Cirrhosis

Overview

Cirrhosis is defined as a morphological pattern of liver pathology that is the endpoint of a wide variety of chronic liver diseases. The morphological changes associated with cirrhosis are largely irreversible although in some cases a slow return to the architecture of a normal liver has been observed when the offending etiology has been corrected. A characteristic clinical syndrome results from such morphological changes and centers around reduced liver function and severe alterations in hepatic blood flow.

Morphology

Each cirrhotic etiology has some unique morphological features but with progression they begin to look increasingly similar to one another. They hold in common the following features which define "Cirrhosis".

The hepatic architecture across the entire organ is distorted. Importantly, localized architectural disruption is not considered Cirrhosis.

Fibrotic septae interlink portal tracts with one another or with terminal hepatic venules. Abnormal vascular channels form within these fibrous septae that directly link hepatic inflow and outflow channels (see "Pathogenesis" below).

Within the fibrotic septae, nodules of regenerating hepatocytes can form and can give the liver a grossly nodular surface. A pattern of small nodules (millimeters in diameter) is termed micronodular cirrhosis while a pattern of large nodules (centimeters in diameter) is termed macronodular cirrhosis. Different cirrhotic etiologies tend to result in either micronodular, macronodular, or a mixed picture. Historically, this was used as a classification scheme for cirrhotic etiologies but has been put aside in recent years.

Pathogenesis

The hepatic response to chronic injury can be thought of as occurring along two basic axes: fibrosis and regeneration. Together, these responses result in the morphological picture of cirrhosis.

In the healthy liver, collagen is limited to the area immediately surrounding the portal tracts and terminal hepatic venules as well as a very thin network within the Space of Disse. Chronic liver injury changes the morphology of Ito Cells into something akin to a collagen-secreting fibroblasts. As the liver progresses to cirrhosis, collagen is deposited throughout the hepatic lobule and can be observed histologically as septae of fibrosis between adjacent portal tracts or between portal tracts and terminal hepatic venules. The Space of Disse is also thickened with collagen which results in the sinusoidal capillaries losing their discontinuous nature and resembling traditional continuous capillaries. Consequently, the the large number of low-pressure, discontinuous sinusoidal capillaries of the normal liver which allow prolonged contact of blood directly with hepatocytes are converted into a reduced number of high-pressure, fast-flow channels. This reduces the capacity of hepatocytes to exchange proteins with the blood, leading to declining liver functionality.

The natural response of hepatocytes to injury is regeneration. However, in the context of fibrotically-distorted liver architecture, regeneration of hepatocytes occurs in abnormal nodules trapped within the fibrotic septae. This results in the nodular morphology characteristic of cirrhosis.

Clinical Consequences

Fatigue, anorexia, and weight loss are common nonspecific symptoms of cirrhosis.

Portal Hypertension in cirrhosis results from increased hepatic resistance to total blood flow due to the total disorganization of the hepatic architecture. Additionally, direct anastomoses between branches of the hepatic artery and portal vein within fibrotic portal tracts leads to the arterial pressure of the hepatic artery being imposed on the lower-pressure portal vein. The consequent portal hypertension is the proximate cause of several other important cirrhotic complications.

Portal hypertension results in shunting of blood into the lower-pressure systemic veins at specialized capillary beds where these two venous systems anastomose, known as portal-systemic junctions. Increased pressure and flow through these capillary beds results in their progressive morphological remodeling to varicose veins. These varicosities can be observed at a variety of anatomical locations which represent portal-systemic junctions, resulting in esophageal varices, caput medusae, and hemorrhoids.

Increased pressure in the portal vein is conducted to the splenic vein resulting in congestive enlargement of the spleen. Over time this can cause symptoms of hypersplenism such as thrombocytopenia.

The pathogenesis of cirrhotic ascites is complex but is ultimately initiated by portal hypertension which results in the generation of increased lymph that then accumulates within the peritoneum. When fluid in the peritoneal cavity exceeds 0.5L it can be clinically detectable as ascites.

Increased levels of estrogen in those with cirrhosis can result in development of spider telangiectasias, as well as testicular atrophy in men

Cirrhotic patients can ultimately develop a number of end-stage syndromes caused by critical declines in hepatic function. These include hepatic failure, hepatorenal syndrome, and hepatic encephalopathy.

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