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We read with great interest the article by Giannini et al on platelet count/spleen diameter ratio or platelets alone as predictors of oesophageal varices (Gut 2003;52:1200–5).
As the incidence of chronic liver diseases is growing, we are convinced that the development of non-invasive predictive tools to identify cirrhotic patients with oesophageal varices is of major interest. Several markers have been studied, and among them platelet count is commonly reported to be a good predictor of oesophageal varices. However, in the eight studies already published,1–8 their discriminative power was moderate, with areas under the receiver operating curve (ROC) of 0.70 or less for platelets alone4 and for indexes combining platelets with other markers.1,4,5 Most of these studies included heterogeneous groups of patients, with compensated and decompensated cirrhosis.
In our unit, we performed prospectively platelet count and screening upper oesogastroduodenoscopy on the same day in 41 patients with compensated cirrhosis and confirmed the moderate value of platelet count alone (AUROC = 0.70 (0.07); Thabut, data not shown). The major drawback of platelet count is that it can depend on factors other than portal hypertension in cirrhotic patients. To avoid this bias, Giannini et al developed an index based on platelet count/spleen diameter ratio and found far better results than previous studies, with a c index (equivalent to the area under the ROC) of 0.92 for patients with compensated liver cirrhosis. However, we were surprised to see that the use of platelets/spleen diameter ratio did not add significant discrimination to platelet count alone (c index of 0.92 v 0.88) in their population.
On this point, their excellent results could not be explained by the discriminative power of their index but by the excellent diagnostic power of platelet count alone in their series. Several explanations can be raised, and one is the high rate of viral related cirrhosis in their patients where platelet count is less liable to variations compared with, for example, in alcoholic patients. This point is of major concern for the further validation of their index, recommended by the authors themselves, in other populations.
In conclusion, Giannini et al have found a very good index for predicting the presence of oesophageal varices in cirrhotic patients. We believe that the excellent results they obtained were not due to their index but to the surprisingly good performance of platelet count alone in their patients. Considering the results for platelet count as a predictor of oesophageal varices in previously published studies, we fear that the warranted validation studies of this index will show less exciting results.
We thank Thabut et al for their interesting comments on our paper (Gut 2003;52:1200–5). Indeed, their letter allows us to focus on some aspects of our study that we feel need to be emphasised further.
As a general rule, a surrogate marker for a given variable (that is, presence/absence of oesophageal varices) that already has a definite diagnostic procedure (that is, endoscopy) should fulfil two major criteria. Firstly, it should be the product of a thorough statistical analysis and secondly, but no less importantly, it has to be biologically plausible.
From a statistical point of view, as Thabut et al correctly point out, both platelet count and the platelet count/spleen diameter ratio showed excellent diagnostic accuracy for the non-invasive diagnosis of the presence/absence of oesophageal varices. However, we do not agree with their assumption that the use of the platelet count/spleen diameter ratio did not add significant discrimination to the use of platelet count alone. In fact, the accuracy of the platelet count/spleen diameter ratio for the diagnosis of oesophageal varices was not only better than that of platelet count alone but was also significantly so. Briefly, in the cohort of 145 patients with compensated cirrhosis, which is the group that most likely benefits from screening, the difference between the AUC-ROC of the platelet count/spleen diameter ratio and platelet count was 0.041 (0.013–0.070), with p = 0.005 in favour of the platelet count/spleen diameter ratio. Moreover, in the whole cohort of 266 patients, the platelet count/spleen diameter ratio had a c index of 0.902 (95% confidence interval 0.860–0.935) while platelet count alone had a c index of 0.839 (0.790–0.881), with a difference between AUC-ROC of 0.063 (0.038–0.088) (p = 0.001). Furthermore, the platelet count/spleen diameter ratio was the only parameter significantly associated with the presence/absence of oesophageal varices in a multivariate analysis that also included platelet count. Lastly, as recently highlighted, the negative predictive power of a non-invasive parameter used to predict the absence/presence of oesophageal varices is a fundamental clinical concern.1 In fact, for such a tool to be adopted in clinical practice it has to achieve a negative predictive value of 100% although maintaining an acceptable positive predictive value. This would preserve the safety of the parameter (that is, virtual absence of missing a diagnosis) and keep a satisfactory cost-efficacy profile. In practice, in our study the use of the platelet count/spleen diameter ratio fulfilled these criteria while platelet count alone did not.
Biological plausibility is a not a secondary concern for the clinician. As we emphasised in our paper and recently demonstrated,2 and as Thabut et al also pointed out, the presence of thrombocytopenia in patients with liver cirrhosis is likely a multifactorial event.3 Therefore, the use of platelet count to diagnose a feature that depends on portal hypertension alone may lead to an increase in false positive results, thus decreasing the accuracy as well as the cost-efficacy of the diagnostic procedure. As highlighted in our paper, the use of the platelet count/spleen diameter ratio could bypass this inconvenience by “normalising” platelet count to the platelet count decrease effectively dependent on hypersplenism.
Lastly, some methodological issue should be taken into account when the two items of the ratio are singularly evaluated. On the one hand, the spleen diameter measurement should be performed by a skilled operator, and its results should have excellent accuracy and reproducibility. On the other hand, we have shown that the consistency of the ratio is maintained, even considering the expected mild fluctuations in platelet count commonly seen in cirrhotic patients during a limited period of time.
All in all, we did not presume to propose a diagnostic “magic bullet”, as is more and more commonly being proposed in clinical hepatology. We are well aware that the results we obtained have to be validated in independent series and/or in cohorts with different aetiologies of liver disease before being widely accepted,4 and in our paper we clearly stated the limitations of our study. However, our patient population is that which we commonly encounter in everyday clinical practice, and it is not very different from that seen in other parts of our country (that is, viral cirrhosis in approximately 70% of patients).5 Moreover, if we look outside our borders, we see that our population is not very different from others, viral aetiology of liver disease being the leading cause of liver transplantation in Europe during the period January 1998 to December 2001 (22 924 cirrhotic patients).6 Nevertheless, if we examine our data we see that the use of the platelet count/spleen diameter ratio performs equally good in the limited subset of patients with alcoholic cirrhosis (n = 53, platelet count spleen diameter ratio c index = 0.958, platelet count c index = 0.740, difference between AUC-ROC = 0.218; p = 0.001), although we feel that focusing on a specific subgroup of patients that does not reflect the true prevalence of the disease in the population would introduce bias.
In conclusion, we have proposed a new evaluation tool and called for validation of our method, being conscious that only differences in opinion that arise from results obtained in well conducted studies contribute to scientific progress, and most importantly that “life is short, and art long; the crisis fleeting; experience perilous, and decision difficult. The physician must not only be prepared to do what is right himself, but also to make the patient, the attendants, and externals cooperate”.7