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Abstract
Compensated liver cirrhosis (CLC) is defined as cirrhosis with[out] one or more decompensating events, such as ascites, variceal haemorrhage, or hepatic encephalopathy. Patients with CLC are largely asymptomatic with preserved hepatic function. The transition from CLC to decompensated cirrhosis occurs as a result of a complex interaction between multiple predisposing and precipitating factors. The first decompensation event in CLC patients is considered a significant turning point in the progression of cirrhosis, as it signals a drastic decline in median survival rates from 10-12 years to only 1-2 years. Furthermore, early cirrhosis has the potential to regress as liver fibrosis is a dynamic condition. With the advent of effective non-invasive tools for detecting hepatic fibrosis, more and more patients with CLC are currently being recognised. This offers clinicians a unique opportunity to properly manage such patients in order to achieve cirrhosis regression or, at the very least, prevent its progression. There are numerous emerging approaches for preventing or delaying decompensation in CLC patients. A growing body of evidence indicates that treating the underlying cause can lead to cirrhosis regression, and the use of non-selective beta-blockers can prevent decompensation by lowering portal hypertension. Additionally, addressing various cofactors (such as obesity, diabetes, dyslipidaemia, and alcoholism) and precipitating factors (such as infection, viral hepatitis, and hepatotoxic drugs) that have a detrimental impact on the natural course of cirrhosis may benefit patients with CLC. However, high-quality data must be generated through well-designed and adequately powered randomised clinical trials to validate these disease-modifying techniques for CLC patients. This article discussed the natural history of CLC, risk factors for its progression, and therapeutic approaches that could alter the trajectory of CLC evolution and improve outcomes.
Keywords: Compensated cirrhosis, Compensated advanced chronic liver disease, Clinical decompensation, Cirrhosis reversal, Disease-modifying agents, Acute-on-chronic liver failure
Core Tip: Compensated liver cirrhosis might be reversible if the underlying cause is treated before the disease progresses. The median survival for these individuals is typically 10-12 years; however, after the first decompensation, it drastically drops to 1-2 years. As a result, the outcomes of such patients can be significantly improved by integrating a number of disease-modifying therapy strategies that address complex pathophysiology, risk factors, and triggering events linked with disease progression. This article discussed the natural course of compensated liver cirrhosis, risk factors for its progression, and potential therapeutic strategies to favourably influence its natural evolution and enhance outcomes.
INTRODUCTION
The prevalence and mortality associated with liver cirrhosis (LC) continue to increase despite improvements in knowledge and medical care. According to data from the United States, the annual number of LC-related deaths has risen by 65%, while the number of hospitalisations for LC has nearly doubled in a decade[1,2]. LC has traditionally been regarded as a singular entity with a continuum of increasing degrees of severity until death or liver transplantation. Recently, these paradigms have shifted, leading to the recognition of LC as a heterogenous condition with varying prognosis across the different stages[3,4]. The term “compensated liver cirrhosis” (CLC) is used to describe LC without one or more decompensating events, such as ascites, hepatic encephalopathy, variceal haemorrhage (VH), and jaundice[5]. After experiencing a decompensation event, LC patients are always classified as decompensated LC (DLC) because the pathogenic mechanisms that caused the decompensation persist. When LC patients were separated into two groups based on decompensating events, the median 1-year survival in CLC patients was 95% compared to 61% in DLC patients[6]. Therefore, the first decompensation in CLC patients is regarded as a prognostic watershed due to a substantial reduction in median survival from 10-12 years in CLC to only 1-2 years in DLC[6].
LC has long been viewed as the end stage of chronic liver disease (CLD). However, this perception has started to shift in the past two decades. Wanless et al[7] were the first to describe the reversal of LC, and since then numerous series of LC patients with diverse aetiologies have demonstrated the same[7,8]. Patients with CLC remain asymptomatic and undiagnosed for the first few years[9]. Despite being asymptomatic, between one-third and one-half of CLC patients have varices and clinically significant portal hypertension (CSPH) at the time of diagnosis[10–12]. Over time, CLC patients develop several risk factors that increase their susceptibility to clinical decompensation, such as rising portal pressure, systemic inflammation, and haemodynamic changes. Moreover, certain triggers including bacterial infection, medications, or alcohol can acutely precipitate decompensation. When the underlying cause of CLC is eliminated early on, a significant proportion of patients experience cirrhosis regression[7,8].
