Compensated liver cirrhosis: Natural course and disease-modifying strategies

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.

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.

Table 3 Impact of non-selective beta-blockers on portal hypertension, variceal haemorrhage, decompensation, and survival in patients with liver cirrhosis

Ref.	Study population	Intervention	Study design	Sample size, n	Study conclusion
Poynard et al[70], 1991	LC patients with oesophageal varices	Propranolol, nadolol vs placebo	Meta-analysis of 4 RCTs	589	Both propranolol and nadolol were effective in preventing first VH and reducing the mortality associated with VH
Tripathi et al[71], 2009	LC patients with grade II or more varices	Carvedilol vs EVL	RCT	152	On intention-to-treat analysis, carvedilol had lower rates of the first VH compared to EVL (10% vs 23%)
Gluud et al[69], 2012	LC patients with high-risk varices without prior VH	NSBBs vs EVL	Meta-analysis of 19 RCTs	1504	Both EVL and NSBB reduced VH (RR: 0.69 and 0.67) without difference in mortality rates
Sinagra et al[75], 2014	LC patients with PHT	Carvedilol vs propranolol	Meta-analysis of 5 studies	175	Carvedilol reduced PHT significantly more than propranolol
Bhardwaj et al[76], 2017	LC patients with small varices	Carvedilol vs placebo	RCT	140	Carvedilol is safe and effective in delaying the progression of small to large oesophageal varices in LC patients
Zacharias et al[77], 2018	Adults with LC and varices	NSBBs	Meta-analysis of 10 RCTs	810	Carvedilol was more effective at reducing the HVPG. However, it was not better than traditional NSBBs with regard to the mortality, VH, or adverse events
Malandris et al[72], 2019	LC patients requiring primary or secondary prevention of VH	Carvedilol, NSBBS, EVL	Meta-analysis of 13 RCTs	1598	Carvedilol was as efficacious and safe as standard-of-care interventions for the primary and secondary prevention of VH. Also, carvedilol was associated with lower all-cause mortality compared to EVL
Sharma et al[73], 2019	LC patients with large oesophageal varices and no prior history of VH	NSBB, isosorbide-mononitrate, carvedilol, and EVL alone or in combination	Meta-analysis of 32 RCTs	3362	NSBB monotherapy decreased all-cause mortality and the risk of first VH. Additionally, NSBB carried a lower risk of serious complications compared with EVL
Villanueva et al[22], 2019	CLC patients and CSPH	Propranolol, carvedilol vs placebo	RCT	201	Long-term treatment with β blockers could increase decompensation-free survival in patients with CLC with CSPH, mainly by reducing the incidence of ascites
Villanueva et al[78], 2022	LC patients with CSPH	Carvedilol vs EVL/no treatment	Meta-analysis of 4 RCTs	352	Long-term carvedilol therapy reduced decompensation and significantly improved survival

CLC: Compensated liver cirrhosis; CSPH: Clinically significant portal hypertension; EVL: Endoscopic variceal ligation; HVPG: Hepatic venous portal gradient; LC: Liver cirrhosis; NSBBs: Non-selective beta-blockers; PHT: Portal hypertension; RCT: Randomised controlled trial; RR: Relative risk; VH: Variceal haemorrhage.