Cholestasis: symptoms

The leading symptoms of cholestasis (both acute and chronic) are skin itching and malabsorption. In chronic cholestasis, bone damage (hepatic osteodystrophy), cholesterol deposition (xanthoma, xanthelasma) and skin pigmentation due to melanin accumulation are observed. Unlike patients with hepatocellular disease, weakness and fatigue are uncharacteristic. At objective research the liver, as a rule, is increased, with a smooth edge, condensed, painless. Splenomegaly is uncharacteristic if there is no biliary cirrhosis and portal hypertension. The feces are discolored.

[1], [2], [3], [4], [5]

Itching of the skin and jaundice

Itching of the skin and jaundice appear with a very pronounced impairment of the excretory function of hepatocytes.

Itching of the skin with cholestatic syndrome is caused by pruritogens synthesized in the liver, as well as endogenous opiate compounds that affect central neurotransmitter mechanisms. Probably, a certain role in the appearance of skin itch is the accumulation of bile acids in the blood and irritation of the nerve endings of the skin. However, there is no strict direct correlation between the intensity of skin itching and the level of bile acids in the blood. Itching of the skin in the syndrome of cholestasis can be very pronounced, even painful, makes the patients irritable, disturbs sleep, makes you constantly scratch. The skin is determined by multiple scratching, abrasions, which can become infected, the skin thickens, becomes dry (which is also facilitated by a deficiency of fat-soluble vitamin A, absorption of which is disrupted during cholestasis).

It is assumed that the pruritus with cholestasis causes compounds normally excreted in bile and, possibly, synthesized in the liver (in favor of this, the disappearance of itching in the terminal stage of liver failure). The use of cholestyramine is effective, but the drug has the ability to bind many compounds, which does not allow the isolation of a particular agent responsible for the development of pruritus.

Increased attention is drawn to compounds that can cause skin itching by affecting central neurotransmitter mechanisms. Data from experimental animal studies and drug test results suggest the role of endogenous opioid peptides in the development of pruritus. In animals with cholestasis, the state of analgesia develops due to the accumulation of endogenous opiates, which can be eliminated by naloxone. The severity of itching in patients with cholestasis is reduced when treated with naloxone. The antagonist of 5-HT3-serotonin receptors ondansetron also reduces itching in patients with cholestasis. Further investigation is needed of the pathogenesis of skin itching and the search for effective and safe methods to combat this painful, sometimes debilitating symptom of cholestasis.

Jaundice can appear simultaneously with cholestasis, and sometimes joins later. The main cause of jaundice is a violation of excretion of bilirubin and its entry into the blood. Excess bilirubin in the blood causes appropriate staining of the skin. With prolonged syndrome of cholestasis jaundice can acquire a greenish or dark olive shade. As a rule, noticeable jaundice of the skin and visible mucous membranes appears at a level of bilirubin in the blood of 50 μmol / l and higher.

In rare cases, with the so-called dissociated cholestasis, the excretion of bilirubin can not be disturbed, and there is no jaundice.

Xanthoma skin

Xanthoma of the skin - a fairly frequent and characteristic marker of cholestasis. Xanthomas are flat or slightly raised above the skin of the formation of a yellow soft consistency. They are usually located around the eyes (in the upper eyelid - xanthelasm), in the palmar creases, under the mammary glands, on the neck, chest, back. Xanthoma in the form of tubercles can be located on the extensor surface of large joints, in the buttocks. Perhaps even defeat of nerves, shells of tendons, bones. Xanthomas are caused by a delay in lipids in the body, hyperlipidemia and lipid deposition in the skin. Usually xanthomas appear with hypercholesterolemia exceeding 11 mmol / l and existing for 3 months or more. When eliminating the cause of cholestasis and normalizing the level of cholesterol, xanthomas can disappear.

Xanthoma of the skin develops in proportion to the level of serum lipids. The appearance of xanthom is preceded by a prolonged (more than 3 months) increase in serum cholesterol level of more than 11.7 μmol / l (450 mg%). Xanthomas disappear at the resolution of cholestasis and normalization of cholesterol level or in terminal stage of hepatic insufficiency.