Even when regression of LC is not possible, there are variety of evolving strategies for preventing or delaying decompensation in such patients. Therefore, the prognosis of such patients can be greatly enhanced by early diagnosis of CLC. However, the medical community has predominantly focused its efforts on managing and improving the outcomes for patients with DLC, with little attention given to the medical management of CLC. In order to enhance the ease of diagnosis of advanced CLD noninvasively using transient elastography, the Baveno VI consensus introduced the new term “compensated advanced CLD” that encompasses CLC and CLD with advanced fibrosis[13]. Due to efficient noninvasive testing tools, more and more LC patients are now being recognised at an early compensated stage[14]. This offers the gastroenterologists and hepatologists greater opportunities to intervene and alter the trajectory of the natural evolution of CLC. This article discussed the natural history of CLC, risk factors for its progression and decompensation, and potential therapeutic strategies to change the course of the illness and improve the outcomes.
NATURAL HISTORY OF CLC
The natural progression of LC is characterised by a continuum from a long silent compensated phase to a more progressive symptomatic decompensation phase (Figure 1). As LC progresses over time, patients develop a variety of risk factors, including altered liver architecture, portal hypertension (PHT), systemic inflammation, and haemodynamic alterations that increase the risk for clinical decompensation. Decompensation may occur insidiously due to slowly increasing portal pressure and deteriorating hepatic function, often referred to as non-acute decompensation (AD)[5]. However, different triggering events, such as bacterial infection, alcohol, bleeding, medications, or a flare-up of liver disease, can lead to AD within days, which may progress to acute-on-chronic liver failure (ACLF). In patients with CLC, decompensation represents a turning point in terms of mortality risk, patient quality of life, and propensity for hospitalisation.
Natural course of patients with compensated liver cirrhosis. The natural progression of cirrhosis is characterised by a continuum from an asymptomatic compensated phase to a symptomatic decompensation phase. The rate of transition from a compensated to a decompensated stage is about 5%-7% each year. The 5-year mortality rate in compensated cirrhosis without or with varices is 5% and 10%, respectively. There are several known factors associated with decompensation such as high portal pressure, persistent etiological injury, systemic inflammation, and haemodynamic alterations. In addition, several types of triggering events, such as bacterial infection, alcohol, viral hepatitis, or medications, may cause acute decompensation (AD) and acute-on-chronic liver failure (ACLF). Prompt and effective control of etiological factors are associated not only with regression of compensated cirrhosis but also with recompensation of decompensated cirrhosis (data adapted from references 3, 6, 18, and 31). CLC: Compensated liver cirrhosis; DM: Diabetes mellitus; HBV: Hepatitis B virus; HCV: Hepatitis C virus; LT: Liver transplantation.
In a systematic review, pooling of data from relevant studies, revealed that the survival of patients with LC varied from 1 mo to 186 mo, with a median survival > 12 years for CLC and 1.8 years for DLC[6]. The rate of transition from a compensated to a decompensated stage is approximately 5%-7% each year[15]. Ascites is typically the first sign of decompensation in most studies. Overall, the 5-year mortality rate in CLC patients is only 1.5% for those without CSPH, 5.0% for those with CSPH but no varices, and 10.0% for those with CSPH and varices, highlighting the significance of PHT in mortality risk[3]. Therefore, CLC patients without varices and without CSPH constitute a highly compensated group with a very low mortality risk[6].
The first decompensation of CLC does not always indicate a point of no return in the natural course of LC. Emerging data suggests that although it is an uncommon occurrence, recompensation of DLC is possible if the underlying cause of LC is suppressed[16]. Recompensated cirrhosis is indeed a real condition, and the Baveno VII consensus has provided a standard definition for it[17]. Similarly, it is now more widely acknowledged that CLC can regress to a non-cirrhotic stage when etiological factors are promptly controlled[7,18]. Liver fibrosis is a dynamic condition, and early LC, which lacks extracellular matrix crosslinking and marked angiogenesis, can even revert into normal architecture[19].
