Summary Background Morphological, haemodynamic and clinical stages of cirrhosis have been proposed, although no definite staging system is yet accepted for clinical practice. Aim To investigate whether clinical complications of cirrhosis may define different prognostic disease stages. Methods Analysis of the database from a prospective inception cohort of 494 patients. Decompensation was defined by ascites, bleeding, jaundice or encephalopathy. Explored potential prognostic stages: 1, compensated cirrhosis without oesophago‐gastric varices; 2, compensated cirrhosis with varices; 3, bleeding without other complications; 4, first nonbleeding decompensation; 5, any second decompensating event. Patient flow across stages was assessed by a competing risks analysis. Results Major patient characteristics were: 199 females, 295 males, 404 HCV+, 377 compensated, 117 decompensated cirrhosis. The mean follow‐up was 145 ± 109 months without dropouts. Major events: 380 deaths, 326 oesophago‐gastric varices, 283 ascites, 158 bleeding, 146 encephalopathy, 113 jaundice, 126 hepatocellular carcinoma and 19 liver transplantation. Patients entering each prognostic stage along the disease course were: 202, stage 1; 216, stage 2; 75 stage 3; 206 stage 4; 213 stage 5. Five‐year transition rate towards a different stage, for stages 1–4 was 34.5%, 42%, 65% and 78%, respectively (P < 0.0001); 5‐year mortality for stages 1–5 was 1.5%, 10%, 20%, 30% and 88% respectively (P < 0.0001). An exploratory analysis showed that this patient stratification may configure a prognostic system independent of the Child–Pugh score, Model for End Stage Liver Disease and comorbidity. Conclusion The development of oesophago‐gastric varices and decompensating events in cirrhosis identify five prognostic stages with significantly increasing mortality risks.

The clinical course of cirrhosis is mostly determined by the progressive increase of portal hypertension, hyperdynamic circulation, bacterial translocation and activation of systemic inflammation. Different disease states, encompassing compensated and decompensated cirrhosis and a late decompensated state, are related to the progression of these mechanisms and may be recognised by haemodynamic or clinical characteristics. While these disease states do not follow a predictable sequence, they correspond to varying mortality risk. Acute-on-chronic liver failure may occur either in decompensated or in compensated cirrhosis and is always associated with a high short-term mortality. The increasing severity of these disease states prompted the concept of clinical states of cirrhosis. A multistate approach has been considered to describe the clinical course of the disease. Such an approach requires the assessment of the probabilities of different outcomes in each state, which compete with each other to occur first and mark the transition towards a different state. This requires the use of competing risks analysis, since the traditional Kaplan-Meier analysis should only be used in two-state settings. Accounting for competing risks also has implications for prognosis and treatment efficacy research. The aim of this review is to summarise relevant clinical states and to show examples of competing risks analysis in multistate models of cirrhosis.

Propranolol and nadolol are effective in preventing first bleeding and reducing the mortality rate associated with gastrointestinal bleeding in patients with cirrhosis, regardless of severity.

The clinical course of cirrhosis has been typically described by a compensated and a decompensated state based on the absence or, respectively, the presence of any of bleeding, ascites, encephalopathy or jaundice. More recently, it has been recognized that increasing portal hypertension and several major clinical events are followed by a marked worsening in prognosis, and disease states have been proposed accordingly in a multistate model. The development of multistate models implies the assessment of the probabilities of more than one possible outcome from each disease state. This requires the use of competing risks analysis which investigates the risk of several competing outcomes. In such a situation, the Kaplan-Meier risk estimates and the Cox regression may be not appropriate. Clinical states of cirrhosis presently considered as suitable for a comprehensive multistate model include: in compensated cirrhosis, early (mild) portal hypertension with hepatic venous pressure gradient (HVPG) >5 and <10 mmHg, clinically significant portal hypertension (HVPG ≥ 10 mmHg) without gastro-esophageal varices (GEV), and GEV; in decompensated cirrhosis, a first variceal bleeding without other decompensating events, any first non-bleeding decompensation and any second decompensating event; and in a late decompensation state, refractory ascites, sepsis, renal failure, recurrent encephalopathy, profound jaundice, acute on chronic liver failure, all predicting a very short survival. In this review, we illustrate how competing risks analysis and multistate models may be applied to cirrhosis.

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We studied thrombophilic genetic factors (TGFs) MTHFR C677TT, PAI1 4G-4G, V Leiden Q506, prothrombin G20210A as risk factors in 94 patients with HCC with and without portal vein thrombosis (PVT), compared with 214 patients with liver cirrhosis (LC) with and without PVT and 94 healthy controls (HC). The OR (95% CI) for MTHFR C677TT with HCC was 3.85 (1.55-7.39) vs. HC. The OR for PAI1 4G-4G in HCC, was 2.87 (1.27-6.55) vs. HC. Also prothrombin G20210A was significantly more frequent among HCC, mainly in patients with PVT, while V Leiden factor was equally distributed among HCC and HC. Differences were more significant in patients with associated PVT. These findings suggest that frequently TGFs are needed for patients to be at risk of HCC and PVT. We conclude that in all patients with chronic liver disease TGF screening should be performed to individuate patients at risk of HCC and PVT.

␤-Blockers and sclerotherapy prevent long-term upper digestive rebleeding in cirrhosis but they seem ineffective for early rebleeding. We compared octreotide with a placebo for the prevention of early rebleeding in cirrhotic patients. After control of acute upper digestive bleeding, 262 consecutive cirrhotic patients were randomized to octreotide 100 g subcutaneously three times a day for 15 days (n ‫؍‬ 131) or to the placebo (n ‫؍‬ 131), in a double blind pragmatic trial in which ␤-blockers and/or sclerotherapy were allowed together with the experimental treatment. Separate randomization and analysis were performed according to whether patients were eligible for ␤-blockers and/or sclerotherapy (101 placebo, 97 octreotide) or not (30 placebo, 34 octreotide). Rebleeding within 15 days was the primary measure of treatment efficacy; 6-week rebleeding rate was also assessed as a secondary measure. Fifteen-day cumulative proportions of patients rebleeding were 28% in the placebo group and 24% in the octreotide group (P ‫؍‬ .40); corresponding figures among the 198 patients eligible to ␤-blockers and/or sclerotherapy were 26% and 16% (P ‫؍‬ .05) and among the 64 not eligible for these treatments 33% and 49% (P ‫؍‬ .29). Among patients eligible to ␤-blockers and/or sclerotherapy, a significant reduction of rebleeding episodes (35 vs. 18, P ‫؍‬ .03), blood transfusions (75 vs. 50, P ‫؍‬ .04), and days of stay in hospital (1,544 vs. 1,190, P ‫؍‬ .0001) was also found in the octreotide group: this beneficial effect was confirmed 6 weeks after randomization. Following upper digestive bleeding in cirrhosis, almost 50% of patients rebleed and 30% die within 6 weeks.

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