Acholia feces and steatorrhea

In the syndrome of cholestasis, the feces become discolored, white (acholia), which is caused by the absence of stericubinogen in it, which is not formed in the large intestine due to the absence of bile flow into the 12-colon. At the same time, the absorption of fats in the small intestine (due to a deficiency of bile acids) is also impaired, which leads to steatorrhea ("fat" stool).

Stethorrhea is caused by insufficient content of bile salts in the lumen of the intestine, necessary for absorption of fats and fat-soluble vitamins A, D, K, E, and corresponds to the severity of jaundice. There is no adequate micellar dissolution of lipids. The chair becomes liquid, slightly colored, voluminous, offensive. By the color of the feces it is possible to judge the dynamics of obstruction of the biliary tract (complete, intermittent, resolving).

A pronounced and long-lasting violation of fat absorption contributes to the development of weight loss.

[6], [7]

Deficiency of fat-soluble vitamins

In the syndrome of cholestasis, the absorption of fat-soluble vitamins A, D, E, K is impaired, and clinical signs of the corresponding hypovitaminosis appear.

Deficiency of vitamin D leads to the development of so-called hepatic osteodystrophy. This is also facilitated by a simultaneous impairment of calcium absorption in the intestine. Hepatic osteodystrophy manifests itself in the defeat of bones, the development of diffuse osteoporosis, which is characterized by pain in the bones, in the spine, easily appearing fractures of bones, especially the ribs, compression fractures of the spine.

In the development of osteoporosis, not only vitamin D deficiency and calcium absorption in the intestine are involved, but also factors such as hyperproduction of parathyroid hormone, inadequate secretion of calcitonin, a decrease in the proliferation of osteoblasts under the influence of excess bilirubin.

Deficiency of vitamin K is manifested by a decrease in the level of prothrombin in the blood and hemorrhagic syndrome.

Deficiency of vitamin E is manifested by a disorder in the functioning of the cerebellum (cerebellar ataxia), peripheral polyneuropathy (sensation of numbness, burning sensation in the legs, weakness of the leg muscles, decreased sensitivity and tendon reflexes), degeneration of the retina.

Clinical signs of vitamin E deficiency are most often observed in children and significantly less often in adults.

Deficiency of vitamin A is manifested by dryness and scaling of the skin (especially in the palm of the hand) and visual impairment in the dark (reduction of dark adaptation - "night blindness").

[8], [9], [10], [11], [12], [13]

The formation of stones in the biliary tract

The formation of stones in the biliary tract can be observed with prolonged existence of cholestasis. Clinical and instrumental diagnostics. Possible complication of cholelithiasis with bacterial cholangitis, the main symptoms of which are pain in the right hypochondrium, fever with chills, enlargement of the liver).

Hepatic osteodystrophy

The defeat of bones is a complication of chronic liver diseases, especially cholestatic, in which it is most thoroughly studied. There are pains in the bones and fractures. Probable causes of this are osteomalacia and osteoporosis. Studies with primary biliary cirrhosis and primary sclerosing cholangitis showed that in most cases bone damage is caused by osteoporosis, although osteomalacia also has a certain value.

Bone lesion is manifested by pain in the back (usually in the thoracic or lumbar spine), decreased growth, compression of vertebral bodies, fractures with minimal injuries, especially ribs. Radiography of the spine allows us to detect a decrease in density and compression fractures of vertebral bodies.

The mineral density of bone tissue can be determined by the method of double absorption photometry. In 31% of 123 women with primary biliary cirrhosis, this method was used to detect severe bone damage. In the future, 7% showed fractures. Reduction of bone mineral density was also detected in patients with far-reaching primary sclerosing cholangitis with an increased level of bilirubin.

