Predictions from a hard liver
Article Outline
- 1. Introduction
- 2. Does size matter?
- 3. Non-invasive predictors of varices
- 4. May liver stiffness measurement predict risk of bleeding, of hepatic decompensation and of death?
- Acknowledgements
- References
- Copyright
1. Introduction
That cirrhosis is characterized by increased liver stiffness was recognized some millenniums ago. Generations of physicians have tried hard to feel it when examining a patient with an enlarged liver. A hard liver, an enlarged spleen, the presence of abdominal collaterals and spider angioma, and the finding of a reduced platelet count, low albumin and prolonged PT were the hallmarks for the diagnosis of cirrhosis in compensated patients until the advent of modern imaging methods. It took until 2003 to translate the “feeling” that a liver was hard into an objective, numerical measurement, easy to obtain in a totally non-invasive way [1]. This has thereafter been proved useful in assessing the presence of significant fibrosis in patients with chronic hepatitis [2] and in suggesting the presence of cirrhosis [2], [3]. This concept can be extended in the sense that increased liver stiffness is likely to reflect the structural abnormalities that are responsible, by and large, for the increased hepatic vascular resistance that leads to portal hypertension in cirrhosis [4]. This is supported by the recent observation by Carrion et al. [5] that liver stiffness measurement reflects both the extent of fibrosis and the elevation of hepatic venous pressure gradient in recurrent hepatitis C after liver transplantation. Altogether these observations suggest that increased liver stiffness can be a useful surrogate of fibrogenesis and of increased portal pressure in cirrhosis. If this is so, then it is logical to ask the question of whether liver stiffness may represent a non-invasive surrogate for complications of portal hypertension in patients with cirrhosis.
This question is nicely addressed in the current issue of the Journal by the study of Kazemi et al. [6], who further elaborate in the potential of liver stiffness measurements to predict the presence of oesophageal varices in patients with compensated cirrhosis. Their data show that the finding of a liver stiffness value above 19
kPa may predict the presence of large oesophageal varices. At this point it is worth reminding that up to the 2000 Baveno III Consensus Conference it was accepted that only patients with moderate/large varices should receive prophylactic treatment to reduce the risk of variceal bleeding [7]. Accordingly, Kazemi et al. propose that fibroscan measurements can be used to select patients for endoscopy. Those with a liver stiffness value below 19kPa, approximately 43% of their cohort, would not require endoscopy since the likelihood of presenting varices grades II and III would be of less than 10%, while over this value approximately 60% will have moderate/large varices. Before accepting this suggestion, we have to answer the question of:
2. Does size matter?
It has been customary in most guidelines and consensus recommendations to state that prophylactic treatment for portal hypertension should be reserved to patients with moderate/large varices [8]. The recommendation is based on the fact that most prophylactic studies showing the benefit of therapy with non-selective β-blockers were conducted in these patients, while the benefit was not obvious in the subgroup with small varices (in the trials that identified this subgroup) [8]. Therefore, this is an instance in which lack of specific information was taken as evidence of lack of effect. However, classification of the size of varices is a bit subjective, and there have been difficulties in subjectively differentiating “moderate” from either “small” or “large” varices, to the point that since Baveno I [9] the recommendation has been to classify varices only as small and large (evidently with not much success).
The concept that therapy should be restricted to large varices (or to moderate/large varices) has been challenged by two facts. The first is the results of the careful RCT by Merkel et al. demonstrating that nadolol therapy prevents the progression of varices and bleeding in patients with small varices [10]. The second is the reconsideration of the pioneer NIEC study [11], that showed that risk of bleeding (under no treatment) was independently associated not only with the size of the varices, but also with the presence of red wale marks (RWM), as well as with the Child-Pugh class. As shown in Fig. 1, in each Child-Pugh category, the risk of bleeding was almost identical in patients with small varices with RWM as in those with large varices without RWM. It is equally evident that small varices in a Child-Pugh C patient have a high bleeding risk, independent of the presence of RWM. In other words, size matters only when varices are small, have no RWM and the patient is not in Child class C. This is not trivial, since 40% of all bleeds during follow-up in this study were observed in patients from the low risk group [11].
Fig. 1.
Small varices with RWM have same risk of bleeding as large varices without RWM, in any Child-Pugh class (red circles). Small varices in Child C patients have high bleeding risk, independent of presence of RWM. Constructed with data from NIEC, NEJM (1988)(11).