FACTORS ASSOCIATED WITH DECOMPENSATION OF CLC
The transition from CLC to DLC occurs as a result of a complex interaction between predisposing and precipitating factors (Table 1). The development of PHT is the key factor causing the switch from CLC to DLC[10,20–22].
Table 1.
Factors associated with decompensation of compensated liver cirrhosis
Risk factors for non-acute decompensation
Precipitating factors for acute decompensation
Thick fibrous septa and micronodularity on liver biopsy Bacterial infection Persistent liver injury by etiological factor Active alcoholism High portal pressure Gastrointestinal haemorrhage Systemic inflammation & hemodynamic changes Consumption of hepatotoxic drug/alternative medicine Metabolic risk factors: DM, obesity, and dyslipidaemia Superinfection or flare of viral hepatitis Genetic risk factors: PNPLA3 G/G genotype Major surgery and general anaesthesia DM: Diabetes mellitus; PNPLA3: Patatin-like phospholipase domain-containing protein 3.
In a study, patients with a hepatic venous pressure gradient (HVPG) < 10 mmHg had a 90% probability of not developing clinical decompensation over 4 years. As the HVPG rises above 10 mmHg, which signifies CSPH, the risk of decompensation begins to rise[10]. VH typically occurs when HVPG is higher than 12 mmHg[15]. Another study found that CLC with a baseline HVPG > 20 mmHg had a 47% risk of decompensation in mean duration of just 1.6 years[21]. There is also growing evidence that long-term use of non-selective beta-blockers (NSBBs) significantly reduces the risk of decompensation[22]. Thick fibrous septa and small nodules observed in liver biopsy specimens of CLC patients are associated with CSPH and an increased risk of decompensation[23–25]. Ongoing liver damage caused by etiological factors also increases the risk of decompensation. This is supported by the finding that attaining a sustained virological response (SVR) in hepatitis C virus (HCV)-cirrhosis and maintaining viral suppression in hepatitis B virus (HBV)-cirrhosis significantly lowers the incidence of decompensation[26–29]. The neurohormonal and inflammatory alterations in LC contribute to decompensation in the form of ascites by causing splanchnic vasodilatation and lymphatic dysfunction[30–32].
Several metabolic factors have also been found to influence the risk of decompensation[33–36]. CLC patients with diabetes have a higher risk of developing any decompensating event than those without diabetes[33]. Obesity has a negative impact on the natural course of CLC, regardless of aetiology, and increases the risk of decompensation[34]. Sarcopenia and myosteatosis, which are common in CLD with various aetiologies, appear to promote the progression of CLD to advanced stages[35]. Another study found that the PNPLA3 G/G genotype, involved in triacylglycerol hydrolysis, was associated with a 2-fold increase in the probability of decompensation[36]. Gut dysbiosis, characterised by a loss of beneficial commensals and an increase in pathogenic organisms, significantly influences the natural course of LC patients[36–40]. Furthermore, cirrhosis-associated immune dysfunction, involving both immune deficiency and proinflammatory immune cell activation, contributes to haemodynamic disturbances and PHT, accelerating the development of decompensation[41–43].
Bacterial infection can cause AD by escalating the intensity of systemic inflammation and PHT. In a large prospective study of 1672 patients with compensated HCV-related or HBV-related cirrhosis, bacterial infections preceded and precipitated decompensation in 13% of patients over a 5-year period[44]. Overall, bacterial infection is considered to be the most frequent precipitant of AD (22%-29%) and ACLF (33%-50%)[45]. Alcoholic hepatitis can cause decompensation in patients with CLC through various mechanisms[46,47]. AD and ACLF frequently develop in patients with LC undergoing surgery[48]. In a study using an animal model of CLC, it was discovered that extrahepatic surgery raises the portal pressure during the postoperative period, leading to decompensation[49]. Other situations where decompensation can develop in patients with CLC include superimposed viral hepatitis, consumption of hepatotoxic medications, and vascular thromboses[50].
