Cholestasis - Symptoms

The leading symptoms of cholestasis (both acute and chronic) are skin itching and malabsorption. Chronic cholestasis is characterized by bone damage (hepatic osteodystrophy), cholesterol deposits (xanthomas, xanthelasmas) and skin pigmentation due to melanin accumulation. Unlike patients with hepatocellular disease, weakness and fatigue are uncommon. On physical examination, the liver is usually enlarged, smooth-edged, compacted and painless. Splenomegaly is uncommon unless there is biliary cirrhosis and portal hypertension. Stool is discolored.

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Itchy skin and jaundice

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

Skin itching in 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 itching is played by the accumulation of bile acids in the blood and their 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. Skin itching in cholestasis syndrome can be very pronounced, even painful, makes patients irritable, disrupts sleep, and causes constant scratching. Multiple scratches and abrasions are determined on the skin, which can become infected, the skin thickens, becomes dry (which is also facilitated by a deficiency of fat-soluble vitamin A, the absorption of which is impaired in cholestasis).

It is assumed that the skin itch in cholestasis is caused by compounds that are normally excreted in bile and, possibly, synthesized in the liver (this is supported by the disappearance of itching in the terminal stage of liver failure). Taking cholestyramine is effective, but the drug has the ability to bind many compounds, which makes it impossible to isolate the specific agent responsible for the development of itching.

Compounds that can cause pruritus by affecting central neurotransmitter mechanisms have attracted increased attention. Data from animal studies and drug trials suggest a role for endogenous opioid peptides in the development of pruritus. Animals with cholestasis develop a state of analgesia due to accumulation of endogenous opiates, which can be eliminated by naloxone. The severity of pruritus in patients with cholestasis is reduced by treatment with naloxone. The 5-HT3-serotonin receptor antagonist ondansetron also reduces pruritus in patients with cholestasis. Further research into the pathogenesis of pruritus and the search for effective and safe methods to combat this painful, sometimes debilitating symptom of cholestasis are needed.

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

In rare cases, in so-called dissociated cholestasis, bilirubin excretion may not be impaired and jaundice is absent.

Skin xanthomas

Skin xanthomas are a fairly common and characteristic marker of cholestasis. Xanthomas are flat or slightly raised yellow soft formations above the skin. They are usually located around the eyes (in the area of the upper eyelid - xanthelasma), in the palmar folds, under the mammary glands, on the neck, chest, and back. Xanthomas in the form of tubercles can be located on the extensor surface of large joints, in the buttocks. It is even possible to damage nerves, tendon sheaths, and bones. Xanthomas are caused by lipid retention in the body, hyperlipidemia, and lipid deposition in the skin. Xanthomas usually appear with hypercholesterolemia exceeding 11 mmol/l and existing for 3 months or more. When the cause of cholestasis is eliminated and cholesterol levels are normalized, xanthomas may disappear.

Skin xanthomas develop proportionally to the serum lipid level. The appearance of xanthomas is preceded by a long-term (more than 3 months) increase in serum cholesterol level over 11.7 μmol/l (450 mg%). Xanthomas disappear with resolution of cholestasis and normalization of cholesterol level or in the terminal stage of liver failure.

Acholia feces and steatorrhea

In cholestasis syndrome, feces become discolored, white (acholia), which is caused by the absence of stercobilinogen, which is not formed in the large intestine due to the lack of bile entering the duodenum. At the same time, the absorption of fats in the small intestine is disrupted (due to a deficiency of bile acids), which leads to steatorrhea ("fatty" feces).

Steatorrhea is caused by insufficient content of bile salts in the intestinal lumen, which are necessary for the 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 stool becomes liquid, weakly colored, voluminous, and foul-smelling. The color of the stool can be used to judge the dynamics of biliary obstruction (complete, intermittent, resolving).

A severe and long-term impairment of fat absorption contributes to the development of weight loss.

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Deficiency of fat-soluble vitamins

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

Vitamin D deficiency leads to the development of so-called hepatic osteodystrophy. This is also facilitated by the simultaneous disruption of calcium absorption in the intestine. Hepatic osteodystrophy manifests itself in bone damage, the development of diffuse osteoporosis, which is characterized by pain in the bones, in the spine, easily occurring bone fractures, especially ribs, compression fractures of the spine.

Not only vitamin D deficiency and impaired calcium absorption in the intestines participate in the development of osteoporosis, but also factors such as hyperproduction of parathyroid hormone, inadequate secretion of calcitonin, and decreased proliferation of osteoblasts under the influence of excess bilirubin.

