Cholestasis - Pathogenesis

The pathogenesis of cholestasis in mechanical obstruction by a stone or duct stricture is obvious. Drugs, hormones, sepsis cause damage to the cytoskeleton and membrane of the hepatocyte.

As is known, the process of bile formation includes the following energy-dependent transport processes:

• capture of bile components (bile acids, organic and inorganic ions) by hepatocytes;
• their transfer through the sinusoidal membrane into hepatocytes;
• excretion through the canalicular membrane into the bile capillary.

The transport of bile components depends on the normal functioning of special carrier proteins of the sinusoidal and canalicular membranes.

The development of intrahepatic cholestasis is based on disturbances in transport mechanisms:

• disruption of the synthesis of transport proteins or their function under the influence of etiological factors;
• impaired permeability of hepatocyte membranes and bile ducts;
• violation of the integrity of the tubules.

In extrahepatic cholestasis, the leading role belongs to the disruption of bile outflow and increased pressure in the bile ducts.

As a result of these processes, cholestasis occurs and bile components are able to enter the blood in excess.

Changes in membrane fluidity and Na ⁺, K ⁺ -ATPase activity may be accompanied by the development of cholestasis. Ethinyl estradiol reduces the fluidity of sinusoidal plasma membranes. In an experiment on rats, the effect of ethinyl estradiol can be prevented by the introduction of S-adenosylmethionine, a methyl group donor that affects membrane fluidity. Escherichia coli endotoxin inhibits Na⁺, K ⁺ -ATPase activity, apparently acting similarly to ethinyl estradiol.

The integrity of the canalicular membrane can be compromised by damage to the microfilaments (responsible for the tone and contraction of the canaliculi) or tight junctions. Cholestasis under the influence of phalloidin is caused by depolymerization of actin microfilaments. Chlorpromazine also affects actin polymerization. Cytochalasin B and androgens have a damaging effect on microfilaments, reducing the contractility of the canaliculi. Rupture of tight junctions (under the influence of estrogens and phalloidin) leads to the disappearance of the dividing barrier between hepatocytes and direct entry of large molecules from the bloodstream into the canaliculi, regurgitation of dissolved bile substances into the blood. It should be noted that the same agent can affect several mechanisms of bile formation.

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Possible cellular mechanisms of cholestasis

Lipid composition/membrane fluidity	They are changing
Na +, K + -ATPase/other transport proteins	Inhibited
Cytoskeleton	It is collapsing
Integrity of tubules (membranes, tight junctions)	It is violated

Vesicular transport depends on microtubules, the integrity of which can be disrupted by colchicine and chlorpromazine. Inadequate excretion of bile acids into the tubules or leakage from the tubules disrupts bile acid-dependent bile flow. This is also facilitated by disruption of enterohepatic circulation of bile acids. Cyclosporine A inhibits the ATP-dependent transport protein for bile acids in the canalicular membrane.

Changes in bile flow are observed in duct damage caused by inflammation, destruction of the epithelium, but these changes are secondary rather than primary. The role of disturbances in the transmembrane conductivity regulator of epithelial cells of the ducts in cystic fibrosis requires further study. In primary sclerosing cholangitis, gene mutations are observed no more often than in the control group.

Some bile acids that accumulate in cholestasis can damage cells and increase cholestasis. Administration of less toxic bile acids (tauroursodeoxycholic acid) has a protective effect. When rat hepatocytes are exposed to hydrophobic bile acids (taurochenodeoxycholic acid), formation of oxygen-free radicals in the mitochondria is observed. Damage to hepatocytes is reduced by displacement of canalicular transport proteins for bile acids to the basolateral membrane, as a result of which the polarity of the hepatocyte and the direction of bile acid transport are changed, and accumulation of bile acids in the cytoplasm is prevented.

Pathomorphology of cholestasis

Some changes are caused directly by cholestasis and depend on its duration. Morphological changes characterizing certain diseases accompanied by cholestasis are given in the corresponding chapters.

