Liver cirrhosis

Liver cirrhosis is the final stage of many chronic liver diseases: viral hepatitis B and C, alcoholic liver disease, non-alcoholic steatohepatitis, autoimmune hepatitis, primary biliary cholangitis, storage disorders (Wilson disease, haemochromatosis). According to WHO, cirrhosis is among the leading causes of mortality from digestive disease. Clinical features include portal hypertension (ascites, oesophageal varices), hepatic failure (jaundice, coagulopathy, encephalopathy), spider angiomas, and endocrine disturbances. Standard therapy is aetiological (antiviral, alcohol cessation), with hepatoprotectors, diuretics, lactulose for encephalopathy, beta-blockers for varices. End-stage care is liver transplantation. Cell therapy is considered a way to act on fibrogenesis in compensated and subcompensated cirrhosis, slowing progression and improving function.

Cirrhosis claims approximately 1.3 million lives globally each year. The aetiological structure has shifted significantly over the past decade. Following the registration of direct-acting antivirals (DAA), hepatitis C has ceased in many countries to be the leading cause — sustained virologic response is achieved in over 95% of cases and is often accompanied by partial fibrosis regression. Metabolically associated fatty liver disease (MAFLD/NASH) and alcoholic liver disease have moved to the top in Europe and North America; against the obesity and T2D epidemic, MAFLD growth is particularly rapid. In Asia, HBV remains the dominant cause despite mass vaccination. Autoimmune and hereditary causes together account for about 10–15%. Prognosis depends on stage: 5-year mortality in compensated cirrhosis is about 10%, in decompensated cirrhosis 50% or higher; the average interval from first decompensation to death without transplantation is 1–5 years.

Cirrhosis pathogenesis converges, regardless of aetiology, on activation of hepatic stellate cells (Ito cells, HSCs). Normally these cells reside in the space of Disse, store vitamin A, and regulate extracellular matrix. With repeated hepatocyte injury (viral, toxic, metabolic, autoimmune), HSCs transdifferentiate into myofibroblasts under TGF-β1, PDGF, inflammatory chemokines, and oxidative stress products. Activated myofibroblasts overproduce type I and III collagen, fibronectin, and laminin, and disrupt the matrix metalloproteinase (MMP-2, MMP-9) / TIMP balance. Chronic ECM accumulation distorts lobular architecture; regenerative nodules and fibrous septa form. Architectural rearrangement leads to portal hypertension — portosystemic collaterals (oesophageal and gastric varices), ascites via splanchnic vasodilation and secondary hyperaldosteronism, and hepatic encephalopathy through ammonia accumulation. Functional hepatocyte mass declines: synthesis of albumin and clotting factors falls; jaundice, coagulopathy, and endocrine disturbances develop. The stage is set for the final act — hepatocellular carcinoma (HCC), with annual cirrhosis-related risk of 1–5%.

Modern standard care for cirrhosis is multistep. The first and obligatory line is aetiological therapy. In HCV cirrhosis, pangenotypic DAA regimens (sofosbuvir/velpatasvir, glecaprevir/pibrentasvir) deliver SVR >95% even at Child-Pugh A–B; a subset of patients show partial fibrosis regression on elastography after sustained response. In HBV cirrhosis, tenofovir (TAF) and entecavir are first-line for long-term suppression, with first-year fibrosis regression. In alcohol-related disease the only effective measure is complete abstinence; addiction-medicine support and pharmacotherapy of dependence (naltrexone, acamprosate, disulfiram) are integrated into management. In MAFLD/NASH — 7–10% weight loss, control of T2D and dyslipidaemia, GLP-1 agonists, and the recently approved resmetirom (THR-β agonist) specifically for NASH with F2–F3 fibrosis. Symptomatic decompensation management: salt restriction + diuretics for ascites, non-selective beta-blocker (carvedilol, propranolol) for primary and secondary variceal bleeding prophylaxis, lactulose + rifaximin for encephalopathy, albumin + terlipressin for hepatorenal syndrome. HCC screening — ultrasound + alpha-fetoprotein every 6 months. End-stage management is liver transplantation, but waiting lists are long; donor allocation follows MELD. Standard care does not reverse advanced fibrosis in most aetiologies, and regenerative therapy is regarded as the missing component.

Mesenchymal cell therapy acts directly on cirrhosis pathogenesis. Following intravenous administration, UC-MSCs and placenta-derived MSCs migrate into the liver via the SDF-1/CXCR4 chemotactic gradient and over several weeks function as a source of paracrine factors: inhibiting hepatic stellate cell activation through HGF, BMP-7, and TGF-β blockers; inducing apoptosis of activated myofibroblasts through TRAIL; raising matrix metalloproteinase activity and partially degrading accumulated collagen; stimulating proliferation of surviving hepatocytes; restoring sinusoidal microcirculation and lowering portal hypertension. The fundamental RCT of Shi and colleagues (Hepatology International, 2021) in 219 patients with HBV-associated decompensated cirrhosis demonstrated significantly higher overall survival in the UC-MSC group versus controls over 13–75 months of follow-up; albumin, prothrombin activity, cholinesterase, and total bilirubin all improved. The 2023 systematic review (Stem Cell Research & Therapy) consolidated 11 trials with reproducible improvements in Child-Pugh, MELD, and quality of life. The 2025 dose-escalation trial in Signal Transduction and Targeted Therapy showed that intravenous infusion of 300–600 million MSCs over 3 weeks improved liver function in 88.9% of patients and quality of life in 100% with no serious adverse events.

The Hanshi United programme for cirrhosis comprises three intravenous procedures of UC-MSC or placenta-derived MSCs at 15–20 day intervals. Optimal candidates are patients with compensated (Child-Pugh A) or subcompensated (Child-Pugh B) cirrhosis without active decompensation. Aetiological therapy is mandatory: HCV must be fully eradicated, HBV DNA suppressed below detectable level, alcohol abstinence for at least 6 months, MAFLD with stable weight and metabolic control. Liver enzymes, albumin, INR, total bilirubin, creatinine, and elastography are monitored at baseline, 3, and 6 months. In decompensated Child-Pugh C cirrhosis or MELD >20, the course is considered only in a specialised hepatology setting after stabilisation of ascites, variceal bleeding prophylaxis, and encephalopathy control. Hepatocellular carcinoma at any stage is an absolute contraindication, as MSCs may support tumour growth via paracrine factors; ultrasound + AFP are mandatory before the course.