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

Vitamin E deficiency manifests itself in dysfunction of the cerebellum (cerebellar ataxia), peripheral polyneuropathy (numbness, burning sensation in the legs, weakness of the leg muscles, decreased sensitivity and tendon reflexes), and retinal degeneration.

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

Vitamin A deficiency manifests itself as dry and flaky skin (especially on the palms of the hands) and impaired vision in the dark (decreased dark adaptation - "night blindness").

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Formation of stones in the bile ducts

Formation of stones in the bile ducts can be observed with prolonged cholestasis. Clinical and instrumental diagnostics. Gallstone disease can be complicated by bacterial cholangitis, the main symptoms of which are pain in the right hypochondrium, fever with chills, and liver enlargement).

Hepatic osteodystrophy

Bone damage is a complication of chronic liver diseases, especially cholestatic ones, in which it has been studied in most detail. Bone pain and fractures are observed. Osteomalacia and osteoporosis are probable causes. Studies in primary biliary cirrhosis and primary sclerosing cholangitis have shown that in most cases bone damage is due to osteoporosis, although osteomalacia also plays a certain role.

Bone lesions manifest themselves as back pain (usually in the thoracic or lumbar spine), decreased height, compression of the vertebral bodies, fractures with minimal trauma, especially of the ribs. X-rays of the spine can reveal decreased density and compression fractures of the vertebral bodies.

Bone mineral density can be determined by dual absorption photometry. In 31% of 123 women with primary biliary cirrhosis, severe bone damage was detected using this method. Subsequently, fractures were observed in 7%. Reduced bone mineral density was also detected in patients with advanced primary sclerosing cholangitis with elevated bilirubin levels.

The pathogenesis of bone lesions has not been fully clarified. Several factors are assumed to be involved. The normal structure of bone tissue is maintained by the balance of two oppositely directed processes: bone resorption by osteoclasts and formation of new bone by osteoblasts. Bone tissue remodeling begins with a decrease in the number of cells in inactive bone zones. Osteoclasts, resorbing bone, form lacunae. These cells are subsequently replaced by osteoblasts, which fill the lacunae with new bone (osteoid), collagen and other matrix proteins. Then, a calcium-dependent and, consequently, vitamin D-dependent process of osteoid mineralization occurs. Metabolic bone disorders include two main forms: osteomalacia and osteoporosis. In osteoporosis, bone tissue loss (matrix and mineral elements) is observed. In osteomalacia, osteoid mineralization is impaired. Verification of bone disorders in chronic cholestasis was performed using biopsy and bone tissue examination 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 new bone and an increase in bone resorption have been identified. It has been suggested that in the early, precirrhotic stage of the lesion, there is a violation of the bone formation process, while in cirrhosis, there is an increase in resorption. In women without liver disease, the processes of new bone formation and bone resorption are enhanced during menopause, with the latter predominating. This may 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 definitively established. Many factors involved in bone metabolism may have pathogenetic significance: vitamin D, calcitonin, parathyroid hormone, growth hormone, sex hormones. The condition of bones in patients with chronic cholestasis is affected by such external factors as limited mobility, poor nutrition, and decreased muscle mass. Vitamin D levels decrease due to impaired absorption, inadequate dietary intake, and insufficient exposure to sunlight. However, vitamin D treatment does not affect the condition of bone tissue. The processes of vitamin D activation in the liver (25-hydroxylation) and kidneys (1-hydroxylation) are not impaired.

Recent studies have shown a decrease in osteoblast proliferation in response to plasma from patients with jaundice; unconjugated bilirubin, but not bile acids, exerted an inhibitory effect |451. These data may help explain the disturbances in bone formation in chronic cholestasis, but require further confirmation.

Treatment with ursodeoxycholic acid does not stop bone loss in patients with primary biliary cirrhosis. After liver transplantation, bone density increases only after 1-5 years. During the first year, spontaneous fractures are common in 35% of patients with primary sclerosing cholangitis. One of the reasons for the high fracture rate may be the use of corticosteroids for immunosuppression. Vitamin D levels do not return to normal for several months after transplantation. Therefore, replacement therapy is recommended.

Determination of vitamin D levels in patients with chronic cholestasis is of great importance, since osteomalacia, despite its rarity, is easily treated. When studying serum alkaline phosphatase isoenzymes, in addition to the liver fraction, the bone fraction of the enzyme may be elevated. It is impossible to predict the development of bone changes by the level of calcium and phosphorus in the serum. Radiography reveals changes characteristic of osteomalacia: pseudofractures, Looser zones. X-ray of the hands reveals rarefaction of bone tissue. Bone biopsy reveals wide non-calcified osteoid masses surrounding trabeculae. There are many reasons for a decrease in vitamin D levels. Patients with chronic cholestasis do not spend enough time outdoors in the sun and follow an inadequate diet. Steatorrhea and malabsorption may be aggravated by long-term use of cholestyramine.

