The clinical course of cirrhosis encompasses several disease states which require multistate models and competing risks analysis for proper assessment.
ReviewClinical states of cirrhosis and competing risks
Introduction
Cirrhosis is typically classified as compensated or decompensated, based on the absence or presence (or previous history) of variceal bleeding, ascites, jaundice or encephalopathy.[1], [2], [3] The significantly longer survival, usually symptomless, and better quality of life experienced by patients with compensated cirrhosis compared to those with decompensated cirrhosis, has brought about the concept that compensated and decompensated cirrhosis are distinct clinical states of the disease.[4], [5] Further disease states have been identified according to the presence of oesophageal varices and to the presence of only one or more disease complications.[4], [6], [7], [8], [9], [10]
Development of gastro-oesophageal varices and decompensation usually do not occur below the portal pressure threshold of clinically significant portal hypertension (CSPH) defined by hepatic venous pressure gradient (HVPG) ≥10 mmHg.[11], [12], [13] Increasing portal pressure, bacterial translocation, inflammation and hyperdynamic circulation are likely mechanisms of decompensation,14 which progresses to a late decompensation state characterised by further worsening of liver function associated with other organ dysfunction, while acute-on-chronic liver failure (ACLF) may occur in any disease state. Histological stages15 of cirrhosis also parallel the progression of portal hypertension[16], [17] and clinical states of the disease.[18], [19]
This body of evidence supports a multistate approach to the clinical course of cirrhosis, which implies a specific statistical methodology, since the Kaplan-Meier (KM) survival curves[20], [21] may not capture clinical state transitions following the occurrence of a competing event, before the event of interest. For example, decompensation before death is not captured by a survival curve of compensated cirrhosis. In this situation, the cumulative incidence function (CIF), based on the Aalen-Johansen estimator allows a more realistic description of the disease course, by providing the incidence of the competing events.[22], [23], [24]
Herein, the clinical course, competing risks and clinical states of cirrhosis will be reviewed and examples of possible multistate models of the disease will be provided.
Section snippets
The clinical course of cirrhosis
Cirrhosis may result from chronic liver inflammation from any cause, following parenchymal necrosis, activated fibrogenesis, angiogenesis and profound vascular changes. Increased hepatic resistance to blood flow, derived from both mechanical obstacle and vasoconstriction resulting from endothelial dysfunction and hepatic stellate cells contraction, gradually leads to portal hypertension. The ensuing adaptive splanchnic vasodilation further contributes to aggravate portal hypertension and
Clinical states in cirrhosis
Several clinical conditions associated with significantly different outcomes have been proposed as relevant clinical states during the course of the disease[4], [5], [8], [10], [14], [106], [107] (Fig. 1). However, it is notable that there is no predictable sequence of such clinical states and that they may not be considered as progressive disease stages. However, clinical states enable the classification of patients according to increasing mortality risk. Moreover, assessing transitions across
Management implications of clinical states of cirrhosis
Recognising different clinical states may have important implications on the most likely clinical outcomes. Hence, clinical states may be used to inform treatment interventions to prevent disease progression. In fact, there is evidence that in compensated patients without varices (state 1) the most appropriate approach is aetiological treatment, particularly in those with MPH (state 0) in whom NSBBs do not appreciably reduce portal hypertension.[13], [97] In these patients, non-invasive
Competing risks in cirrhosis
A competing risk is the risk of an event whose occurrence either precludes the occurrence of another event or modifies the probability that it will occur. Along the clinical course of cirrhosis, many clinical conditions, or states, may be characterised by competing outcomes which require competing risks analysis to correctly assess the relevant risks. Several such conditions are shown (Table 1), where examples of outcomes of interest are reported together with potentially relevant competing
Competing risks analysis
Recognising competing risks is important because, in the presence of competing risks, the KM estimator21 invariably results in upward biased estimates.[22], [23], [24], [135] Competing risks analysis is based on the CIF which, by using the Aalen-Johansen estimator,23 partitions the probability of any event into the probabilities that each event occurs first, resulting in an overall event probability (or the sum of the probabilities of each event) correctly ranging from zero to one. The
Building multistate models in cirrhosis
Clinical states should be conceived as a flexible concept and specific clinical states should be defined whenever a specific prognostic question makes it appropriate (Table 1). As an example, in the same study of the clinical course of cirrhosis referred to earlier,10 the 20-year cumulative probability of death (1-KM) was 0.62, in 377 patients with compensated cirrhosis, and 0.93 after decompensation in 224 patients who developed decompensation during the follow-up (Fig. 4A). However, in
Competing risks and clinical research
As shown in previous sections in this article, the most obvious field of application for competing risks analysis is the study of the clinical course of diseases in every situation where relevant competing risks are identified.
A second relevant field where competing risks should be appropriately accounted for is prognosis research. A major aim of this type of research is to find accurate predictors of a disease outcome in a given time. The hypothesis underlying this research is that one or more
Conclusions
The clinical spectrum of cirrhosis encompasses several clinical states, from a very early state of compensated cirrhosis with subclinical portal hypertension, to the late decompensation state with extreme hyperdynamic circulation, bacterial translocation and inflammation. The progression across such states does not occur through a predictable sequence, because of the variable interplay between pathophysiological mechanisms. Therefore, a multistate approach provides a more realistic description
Financial support
P. Rebora was supported by the grant of the Italian Minister of Education, University and Research (MIUR) – Italy SIR 2014 (RBSI14LOVD).
Conflict of interest
The authors declare no conflicts of interest that pertain to this work.
Please refer to the accompanying ICMJE disclosure forms for further details.
Authors’ contribution
Gennaro D’Amico: review concepts and project, data collection, elaboration of examples, text and figures. Alberto Morabito: statistical concepts and data analysis for examples. Mario D’Amico: data collection; cohort study for the examples included in the review; text revision. Linda Pasta: responsible for the cohort study used for the examples included in the review. Giuseppe Malizia: review project and text revision. Paola Rebora: statistical concepts, examples and text revision. Maria Grazia
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