DISEASE-MODIFYING TREATMENT STRATEGIES
The present strategy for managing patients with LC is centred on strategies intended to avoid or treat complications, without giving much thought to their effects on the natural history of LC. There is a need to pay more attention to agents that target key points in the complex pathophysiology of LC. The ideal goal of a disease-modifying medication should be the regression or reversal of cirrhosis. If this is not possible, the next goal should be to prevent or at least delay the progression of the disease. Growing evidence suggests that addressing the underlying cause of LC and reducing PHT by NSBB have positive impacts on the natural history of patients with CLC[7,8,22,26,29]. Moreover, such patients may potentially benefit from addressing a number of cofactors and precipitating factors that have a negative influence on the natural course of LC[51]. Thus, effective disease-modifying treatment strategies might include: (1) Removal of etiological factors; (2) Pathophysiology-oriented therapy; (3) Management of adverse cofactors like obesity, DM, dyslipidaemia, and alcoholism; (4) Anti-fibrotic and regenerative therapies; and (5) Elimination of precipitating factors that lead to AD/ACLF.
Removal of etiological factors
The main prerequisite for fibrosis regression is the cessation of liver injury, which is accomplished through therapeutic control of causal factors. Regression of LC has been extensively described in patients with HBV-related and HCV-related cirrhosis after aetiological treatment (Table 2). Nevertheless, robust data supporting the regression of non-viral causes of LC are generally lacking.
Table 2.
Impact of etiological treatment on regression of liver cirrhosis
Ref.
Study design
Drug/duration
Patients, n
Baseline LC
Main results
Dienstag et al[26], 2003 Prospective, partially randomised Lamivudin/3 yr 63 CHB 11 LC regressed in 8 of 11 patients (73%) Hadziyannis et al[27], 2006 Prospective Adefovir dipivoxil, up to 240 wk 125 CHB 4 58% had reversal of bridging fibrosis/cirrhosis; 3 of 4 LC patients had reversal Marcellin et al[29], 2013 Randomised trial TDF/adefovir for 48 wk then open-label TDF 641 CHB 96 71 of 96 (74%) became non-cirrhotic at 5 yr Poynard et al[52], 2002 Pooled data from RCTs IFN/PEG-IFN + RBV 3010 CHC 153 The reversal of LC was observed in 75 patients (49%) Mauro et al[53], 2018 Retrospective DAAs/IFN + RBV 112 HCV-infected LT recipients 37 Regression of fibrosis in 43% of LC (16/37) Lassailly et al[55], 2020 Prospective Bariatric surgery 180 obese NASH 9 At 5 yr, fibrosis regression was seen in 68% of advanced fibrosis and 33% of patients had reversal of LC Sanyal et al[54], 2022 Data from two RCTs Simtuzumab or selonsertib or placebo 1135 NASH patients, 709 (62%) had Ishak stage 6 fibrosis 709 LC regression occurred in 16% (176/1135). Drugs were not better than placebo Dufour et al[64], 1997 Retrospective Immunosuppressant 8 AIH cirrhosis 8 LC regressed in all Czaja et al[63], 2004 Retrospective Corticosteroid 87 AIH 14 LC regressed in 4 of 14 patients Bardou-Jacquet et al[66], 2020 Retrospective Venesection 106 patients with haemochromatosis 66 LC regressed in 15 of 66 (23%) during median follow-up of 9.5 yr AIH: Autoimmune hepatitis; CHB: Chronic hepatitis B; CHC: Chronic hepatitis C; DAAs: Direct-acting antivirals; HCV: Hepatitis C virus; IFN: Interferon; LC: Liver cirrhosis; LT: Liver transplantation; NASH: Nonalcoholic steatohepatitis; PEG-IFN: Pegylated interferon; RBV: Ribavirin; RCT: Randomised controlled trial; TDF: Tenofovir disoproxil fumarate.
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