Another manifestation of bone pathology is painful osteoarthropathy of the ankles and wrists - a non-specific complication of chronic liver disease.

Copper metabolism disorder

Approximately 80% of absorbed copper is normally excreted in the bile and eliminated in the feces. In all forms of cholestasis, but especially in chronic forms (e.g., primary biliary cirrhosis, primary sclerosing cholangitis, biliary atresia), copper accumulates in the liver at concentrations that are typical of Wilson's disease or even exceed them. In rare cases, a pigmented corneal ring resembling a Kayser-Fleischer ring may be detected.

Copper deposits in the liver are detected by histochemistry (rhodanine staining) and can be quantified by biopsy. Copper-binding protein is detected by orcein staining. These methods indirectly confirm the diagnosis of cholestasis. Copper that accumulates in cholestasis does not appear to be hepatotoxic. Electron microscopy detects copper in electron-dense lysosomes, but the organelle changes associated with cytosolic copper that are characteristic of Wilson's disease are not observed. In cholestasis, copper accumulates within the hepatocyte in a nontoxic form.

Development of hepatocellular insufficiency

Hepatocellular insufficiency develops slowly, liver function in cholestasis remains intact for a long time. Liver insufficiency occurs when jaundice lasts for 3-5 years; this is evidenced by a rapid increase in jaundice, the appearance of ascites, edema, and a decrease in the level of albumin in the serum. Skin itching decreases, bleeding does not respond to treatment with parenteral administration of vitamin K. In the terminal stage, liver encephalopathy develops.

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

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Extrahepatic symptoms of cholestasis

In addition to such obvious symptoms as jaundice and itching, cholestasis is accompanied by other, less noticeable manifestations, studied mainly in cases of biliary obstruction. Serious complications may occur if the patient is weakened (dehydration, blood loss, operations, medical and diagnostic manipulations). The activity of the cardiovascular system changes, vascular reactions in response to arterial hypotension (vasoconstriction) are impaired. The sensitivity of the kidneys to the damaging effects of arterial hypotension and hypoxia increases. The body's defenses are impaired in sepsis and wound healing. An increase in prothrombin time is corrected by the introduction of vitamin K, but platelet dysfunction may be the cause of coagulation disorders. The gastric mucosa becomes more susceptible to ulceration. The causes of such changes are varied. Bile acids and bilirubin disrupt metabolism and cell function. Changes in the composition of serum lipids affect the structure and function of membranes. Endotoxemia can have a damaging effect. Thus, metabolic and functional disorders in patients with cholestasis and severe jaundice under certain conditions (surgeries, therapeutic and diagnostic manipulations) can lead to the development of acute renal failure, bleeding, are accompanied by poor wound healing and a high risk of sepsis.

Rare hereditary forms of cholestasis include Summerskill syndrome and Byler's disease (syndrome).

Summerskill syndrome is a benign recurrent familial cholestasis characterized by repeated episodes of cholestatic jaundice, beginning in early childhood, and a favorable course (without progression to liver cirrhosis).

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

Intrahepatic cholestasis of pregnancy is a benign disease that develops during pregnancy and is manifested by cholestasis syndrome.

The pathogenesis of the disease is due to increased secretion of progesterone, estrogens, placental hormones and high synthesis of cholesterol in the liver. It is possible that pregnancy predisposes to the appearance of previously existing genetic defects in bile secretion. Intrahepatic cholestasis of pregnancy 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 centrilobular cholestasis without hepatocyte necrosis.

In recent years, the syndrome of "vanishing bile ducts" has been discussed. It includes diseases characterized by reduction of bile ducts:

• primary biliary cirrhosis of the liver;
• primary sclerosing cholangitis;
• autoimmune cholangitis (corresponds to primary biliary cirrhosis of the liver in terms of clinical and morphological manifestations, but differs from it in the absence of antimitochondrial antibodies);
• cholangitis of known etiology (with cytomegalovirus infection, cryptosporidiosis, against the background of immunodeficiency states, including AIDS);
• recurrent bacterial cholangitis due to infection of intrahepatic duct cysts (in Caroli disease);
• congenital atresia or hypoplasia of the biliary tract;
• cholestasis, cystic fibrosis and sarcoidosis.

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