Liver fibrosis: causes, symptoms, diagnosis, treatment

Liver fibrosis is the accumulation of connective tissue in the liver in response to hepatocellular injury of any etiology. Fibrosis results from excessive formation or abnormal destruction of the extracellular matrix. Fibrosis itself is asymptomatic but may lead to portal hypertension or cirrhosis. Diagnosis is based on liver biopsy. Treatment involves eliminating the underlying cause, if possible. Therapy is aimed at reversing fibrosis and is currently under investigation.

Activation of hepatic perivascular stellate cells (Ito cells, fat-storing cells) causes fibrosis. These and adjacent cells proliferate to become contractile cells called myofibroblasts. These cells degrade normal matrix and, in part through changes in the metalloproteinase enzymes that regulate collagen matrix metabolism, stimulate excess formation of defective matrix. Kupffer cells (resident macrophages), which

Diseases and drugs that cause liver fibrosis

Diseases with direct liver damage

• Some hereditary diseases and inborn errors of metabolism
• α1-antitrypsin deficiency
• Wilson's disease (excessive copper accumulation)
• Fructosemia
• Galactosemia
• Glycogen storage diseases (especially types III, IV, VI, IX and X)
• Iron storage syndromes (hemochromatosis)
• Lipid metabolism disorders (eg, Gaucher disease)
• Peroxisomal diseases (Zellweger syndrome) Tyrosinosis
• Congenital liver fibrosis
• Infections Bacterial (eg brucellosis)
• Parasitic (for example, echinococcosis)
• Viral (eg, chronic hepatitis B or C)

Disorders affecting hepatic blood flow

• Budd-Chiari syndrome
• Heart failure
• Occlusive diseases of the liver veins
• Portal vein thrombosis

Medicines and chemicals

• Alcohol
• Amiodarone
• Chlorpromazine
• Isoniazid
• Methotrexate
• Methyldopa
• Oxyphenisatin
• Tolbutamide
• Toxins (eg iron, copper salts)

Damaged hepatocytes, platelets, and aggregated leukocytes release various reactive oxygen species _and inflammatory mediators (eg, platelet-derived growth factor, transformed growth factors, and connective tissue growth factor), accelerating fibrosis.

Myofibroblasts stimulated by endothelin-1 also contribute to the increase in portal vein resistance, which increases the density of the altered matrix. Fibrous strands separate the afferent branches of the portal vein and the vessels of the efferent hepatic veins at the confluence, bypassing hepatocytes and limiting their blood supply. Consequently, fibrosis contributes both to hepatocyte ischemia (and hepatocellular dysfunction) and to the development of portal hypertension. The significance of each process depends on the nature of the liver lesion. For example, congenital liver fibrosis involves the portal vein branches, largely sparing the parenchyma. As a result, portal hypertension with preserved hepatocellular function develops.

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Symptoms of liver fibrosis

Liver fibrosis itself does not manifest symptoms. Signs may appear with the development of secondary changes or portal hypertension. However, portal hypertension is often asymptomatic until liver cirrhosis develops.

Liver biopsy is the only method for diagnosing and verifying liver fibrosis. Quite often, the diagnosis is established after a liver biopsy performed for other indications. Special staining (e.g., aniline blue, trichrome, silver staining) may initially reveal fibrous tissue.

Treatment of liver fibrosis

Since fibrosis is a sign of liver damage, treatment is usually aimed at the underlying cause. Treatments aimed at reversing fibrosis itself are under research and are focused on the following areas:

1. reducing inflammation (eg, ursodeoxycholic acid, glucocorticoids),
2. inhibition of hepatic stellate cell activation (eg, alpha interferon, vitamin E as an antioxidant, peroxisome proliferator-activated receptor [PPAR] ligand, eg, thiazolidinedione),
3. inhibition of collagen synthesis or metabolism (eg, penicillamine, colchicines, glucocorticoids),
4. suppression of stellate cell contraction (eg, endothelin antagonists or nitric oxide donors) and
5. increased degradation of the extracellular matrix (for example, the use of various experimental drugs that cause degradation of the extracellular matrix through action on transforming growth factor β or matrix metalloproteinases).

Unfortunately, many drugs are quite harmful when used long-term (e.g., glucocorticoids, penicillamine) or have no proven effectiveness (e.g., colchicine). Complex antisclerotic therapy may be the most effective.