minutes, age > 60 years, and non-alcoholic cause of cirrhosis were factors predicting lower survival. CCl was the only independent predictive factor in the multivariate analysis. The authors concluded that that CCl enables hepatologists to predict survival in cirrhotic patients and, considering its harmlessness, simplicity and cost, it can be used as a routine procedure in the assessment of these patients[14].

A simplification of this test, the so-called Total Overnight Salivary Caffeine Assessment (TOSCA), comes from an other study[15] with a further application (patients divided into rapid and slow metabolizers). Furthermore, TOSCA shows near complete safety (patients drink one or two cups of coffee according their habit in the morning). One drawback of QLFTs is the possible occurrence of severe side effects that are sometimes life-threatening (e.g. anaphylaxis).

Magnetic resonance imaging (MRI) offers several advantages. Gadolinium methoxybenzyl diethylenetriamine penta-acetic acid is a newly developed MR contrast agent. Its hepatic extraction fraction is a direct, noninvasive technique for the quantitative evaluation of liver function. It may be a promising alternative, although expensive, for the determination of noninvasive hepatic function in patients with liver disease[16].

Whether and to what extent does antiviral therapy for chronic hepatitis C influence a broad panel of QLFTs? Fifty patients with chronic hepatitis C were treated with interferon (n = 8), interferon/ribavirin (n = 19) or peg-interferon/ribavirin (n = 23). Quantitative testing of liver function, including ABT, GEC, sorbitol clearance (SCl) and ICG clearance was performed before and 3 mo after initiation of antiviral therapy. After 3 mo, 36 patients showed normal transaminases and were negative for hepatitis C virus RNA, and 14 patients did not respond to therapy. ABT and GEC as parameters of microsomal and cytosolic liver function were reduced in all patients before therapy initiation and returned to normal values in the 36 therapy responders after 3 mo. Parameters of liver perfusion (SCl and ICG) were not affected by antiviral therapy. In the 14 non-responders, no changes in QLFT values were observed during the treatment period. ICG and SCl remained unaffected in patients with chronic hepatitis C, while ABT and GEC were significantly compromised. ABT and GEC normalized in responders to antiviral therapy. Early determination of ABT and GEC may differentiate responders from non-responders to antiviral treatment in hepatitis C[17].

Improvement of nitrogen balance is desirable in patients with acute or chronic illness. Both growth hormone and insulin-like growth factor-I are promising anabolic agents, and their combined administration has been shown to reverse catabolism more efficiently than each of the peptides alone. The capacity of urea-nitrogen synthesis [&mgr;mol/(min × 100 g body weight)] was evaluated in rats, unravelling a neglected QLFT, based on mitochondrial-cytosolic metabolic capacity (M-CMC) for conversion of amino-nitrogen[18]. Following this approach, the authors used GEC to assess hepatocyte cytosol activity, plasma clearance of ICG to assess excretory function, antipyrine clearance to estimate microsomal activity, and functional hepatic nitrogen clearance to assess M-CMC in females with Turner syndrome[19].

Finally, 13C-C, a noninvasive tool for the evaluation of the cytochrome P450 system, which is implicated in the development of NASH, has been proposed in patients with metabolic dysfunction. Up-to-date research has demonstrated that 13C-C can predict reliably severe hepatic fibrosis in patients with the most severe form of non-alcoholic fatty liver disease (NAFLD). Although this test does not quantify the residual functional liver mass, it is safe and easy to perform. Further large-scale studies are needed to verify its reliability[20]. A previous study that tested 13C-M and ¹³C-ketoisocaproate for microsomal and mitochondrial liver function has demonstrated its usefulness for better and noninvasive characterization of patients with NAFLD[21]. It is worth stressing that every breath test can be affected badly by severe restrictive lung disease, and in elderly patients with chronic heart failure[22].

Unfortunately, MRI findings of liver steatosis and fibrosis in NASH show moderate correlations with histopathological grade of steatosis and stage of fibrosis, but MRI findings of NASH do not demonstrate any significant correlations with MELD score[23]. Liver scintigraphy (SPECT) might be a promising noninvasive tool in the follow-up of NASH patients in therapeutic trials[24].