Liver cirrhosis

doi:10.1016/S0140-6736(08)60383-9

The Lancet

Volume 371, Issue 9615, 8–14 March 2008, Pages 838-851

https://doi.org/10.1016/S0140-6736(08)60383-9 Get rights and content

Summary

Cirrhosis is defined as the histological development of regenerative nodules surrounded by fibrous bands in response to chronic liver injury, which leads to portal hypertension and end-stage liver disease. Recent advances in the understanding of the natural history and pathophysiology of cirrhosis, and in treatment of its complications, have resulted in improved management, quality of life, and life expectancy of patients. Liver transplantation remains the only curative option for a selected group of patients, but pharmacological treatments that can halt progression to decompensated cirrhosis or even reverse cirrhosis are currently being developed. This Seminar focuses on the diagnosis, complications, and management of cirrhosis, and new clinical and scientific developments.

Introduction

Fibrosis describes encapsulation or replacement of injured tissue by a collagenous scar. Liver fibrosis results from the perpetuation of the normal wound-healing response, resulting in an abnormal continuation of fibrogenesis (connective tissue production and deposition). Fibrosis progresses at variable rates depending on the cause of liver disease, environmental factors, and host factors.1, 2, 3 Cirrhosis is an advanced stage of liver fibrosis that is accompanied by distortion of the hepatic vasculature. The resultant vascular distortion leads to shunting of the portal and arterial blood supply directly into the hepatic outflow (central veins), compromising exchange between hepatic sinusoids and the adjacent liver parenchyma—ie, hepatocytes. The hepatic sinusoids are lined by fenestrated endothelia that rest on a sheet of permeable connective tissue in the space of Disse, which also contains hepatic stellate cells and some mononuclear cells. The other side of the space of Disse is lined by hepatocytes that execute most of the known liver functions. In cirrhosis, the space of Disse is filled with scar tissue and endothelial fenestrations are lost, a process known as sinusoidal capillarisation.⁴ Histologically, cirrhosis is characterised by vascularised fibrotic septa that link portal tracts with each other and with central veins, resulting in hepatocyte islands surrounded by fibrotic septa and that are devoid of a central vein (figure 1). The major clinical consequences of cirrhosis are impaired hepatocyte (liver) function, an increased intrahepatic resistance (portal hypertension), and the development of hepatocellular carcinoma. The general circulatory abnormalities in cirrhosis (splanchnic vasodilation, vasoconstriction and hypoperfusion of kidneys, water and salt retention, increased cardiac output) are intimately linked to the hepatic vascular alterations and resulting portal hypertension. Cirrhosis and its associated vascular distortion are traditionally regarded as irreversible but recent data suggest that cirrhosis regression or even reversal is possible.5, 6

Section snippets

Epidemiology

The exact prevalence of cirrhosis worldwide is unknown. It was estimated at 0·15% or 400 000 in the USA,⁷ which accounted for more than 25 000 deaths and 373 000 hospital discharges in 1998.⁸ These numbers could be an underestimation, since we recognise the high prevalence of undiagnosed cirrhosis in both non-alcoholic steatohepatitis and hepatitis C. Similar numbers have been reported from Europe, and numbers are even higher in most Asian and African countries where chronic viral hepatitis B

Causes of cirrhosis

Causes of cirrhosis can usually be identified by the patient's history combined with serological and histological investigation (table 1).9, 10, 11, 12, 13, 14, 15, 16, 17 Alcoholic liver disease and hepatitis C are the most common causes in developed countries, whereas hepatitis B is the prevailing cause in most parts of Asia and sub-Saharan Africa. After the identification of hepatitis C virus in 1989 and of non-alcoholic steatohepatitis in obese patients with diabetes, the diagnosis of

Clinical presentation

Cirrhosis is often indolent, asymptomatic, and unsuspected until complications of liver disease are present. Many of these patients never come to clinical attention, and previously undiagnosed cirrhosis is often found at autopsy.²³ Diagnosis of asymptomatic cirrhosis is usually made when incidental screening tests such as liver transaminases or radiological findings suggest liver disease, and patients undergo further assessment and liver biopsy (table 2).24, 25, 26, 27, 28 The recognition that

Imaging of cirrhosis

Ultrasonography, CT, and MRI are not sensitive enough to detect cirrhosis, and final diagnosis still relies on histology. However, their specificity is high if the cause is obvious, and imaging reveals an inhomogeous hepatic texture or surface, rarefied hepatic central vein, an enlarged caudate lobe, splenomegaly, or collateral veins.29, 30, 31, 32 However, other causes such as portal-vein thrombosis, parasitic diseases, or haematological cancers need to be excluded, and normal radiographic

