Elsevier

The Lancet

Volume 383, Issue 9930, 17–23 May 2014, Pages 1749-1761
The Lancet

Seminar
Liver cirrhosis

https://doi.org/10.1016/S0140-6736(14)60121-5Get rights and content

Summary

Cirrhosis is an increasing cause of morbidity and mortality in more developed countries, being the 14th most common cause of death worldwide but fourth in central Europe. Increasingly, cirrhosis has been seen to be not a single disease entity, but one that can be subclassified into distinct clinical prognostic stages, with 1-year mortality ranging from 1% to 57% depending on the stage. We review the current understanding of cirrhosis as a dynamic process and outline current therapeutic options for prevention and treatment of complications of cirrhosis, on the basis of the subclassification in clinical stages. The new concept in management of patients with cirrhosis should be prevention and early intervention to stabilise disease progression and to avoid or delay clinical decompensation and the need for liver transplantation. The challenge in the 21st century is to prevent the need for liver transplantation in as many patients with cirrhosis as possible.

Introduction

Cirrhosis results from different mechanisms of liver injury that lead to necroinflammation and fibrogenesis; histologically it is characterised by diffuse nodular regeneration surrounded by dense fibrotic septa with subsequent parenchymal extinction and collapse of liver structures, together causing pronounced distortion of hepatic vascular architecture.1, 2 This distortion results in increased resistance to portal blood flow and hence in portal hypertension and in hepatic synthetic dysfunction. Clinically, cirrhosis has been regarded as an end-stage disease that invariably leads to death, unless liver transplantation is done, and the only preventive strategies have been screening for oesophageal varices and hepatocellular carcinoma.

Lately, this perception has been challenged, because 1-year mortality in cirrhosis varies widely, from 1% to 57%, depending on the occurrence of clinical decompensating events.3 Histopathologists have proposed that the histological term cirrhosis should be substituted by advanced liver disease, to underline the dynamic processes and variable prognosis of the disorder.4 Moreover, fibrosis, even in the cirrhotic range, regresses with specific therapy if available, such as antiviral treatment for chronic hepatitis B5 or C.6

Here, we review the current understanding of cirrhosis as a dynamic process and outline current therapeutic options for prevention and treatment of complications of cirrhosis, on the basis of the subclassification in clinical prognostic stages.3, 7 The new concept in management of patients with cirrhosis is the use of non-specific therapies for prevention and early intervention to stabilise disease progression and to avoid or delay decompensation and the need for liver transplantation.

Section snippets

Epidemiology

Cirrhosis is an increasing cause of morbidity and mortality in more developed countries. It is the 14th most common cause of death in adults worldwide but the fourth in central Europe; it results in 1·03 million deaths per year worldwide,8 170 000 per year in Europe,9 and 33 539 per year in the USA.10 Cirrhosis is the main indication for 5500 liver transplants each year in Europe.9 The main causes in more developed countries are infection with hepatitis C virus, alcohol misuse, and,

Pathophysiology

The transition from chronic liver disease to cirrhosis involves inflammation, activation of hepatic stellate cells with ensuing fibrogenesis, angiogenesis, and parenchymal extinction lesions caused by vascular occlusion.11 This process leads to pronounced hepatic microvascular changes, characterised by sinusoidal remodelling (extracellular matrix deposition from proliferating activated stellate cells resulting in capillarisation of hepatic sinusoids), formation of intrahepatic shunts (due to

Diagnosis

Most chronic liver disease is notoriously asymptomatic until cirrhosis with clinical decompensation occurs. Decompensating events include ascites, sepsis, variceal bleeding, encephalopathy, and non-obstructive jaundice. Imaging by ultrasonography, CT, or MRI of an irregular and nodular liver together with impaired liver synthetic function is sufficient for the diagnosis of cirrhosis. Other findings include small and shrunken liver, splenomegaly, and evidence of portosystemic collaterals.

Natural course

Cirrhosis should no longer be regarded as a terminal disease and the concept of a dynamic process is increasingly accepted. A prognostic clinical subclassification with four distinct stages has been proposed with substantially differing likelihoods of mortality: stage 1 (compensated with no oesophageal varices) has an estimated mortality of 1% per year, and stages 2 (compensated with varices), 3 (decompensated with ascites), and 4 (decompensated with gastrointestinal bleeding) have annual

Prevention and treatment of complications

The focus of this Seminar is on prevention and therapy in the initial stages of cirrhosis, including the first decompensating event.

Future therapies

Currently licensed drugs, such as non-selective β blockers, statins, oral antibiotics, and anticoagulants are likely to be used in various combinations to prevent and treat complications of cirrhosis in the near future.42, 132 Statins reduce HVPG and are associated with reduced incidence of hepatocellular carcinoma. Anticoagulation used to be considered a contraindication in cirrhosis; however, stable cirrhosis is characterised by normal thrombin generation and even hypercoagulability.133

Conclusions—future directions

Cirrhosis should no longer be considered as a single disease stage, because it has distinct clinical prognostic stages with substantial differences in 1-year survival.7 Preventive and therapeutic strategies are summarised in figure 5. Clinicians should try to diagnose advanced liver disease as early as possible and to prevent the progression to further clinical stages and the advent of complications. We have previously reviewed the potential expansion of current indications of widely used drugs

Search strategy and selection criteria

We searched Medline (2000–13) using the search term “liver cirrhosis”. We largely selected publications from the past 5 years, but we did not exclude highly relevant older publications. We selected further relevant publications from the reference lists of articles identified by this search strategy. Review articles and book chapters are cited to provide more details and references than can be cited here.

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