Macroscopically, the liver in cholestasis is enlarged, green in color, with a rounded edge. In the later stages, nodes are visible on the surface.

Light microscopy reveals marked bilirubin stasis in hepatocytes, Kupffer cells, and zone 3 tubules. "Feathery" dystrophy of hepatocytes (apparently caused by accumulation of bile acids), foamy cells surrounded by clusters of mononuclear cells may be detected. Hepatocyte necrosis, regeneration, and nodular hyperplasia are minimally expressed.

In the portal tracts of zone 1, proliferation of ductules is detected due to the mitogenic effect of bile acids. Hepatocytes are transformed into bile duct cells and form a basement membrane. Reabsorption of bile components by duct cells may be accompanied by the formation of microliths./P>

In case of obstruction of the bile ducts, changes in hepatocytes develop very quickly. Signs of cholestasis are detected after 36 hours. At first, proliferation of the bile ducts is observed, later fibrosis of the portal tracts develops. After about 2 weeks, the degree of changes in the liver no longer depends on the duration of cholestasis. Bile lakes correspond to ruptures of the interlobular bile ducts.

In ascending bacterial cholangitis, clusters of polymorphonuclear leukocytes are found in the bile ducts and sinusoids.

Fibrosis develops in zone 1. When cholestasis resolves, fibrosis undergoes reverse development. When fibrosis in zone 1 expands and areas of fibrosis in adjacent zones merge, zone 3 is found in a ring of connective tissue. The relationship between the hepatic and portal veins is not changed in the early stages of the disease, but is disrupted in biliary cirrhosis. Continuing periductal fibrosis can lead to irreversible disappearance of the bile ducts.

Edema and inflammation of zone 1 are associated with bile-lymphatic reflux and the formation of leukotrienes. Mallory bodies can also form here. Copper-binding protein is detected in periportal hepatocytes when stained with orcein.

HLA class I antigens are normally expressed on hepatocytes. Reports on the expression of HLA class II antigens on hepatocytes are contradictory. These antigens are absent on the surface of hepatocytes in healthy children, but are detected in some patients with primary sclerosing cholangitis and autoimmune liver disease.

With prolonged cholestasis, biliary cirrhosis develops. Fields of fibrous tissue in the portal zones merge, leading to a decrease in the size of the lobules. Bridge fibrosis connects the portal tracts and central areas, nodular regeneration of hepatocytes develops. With biliary obstruction, true cirrhosis rarely develops. With complete compression of the common bile duct by a cancerous tumor of the head of the pancreas, patients die before nodular regeneration develops. Biliary cirrhosis associated with partial biliary obstruction develops with strictures of the bile ducts and primary sclerosing cholangitis.

In biliary cirrhosis, the liver is larger and more intensely green than in other types of cirrhosis. Nodules on the surface of the liver are clearly defined (not moth-eaten). As cholestasis resolves, portal fibrosis and bile accumulations slowly disappear.

Electron microscopic changes in the bile ducts are nonspecific and include dilation, edema, thickening and tortuosity, and loss of microvilli. Vacuolization of the Golgi apparatus, hypertrophy of the endoplasmic reticulum, and proliferation of lysosomes containing copper in combination with protein are observed. Vesicles around the canaliculi containing bile give the hepatocytes a "feathery" appearance on light microscopy.

All of the above changes are non-specific and do not depend on the etiology of cholestasis.

Changes in other organs in cholestasis

The spleen is enlarged and hardened due to hyperplasia of the reticuloendothelial system and an increase in the number of mononuclear cells. Portal hypertension develops in the late stage of liver cirrhosis.

The intestinal contents are voluminous and have a fatty appearance. In case of total obstruction of the bile ducts, discoloration of the feces is observed.

The kidneys are edematous and stained with bile. In the distal tubules and collecting ducts, casts containing bilirubin are found. The casts may be abundantly infiltrated with cells, the tubular epithelium is destroyed. Edema and inflammatory infiltration of the connective tissue are expressed. Scar formation is not observed.

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