Liver biopsy

Biopsy is considered the gold standard for diagnosis of cirrhosis, and sequential histological grading of inflammation and staging of fibrosis can assess risk of progression. Furthermore, biopsy is important for establishing the cause of cirrhosis in up to 20% of patients with previous unknown cause (table 3). However, biopsy is prone to considerable sampling variability in all liver diseases.43, 44, 45, 46 The staging of fibrosis in hepatitis C by use of the METAVIR system (which is simple and

Natural history and prognosis

The natural history of cirrhosis depends on both the cause and treatment of the underlying cause. Yearly rates of decompensation are 4% for viral hepatitis C and 10% for viral hepatitis B, and incidence of hepatocellular carcinoma is 2–7% per year. Decompensation in alcoholic cirrhosis with continued alcohol use is even more rapid and often associated with alcoholic hepatitis on a background of cirrhosis. Once decompensation has occurred in all types of liver disease, mortality without

Treatment and reversibility of cirrhosis

Elimination of the triggers leading to cirrhosis will probably delay progression to a higher CPT class and reduce the occurrence of hepatocellular carcinoma. Reports have shown that causal treatment could even reverse cirrhosis, although in some reports the effect of sampling variability cannot be excluded. Patients with alcoholic cirrhosis should not continue alcohol consumption because it drives hepatitis, which favours hepatic fibrogenesis and decompensation.54, 55, 56 Liver function often

Complications of cirrhosis

Major advances have been made in recent years to both prevent and treat the common complications of cirrhosis such as variceal bleeding, ascites, spontaneous bacterial peritonitis, and encephalopathy (table 5).72, 73, 74, 75, 76, 77, 78 However, bacterial infections are common, especially in decompensated cirrhosis, which exacerbates hepatic dysfunction, encephalopathy, and portal hypertension, and underlines the need for vigilance and rigorous antibiotic treatment. Enhanced bacterial

Hepatocellular carcinoma

Hepatocellular carcinoma is one of the commonest solid organ tumours worldwide, and cirrhosis is a major risk factor for progression, among others (panel 1).86, 87, 88 Its pathogenesis seems to arise from the development of regenerative nodules with small-cell dysplasia through to invasive hepatocellular carcinoma. Mortality of hepatocellular carcinoma associated with cirrhosis is rising in most developed countries, whereas mortality from cirrhosis not related to hepatocellular carcinoma is

Liver transplantation

The ultimate treatment for cirrhosis and end-stage liver disease is liver transplantation (panel 2). Most recent survival data from the United Network of Organ Sharing (UNOS) study⁹¹ indicates survival rates of 83%, 70%, and 61% at 1 year, 5 years, and 8 years, respectively. Survival is best in patients who are at home at the time of transplantation compared with those who are in the hospital or intensive-care unit. Advances in liver transplantation have been the improvement in

Molecular pathology of hepatic fibrosis and cirrhosis

The scar tissue in cirrhosis is composed of a complex assembly of different extracellular matrix molecules (ECM), consisting of: the fibril-forming interstitial collagens type I and III; basement membrane collagen type IV; non-collagenous glycoproteins such as fibronectin and laminin; elastic fibres; and glycosaminoglycans and proteoglycans, among others.⁹⁴ Toxins, viruses, cholestasis, or hypoxia can trigger a wound healing reaction termed fibrogenesis—ie, the excess synthesis and deposition

Conclusions

Many advances have occurred in the clinical care of patients with cirrhosis and the complications of end-stage liver disease. Most of these treatments have focused on the underlying cause of cirrhosis and management of complications of portal hypertension. Research in the next 10 years could focus on the primary prevention and treatment of cirrhosis, such as the use of non-invasive tests to screen for earlier stages of fibrosis and to monitor antifibrotic drug effects, and pharmacological

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SeminarLiver cirrhosis

Summary

Introduction

Section snippets

Epidemiology

Causes of cirrhosis

Clinical presentation

Imaging of cirrhosis

Liver biopsy

Natural history and prognosis

Treatment and reversibility of cirrhosis

Complications of cirrhosis

Hepatocellular carcinoma

Liver transplantation

Molecular pathology of hepatic fibrosis and cirrhosis

Conclusions

J Hepatol

Am J Med

Lancet

Lancet

Lancet

Blood

Semin Ultrasound CT MR

Lancet

Hepatology

Hepatology

Am J Gastroenterol

Gastroenterology

Gastroenterol Clin North Am

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J Hepatol

Am J Med

Gastroenterology

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Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

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Hepatology

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Gastroenterology

Hepatology

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J Biol Chem

Gastroenterology

Hepatology

Gastroenterology

Capillarization of the sinusoids

Gastroenterology

Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis

Arch Pathol Lab Med

Digestive diseases in the United States: epidemiology and impact. Publication number 94–1447

National Center for Health Statistics. Series 13

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Seminar
Liver cirrhosis