This was taken into consideration in the conclusions from the Baveno IV Consensus Conference, when it is stated that: “Patients with small varices with red weal signs or of Child class C have an increased risk of bleeding and may benefit from treatment” [12].
Then, the issue is no longer to be able to identify patients with moderate/large varices, but all patients with varices. Availability of effective prophylactic treatments plies that patients with cirrhosis should be screened for the presence of varices, since treatment before the development of varices has not been proven effective [13]. This raises the issue of which screening system shall be used, if any [14], [15].
3. Non-invasive predictors of varices
It is without any doubt that at present, the best way of assessing the presence and severity of varices is by means of endoscopy. The problem is that endoscopy is expensive and if done without deep sedation, unpleasant for the patient. Acceptability and duration of endoscopy have been much improved by the advent of capsule endoscopy [16], which would be the ideal method if its cost could be reduced substantially and if its initial promising results in detecting and assessing the size of varices are confirmed in larger, multicenter studies. Meanwhile, strategies of selection based on simple (but much less specific) methods have been proposed. All attempts are based on the use of surrogates of portal hypertension. Thus, different studies have suggested to restrict endoscopy to decompensated patients, to those with enlarged spleen, thrombopenia, dilated portal vein, collaterals on US examination, or a platelet/spleen size ratio >909 [14].
Can prediction be more accurate by using measurements of liver stiffness? Apparently no, since when comparing the accuracy of liver stiffness with that of these other methods, the only advantage for liver stiffness (in terms of better C statistic) was observed when compared with spleen size (but not over platelet/spleen size ratio or over a low platelet count). Again, all these comparisons were on the basis of detecting “large” varices, not varices per se.
When considering measurements of liver stiffness as predictors of varices of any size, the problems that emerge are even greater. First, the specificity of the prediction was low, of only 39–43%, which leads to a substantial amount of uncertainty when using this method. Second, the liver stiffness cut off for detection of varices of any size was of 13.9kPa, which is difficult to reconcile with the fact that the same group fixed at 14.5kPa the cut off for detecting cirrhosis [2] and with the statement that in the current series all patients had “histologically proven cirrhosis”. Does it mean that the previously reported cut off for cirrhosis should be markedly reduced? Were some patients without histological cirrhosis inadvertently included in their current series? Third, endoscopies were performed by four experienced operators, but there was no effort at making more objective the assessment (no video recordings were obtained, there were no double observers for each endoscopy, no assessment of the degree of agreement between the four endoscopists), which is relevant in view of the subjective assessment of size of varices, especially when differentiating no varices from varices size 1 (defined as “thin varices vanishing with the endoscopic blowing”). Fourth, the findings were not validated in an independent sample, as it should (of note, the present study represents additional validation for the platelet count/spleen index ratio) [17].
Altogether, these problems create a substantial amount of uncertainty that decreases enthusiasm with the use of liver stiffness measurements to select patients for endoscopy. It is doubtful in view of the above that many screening endoscopies could be obviated using these cut off values in an independent series of patients. This by no means should be taken as an argument against the virtues of this non-invasive method, which can be extremely helpful in other situations [2], [3], [5]. I merely underline the fact that the findings of this study are preliminary and should be confirmed in an independent sample (preferably on a multicenter basis). From the data available, measurement of liver stiffness may not be good enough at detecting varices as to delay endoscopy in patients diagnosed to have cirrhosis. Besides, delaying endoscopy until a patient is likely to have large varices may not be the best approach given the fact that a substantial part of bleeds will occur in patients classified as “low risk” [11], [12].
4. May liver stiffness measurement predict risk of bleeding, of hepatic decompensation and of death?
It is clear from the above that prediction of varices of any size from liver stiffness measurements overlaps with the prediction of cirrhosis. However it would be interesting (and important!) to assess whether in patients with cirrhosis/varices, a more pronounced – or progressive – increase in liver stiffness may reflect an increased bleeding risk, and why not, an increased risk of hepatic decompensation and death. It is my gut feeling that it may well be so.