The pathogenesis of bone damage is not completely specified. Several factors are involved. The normal structure of bone tissue is maintained by the balance of two differently directed processes: bone resorption with the help of osteoclasts and the formation of a new bone by osteoblasts. Bone tissue reconstruction begins with a decrease in the number of cells inactive bone zones. Osteoclasts, resorbing the bone, form lacunas. Later on these cells are mixed with osteoblasts, which fill the lacuna with new bone (osteoid), collagen and other matrix proteins. Then calcium-dependent, and therefore vitamin D-dependent, mineralization of the osteoid occurs. Metabolic bone disorders include two main forms: osteomalacia and osteoporosis. In osteoporosis, loss of bone tissue (matrix and mineral elements) is observed. Osteomalacia affects the mineralization of the osteoid. Verification of bone disorders in chronic cholestasis was carried out with the help of biopsy and studying bone tissue using special techniques.

Studies have shown that, in most cases, hepatic osteodystrophy is represented by osteoporosis. In chronic cholestatic diseases, both a decrease in the formation of a new bone and an increase in the resorption of bone tissue have been revealed. It is suggested that in the early, pre-cirrhotic stage of the lesion, there is a disruption in the process of bone formation, while in cirrhosis, an increase in resorption occurs. In women who do not have liver disease, the processes of new bone formation and resorption of bone tissue with a predominance of the latter are strengthened in menopause. It can play a role in bone damage in primary biliary cirrhosis in women in menopause.

The cause of osteoporosis in chronic cholestatic liver diseases has not been fully established. Pathogenetic significance can have many factors involved in the metabolism of bone tissue: vitamin D, calcitonin, parathyroid hormone, growth hormone, sex hormones. The condition of bones in patients with chronic cholestasis is influenced by such external factors as limited mobility, malnutrition, a decrease in muscle mass. The level of vitamin D is reduced due to a violation of absorption, inadequate intake from food, inadequate sun exposure. However, treatment with vitamin D does not affect the condition of bone tissue. The processes of vitamin D activation in the liver (25-hydroxylation) and in the kidneys (1-hydroxylation) are not violated.

In recent studies, a decrease in the proliferation of osteoblasts by plasma derived from patients with jaundice has been shown; with the inhibitory effect of unconjugated bilirubin, but not bile acids | 451. These data allow us to explain the disturbances in the formation of bone tissue in chronic cholestasis, but require further confirmation.

Treatment with ursodeoxycholic acid does not stop the loss of bone mass in patients with primary biliary cirrhosis. After liver transplantation, bone density rises only after 1-5 years. During the first year, spontaneous fractures are often observed in 35% of patients with primary sclerosing cholangitis. Perhaps one of the reasons for the high incidence of fractures is the use of corticosteroids for the purpose of immunosuppression. The level of vitamin D does not return to normal for several months after transplantation. In this regard, substitution therapy is recommended.

Determining the level of vitamin D in patients with chronic cholestasis is of great importance, since osteomalacia, despite the rarity, is easily treatable. In the study of isoenzymes of serum alkaline phosphatase, in addition to the hepatic, the bone fraction of the enzyme can be increased. By the level of calcium and phosphorus in the serum it is impossible to predict the development of bone changes. Radiography reveals changes that are characteristic of osteomalacia: pseudo-fractures, Loozer zones. Radiography of the hands reveals the rarefaction of bone tissue. When bone biopsies, wide uncalcified osteoid masses surrounding the trabeculae are identified. The reasons for the decline in vitamin D levels are numerous. Patients with chronic cholestasis do not spend enough time in the air under the sun's rays, observe an inadequate diet. Steatorrhea, impaired absorption may worsen by prolonged use of cholestyramine.

Another manifestation of bone pathology is painful osteoarthropathy of the ankles and wrists - a nonspecific complication of chronic liver diseases.

Metabolic disorders of copper

Approximately 80% of the absorbed copper is normally excreted with bile and is removed with feces. In all forms of cholestasis, but especially in chronic cases (for example, in primary biliary cirrhosis, primary sclerosing cholangitis, atresia of the biliary tract), copper accumulation occurs in the liver at concentrations typical of Wilson's disease or even exceeding them. In rare cases, a pigmented corneal ring resembling the Kaiser-Fleischer ring can be found.

