Liver fibrosis or hepatic fibrosis is an aggressive wound healing, often triggered by chronic injury and resulting in excessive connective tissue in the liver.
In simple terms, it means scarring in response to liver injury.
Liver fibrosis itself does not cause any symptoms but can lead to portal hypertension or cirrhosis.
Various types of chronic liver injuries can lead to fibrosis of the liver.
In early stages, hepatic fibrosis can regress especially when the cause is removed but after months or years of chronic or repeated injury, fibrosis becomes permanent.
The diagnosis is based on liver biopsy. Treatment involves correcting the underlying condition when possible.
Pathophysiology of Liver Biopsy
Liver fibrosis occurs because of chronic liver damage resulting in the accumulation of extracellular matrix proteins.
[When this accumulation of extracellular matrix proteins cause live architecture distortion by scarring and there appear nodules of regenerating hepatocytes, it is defined as cirrhosis. This is the basic difference between fibrosis and cirrhosis.]
Normally, after an acute injury to the liver, the parenchymal cells regenerate. In case of persistence of injury, the liver regeneration fails, and injured cells are replaced with large quantities of extracellular matrix and collagen fibers which leads to scarring.
The area of fibrosis depends on the origin of liver injury. For example, in viral hepatitis, it is around portal tracts and in alcohol-induced liver disease, it is in pericentral and perisinusoidal areas.
Accumulation of extracellular matrix protein is the result of both, increased synthesis and decreased degradation.
The matrix proteins are removed by Matrix metallopeptidases (MMPs), and there is decreased activity is brought by overexpression of their specific inhibitors [Tissue inhibitors of metalloproteinases (TIMPs)].
Hepatic stellate cells or Ito cells which are in space of Disse and function as vitamin A storage, are main cells involved in extracellular matrix production. Space of Disse is a perisinusoidal space.
After a chronic injury, under the influence of inflammatory cells [lymphocytes or polymorphonuclear cells], stellate cells differentiate into myofibroblast-like cells, acquiring contractile, proinflammatory, and fibrogenic properties. These migrate and accumulate at the sites of tissue repair, secreting large amounts of an abnormal matrix (collagen, other glycoproteins, and glycans) and matricellular proteins.
Also, Kupffer cells (macrophages in the liver), injured hepatocytes, platelets, and leukocytes aggregate to release reactive oxygen species [ROS] and inflammatory mediators which in turn stimulate stellate cells. The inflammatory mediators are
- Platelet-derived growth factor
- Transforming growth factors
- Connective tissue growth factor
Thus activated hepatic stellate cells create a vicious circle in which inflammatory and fibrogenic cells stimulate each other.
Fibrosis is influenced by
- Type 2 helper cells increase fibrogenesis
- Epithelial cells in chronic cholestatic disorders stimulate
- Vasodilators decrease fibrogenesis
- Nitric oxide
- Vasoconstrictors stimulate fibrogenesis
- Angiotensin II
Adipokines are cytokines mainly derived from the adipose tissue and regulate liver fibrogenesis.
- Leptin is required for stellate cell activation and fibrosis
- Adiponectin markedly inhibits liver fibrogenesis
As fibrosis progresses, fibrous tracts join branches of afferent portal veins and efferent hepatic veins. This leads to bypassing the hepatocytes and limiting their blood supply.
Ischemia of liver cells occurs and leads to liver dysfunction at the cellular level. This also leads to portal hypertension.
Causes of Liver Fibrosis
Main causes of liver fibrosis are HCV infection, alcohol abuse, and nonalcoholic steatohepatitis or NASH.
Other important causes of liver fibrosis are listed below
- Alcoholic liver disease
- Viral hepatitis B
- Autoimmune hepatitis
- Biliary obstruction
- Iron overload
Clinical Features and Diagnosis of Liver Fibrosis
Liver fibrosis is not symptomatic itself. Symptoms result from the condition that has caused the fibrosis or its complications like portal hypertension.
The symptoms of liver affection include jaundice, portal hypertension and its complications like variceal bleeding, ascites, and portosystemic encephalopathy.
Cirrhosis can result in liver insufficiency and liver failure represent the final stages.
Liver fibrosis should be suspected in patients of chronic liver disease such as chronic viral hepatitis or alcoholic liver disease.
The patient is investigated to look for hepatic fibrosis and determine its severity if present.
Liver function tests form the basis of blood tests. Other tests done are direct markers of hepatic function. Direct markers are substances involved in the pathogenesis of extracellular matrix deposition or cytokines that induce extracellular matrix deposition.
These markers are
- N-terminal propeptide of type III collagen
- Hyaluronic acid
- Tissue inhibitor of metalloproteinase type 1 (TIMP-1)
- Glycoprotein YKL-40
These markers can detect the presence of advanced fibrosis (cirrhosis) as well as minimal or no fibrosis. But they are unable to differentiate intermediate grades of fibrosis.
Moreover, the fibrogenesis in other organs can also affect their levels.
Thus these markers can differentiate the following types of fibrosis
- Absent to minimal
- Moderate to severe
Liver biopsy should be done only in the group moderate to severe.
Ultrasonography, CT, and MRI can detect evidence of cirrhosis and portal hypertension, such as splenomegaly and varices but when splenomegaly and varices are absent, they are not very good at detecting liver fibrosis or differentiating between fibrosis and fatty changes in the liver.
Newer technologies that can increase the accuracy of ultrasonography and MRI for detecting fibrosis or early cirrhosis include ultrasound elastography, magnetic resonance elastography, and acoustic radiation force impulse imaging
Liver biopsy is the gold standard for diagnosing and staging hepatic fibrosis and for diagnosing the underlying liver disorder. It is an invasive procedure with a significant complication rate.
Staging of Liver Fibrosis
METAVIR Scoring System
Many scales are used to stage the fibrosis. One of the commonly used systems is METAVIR scoring system.
The METAVIR scoring system assesses the extent of inflammation and fibrosis by histopathological examination.
The grade indicates the activity or degree of inflammation while the stage represents the amount of fibrosis or scarring.
- A0: no activity
- A1: mild activity
- A2: moderate activity
- A3: severe activity
- F0: no fibrosis
- F1: portal fibrosis without septa
- F2: portal fibrosis with few septa
- F3: numerous septa without cirrhosis.
- F4: cirrhosis
- 0 – No fibrosis
- 1- Fibrous expansion of some portal areas, with or without short fibrous septa
- 2- Fibrous expansion of most portal areas, with or without short fibrous septa
- 3- Fibrous expansion of most portal areas with an occasional portal to portal bridging
- 4- Fibrous expansion of portal areas with marked bridging (portal to portal as well as the portal to central)
- 5 – Marked bridging (portal–portal and/or portal–central) with occasional nodules (incomplete cirrhosis)
- 6 – Cirrhosis, probable or definite
- 0: No fibrosis
- 1: Portal fibrosis
- 2: Rare portal-to-portal septa
- 3: fibrous septa
- 4: definite or likely cirrhosis
Treatment of Liver Fibrosis
The mainstay of the treatment is the treatment of the underlying cause. For example, in alcoholic liver disease abstinence from alcohol or treatment and elimination of the virus in viral hepatitis or removing heavy metals such as iron in hemochromatosis or copper in Wilson disease.
Antifibrotic drugs are being studied and in future may be used to halt the progression.
Some studies have indicated that liver fibrosis can reverse after successful treatment of the underlying disease.