At this point the reader may think that this suggestion is at odds with my previous considerations. It is my task to defend that it is not necessarily so: even if not that accurate in predicting size of varices, liver stiffness measurement may still reflect the risk of bleeding. Risk of bleeding is not only influenced by variceal size, but also by presence of red weal signs and degree of liver failure/decompensation (Fig. 1). Additional support came from our recent observations that the degree of liver stiffness correlates with the magnitude of portal pressure elevation in recurrent hepatitis C after liver transplantation [5], and that the latter is an excellent prognostic marker of clinical decompensation in these patients [18] (which, in turn, is a major determinant of death) [14], [19]. Therefore, it would be interesting if Kazemi et al. (and/or other groups) may look at their patients after a longer follow-up to verify this hypothesis. Of course, this would not be easy, since such study will face several confounding factors (prophylactic treatments, aetiology, development of hepatocellular carcinoma, liver transplantation policy…). Still, it can be done and may be worth trying.
In summary, available evidence suggests that liver stiffness measurements are strongly associated with the presence of cirrhosis and with progression of the disease. However, these measurements are no better than previously reported indices, such as platelet count/spleen size index, in predicting the presence of moderate/large varices. Thus, it is not yet the time to modify the Baveno IV Consensus Statements: “There are no satisfactory non-endoscopic indicators of the presence of varices”; “While further studies are awaited, endoscopic screening is still the best practice to detect varices”, and “All cirrhotic patients should be screened for varices at diagnosis” [12]. Unfortunately, a hard liver does not allow but soft conclusions with regard to the presence of varices. Nevertheless, it may be that measuring “how hard this liver is” can provide robust data on the risk of decompensation, bleeding and death.
Acknowledgements
The author is indebted to Dr. J.G. Abraldes for useful suggestions and to Ms Maria Montaño for her help in preparing the manuscript. This work has been supported by grants from the Plan Nacional de I+D, Instituto de Salud Carlos III (C03/02, PI04-0655 and PI05-1285).
References
- Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol. 2003;29:1705–1713
- Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology. 2005;41:48–54
- Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut. 2006;55:403–408
- . Increased hepatic resistance: a new target in the pharmacologic therapy of portal hypertension. J Clin Gastroenterol. 2005;39(4 Suppl 2):S131–S137
- Carrion JA, Navasa M, Bosch J, Bruguera M, Gilabert R, Forns X. Transient elastography for diagnosis of advanced fibrosis and portal hypertension in patients with hepatitis C recurrence after liver transplantation. Liver Transpl 2006 (in press).
- Liver stiffness measurement selects patients with cirrhosis at risk of bearing large oesophageal varices. J Hepatol. 2006;45:230–235
- . Updating consensus in portal hypertension: report of the Baveno III Consensus Workshop on definitions, methodology and therapeutic strategies in portal hypertension. J Hepatol. 2000;33:846–852
- Primary prophylaxis for variceal bleeding. In: deFranchis R editors. Portal hypertension. Proceedings of the fourth Baveno International Consensus Workshop on Methodology of Diagnosis and Treatment. Oxford: Blackwell-Science; 2005;p. 168–200
- . Developing consensus in portal hypertension. J Hepatol. 1996;25:390–394
- A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis. Gastroenterology. 2004;127:476–484
- The North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices (NIEC). Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. N Engl J Med 1988; 319:983–989.
- . Evolving Consensus in Portal Hypertension. Report of the Baveno IV Consensus Workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol. 2005;43:167–176
- Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med. 2005;353:2254–2261
- Predictive models in portal hypertension. In: deFranchis R editors. Portal hypertension. Proceedings of the fourth Baveno International Consensus Workshop on Methodology of Diagnosis and Treatment. Oxford: Blackwell-Science; 2005;p. 47–100
- . Endoscopic screening or empiric beta-bloquers for prophilaxis of variceal bleeding?. In: deFranchis R editors. Portal hypertension. Proceedings of the fourth Baveno International Consensus Workshop on Methodology of Diagnosis and Treatment. Oxford: Blackwell Publishing; 2005;p. 131–133
- The accuracy of PillCam ESO capsule endoscopy versus conventional upper endoscopy for the diagnosis of esophageal varices: a prospective three-center pilot study. Endoscopy. 2006;38:31–35
- . Noninvasive markers of esophageal varices: another round, not the last. Hepatology. 2004;39:30–34
- Hepatic venous pressure gradient identifies patients at risk of severe hepatitis C recurrence after liver transplantation. Hepatology. 2006;43:492–499
- . Esophageal varices: from appearance to rupture; natural history and prognostic indicators. In: Groszmann RJ, Bosch J editor. Portal Hypertension in the 21st Century. Dordrecht: Kluwer Academic Publishers; 2004;p. 147–154
PII: S0168-8278(06)00287-X
doi:10.1016/j.jhep.2006.06.002
© 2006 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