Copper deposits in the liver are revealed during histochemical examination (coloration with rhodanin) and can be quantified by biopsy. Copper-binding protein is detected by coloration of orsein. These methods indirectly confirm the diagnosis of cholestasis. Copper, accumulating in cholestasis, apparently does not have a hepatotoxic effect. Electron microscopy detects copper in electron-dense lysosomes, but changes in organelles associated with the action of cytosolic copper are not characteristic of Wilson's disease. With cholestasis, copper accumulates inside the hepatocyte in a non-toxic form.

Development of hepatocellular insufficiency

Liver-liver insufficiency develops slowly, the function of the liver with cholestasis remains for a long time. Liver failure is associated with the duration of jaundice 3-5 years; This is evidenced by a rapid increase in jaundice, the appearance of ascites, edema, a decrease in the level of albumin in the serum. Cutaneous itching decreases, bleeding can not be treated with parenteral administration of vitamin K. In the terminal stage, hepatic encephalopathy develops.

Microsomal oxidation of drugs. In patients with intrahepatic cholestasis, a decrease in the content of cytochrome P450 is proportional to the severity of cholestasis.

[14], [15], [16], [17], [18], [19]

Extrahepatic symptoms of cholestasis

In addition to such bright signs as jaundice and skin itching, with cholestasis there are other, less noticeable manifestations, studied mainly in the obstruction of the bile duct. Serious complications can occur if the patient is weakened (dehydration, blood loss, surgeries, medical-diagnostic manipulations). The activity of the cardiovascular system changes, vascular reactions are violated in response to arterial hypotension (vasoconstriction). The sensitivity of the kidneys to the damaging effect of arterial hypotension and hypoxia increases. Violated the body's defense reactions for sepsis, wound healing. The increase in prothrombin time is corrected by the introduction of vitamin K, but the cause of coagulation disorders may be platelet dysfunction. The mucous membrane of the stomach becomes more prone to ulceration. The reasons for such changes are diverse. Glandic acids and bilirubin disrupt the metabolism and function of cells. The change in the composition of serum lipids affects the structure and function of membranes. Endotoxemia may have a damaging effect. Thus, metabolic and functional disorders in patients with cholestasis and severe jaundice under certain conditions (surgery, medical and diagnostic manipulations) can lead to the development of acute renal failure, bleeding, accompanied by poor wound healing and a high risk of sepsis development.

To rare hereditary forms of cholestasis are Sumerskill syndrome and illness (syndrome) of Byler.

Summerscill syndrome is a benign recurrent family cholestasis, characterized by repeated episodes of hosstatic jaundice, beginning with early childhood, and a favorable course (without outcome in cirrhosis of the liver).

Illness (syndrome) of Byler - progressive intrahepatic familial cholestasis, caused by the pathology of the gene on chromosome XVIII, is characterized by a fatal course with early formation of biliary cirrhosis and fatal outcome.

Intrahepatic cholestasis of pregnant women is a benign disease that develops during pregnancy, manifested by the syndrome of cholestasis.

The pathogenesis of the disease is caused by increased secretion of progesterone, estrogens, placental hormones and high cholesterol synthesis in the liver. It is possible that pregnancy predisposes to the appearance of previously existing genetic defects of bile secretion. Intrahepatic cholestasis of pregnant women develops in the last months of pregnancy and is manifested by jaundice, skin itching and laboratory signs of cholestasis. 

Histological examination of the liver reveals centrolobular cholestasis without necrosis of hepatocytes.

In recent years, the syndrome of "endangered bile ducts" is being discussed . It includes diseases characterized by reduction of the bile ducts:

• primary biliary cirrhosis of the liver;
• primary sclerosing cholangitis;
• autoimmune cholangitis (corresponds clinically and morphologically to primary biliary cirrhosis, but differs from it in the absence of antimitochondrial antibodies);
• Cholangitis of known etiology (with cytomegalovirus infection, cryptosporidiosis, against immunodeficiency states, including AIDS);
• recurrent bacterial cholangitis with infection of the cysts of the intrahepatic ducts (with Caroli's disease);
• congenital atresia or bile duct hypoplasia;
• Cholestasis of primovicrosis and isarcoidosis.

[20], [21], [22]