Cholestasis is a pathological condition in which there is a decrease in the secretion of bile in the small intestine that results from a violation of its production or excretion. Depending on the etiopathogenetic mechanisms development of a violation of bile flow into the duodenum separate extrahepatic cholestasis and its intrahepatic form, which are fundamentally different in clinical manifestations.
In most situations, specialists use the term "cholestasis syndrome", since this pathological condition is not an independent nosological form. Pathomorphologically, this pathology manifests itself in the form of the appearance of drops of bile in the hepatic cells and around dilated canals (intrahepatic cholestasis). If there is an extrahepatic variant of cholestasis, droplets of bile accumulate mainly around the dilated bile ducts, as well as in a small amount directly in the hepatic parenchyma.
Cholestasis of the liver with a prolonged course provokes the development of structural disorders of the liver structure of a reversible and irreversible nature. In the expanded phase of the pathological process, the biliary capillary network is enlarged, the formation of thrombotic masses in the vessels, the disappearance of the villous cover in the projection of the cannula membranes and the increase in the permeability of the cell membranes, which is the histological criterion of cholestasis.
Chronic cholestasis in addition to the above changes is characterized by the formation of irreversible disorders in the form of development of biliary infarctions, sclerosis zones and the formation of microabscesses. Experts of the gastroenterological profile hold the opinion that practically any form of liver damage, as a structural unit, inevitably provokes the pathogenetic mechanisms of cholestasis. In addition, there are a number of pathologies accompanied by damage to the ducts of both intrahepatic and extrahepatic localization.
Causes of cholestasis
Among the pathological conditions capable of provoking the development of cholestasis is a large range of diseases, but all these etiological factors unite a single etiopathogenetic mechanism for the development of cholestasis. So, the main link of pathogenesis is the damaging effect of bile acids on liver cells. All diseases and pathological conditions, which are the background for the development of cholestasis, are usually divided into two pathogenetic categories: diseases accompanied by a violation of the production of bile in the required amount and pathological conditions that disrupt the normal flow of bile.
Violation of the bile-forming function of the liver is observed in alcoholic lesions of the hepatic parenchyma, viral and toxic effects on the body with the predominant localization of toxic agents in the liver. In addition, the process of bile formation is adversely affected by impaired microflora in the intestine, cirrhotic changes in the liver and endotoxemic conditions. To this etiopathogenetic category is intrahepatic cholestasis of pregnant women.
The normal process of bile outflow is adversely affected by pathological changes in the bile duct (cholangitis, duktopathy, Caroli disease), congenital anomalies of the bile duct system, and systemic biliary cirrhosis . Such systemic diseases as tuberculosis , lymphogranulomatosis and sarcoidosis inevitably provoke changes in the normal functioning of the structures of the hepato-biliary system, but these disorders develop mainly in the late stages of the underlying disease.
Intrahepatic cholestasis in all situations is accompanied by excessive accumulation of bile acids not only in the circulating blood, but also in tissues of various types with a simultaneous insufficient content in the lumen of the duodenum of the small intestine. Hepatic cholestasis can occur in several forms. Thus, with its functional variant, there is a significant slowing of the tubular bile flow, and morphological cholestasis is accompanied by a significant deposition of bile components in the projection of hepatocytes and bile ducts. The clinical form of intrahepatic cholestasis is observed when bile components are delayed in circulating blood, while under normal conditions, bile acids are excreted into bile.
The development of intrahepatic cholestasis becomes possible even with the complete absence of obturation of the lumen of the main bile duct. However, the existing obstruction of the bile ducts of the intrahepatic order inevitably provokes the development of cholestasis syndrome.
Symptoms and signs of cholestasis
Cholestatic syndrome caused by excessive excretion of bile acids and other bile components in the liver and other tissues of the human body is inevitably accompanied by the development of pathological structural changes in target organs that have specific clinical and laboratory manifestations.
At the basis of development of clinical variants of cholestasis and their intensity, three main mechanisms are laid: excessive deposition of bile components in circulating blood and tissues, a significant decrease in bile concentration in the duodenal region, toxic damaging effect of bile acids on hepatocytes. The intensity of manifestation of certain clinical symptoms directly depends on the background disease, the severity of hepatic-cell insufficiency and the severity of the violation of the excretory function of hepatocytes.
Skin itching with cholestasis along with signs of disruption of digestion and absorption of nutrients in the intestine are the main clinical criteria of this pathological condition, regardless of the form in which cholestasis occurs. Pathognomonic manifestations of the chronic course of cholestasis is a typical lesion of the skin in the form of development of hyperpigmentation and xantelasm formation, as well as hepatic dystrophy, as a reflection of bone tissue damage. The development of hepatic osteodystrophy is promoted by vitamin D and E deficiency, and the initial manifestations of this complication is a pronounced pain syndrome in the projection of the thoracolumbar spine. In addition, this category of patients is at risk of spontaneous pathological fractures due to diffuse osteoporosis .
The peculiarity of cholestasis is that the development of manifestations of asthenic syndrome occurs only with concomitant hepatocellular lesion and manifests itself in the form of the appearance of unmotivated weakness, dizziness, inability to perform the usual physical load. With available intrahepatic cholestasis, there is a change in the shape and size of the liver toward a significant increase, provided that the pain syndrome is completely absent and the structure of the hepatic parenchyma is disturbed. The increase in the parameters of the spleen takes place only as a concomitant pathology of biliary cirrhosis, which is extremely rare.
One of the most specific manifestations of cholestasis, allowing an experienced specialist to establish a preliminary diagnosis without conducting a specific laboratory examination of the patient, is a change in the stool in the form of an increase in his daily amount, stench, discoloration, and structural abnormalities. In connection with the fact that when cholestasis is limited to the entry of bile acids into the duodenal section of the small intestine, a large concentration of unsplit fats accumulates in the stool masses.
Violations of the absorption function of the intestine inevitably affect the vitamin balance in the body. So, even a short course of cholestasis provokes the development of vitamin K deficiency in the body, manifested by excessive bleeding of the mucous membranes. Chronic cholestasis in all the situation is accompanied by signs of vitamin A deficiency .
The result of violation of the digestive and absorption function of the intestine, which is observed in all pathogenetic variants of cholestasis, is prolonged debilitating diarrhea . Abundant diarrheal syndrome provokes the development of dehydration and the release of a large number of electrolytes and other nutrients. The outcome of this condition is the development of malabsorption syndrome and progressive weight loss of the patient, even under the condition of normal nutrition.
The most important clinical criterion for chronic cholestasis is the pathognomonic lesion of the skin in the form of xanth , which are represented by yellow tumor-like spots that result from a violation of lipid metabolism. The favorite localization of these changes is the skin of the upper half of the trunk, as well as the area of the natural folds of the skin. The appearance and disappearance of xanthomas can be regarded as a diagnostic sign reflecting the level of cholesterol in the blood. In a situation where the pigment spots in the patient are localized exclusively paraorbital, the specialists apply the term "xanthelasm".
Also, cholestasis is accompanied by manifestations that are characteristic for the disturbance of the metabolism of copper in the body, since under normal conditions, the excretion and absorption of copper in the small intestine is shared with the bile. Prolonged cholestasis is accompanied by a significant increase in the concentration of copper and its deposition in target organs by the type of Wilson-Konovalov's disease .
The main complication of cholestasis, observed in 70% of cases under the condition of its prolonged course, is formation of pigmented stones in the structures of the biliary system and concomitant signs of bacterial cholangitis. In addition, the clinical picture in each patient may differ, depending on the manifestation of the background disease.
In addition to the characteristic clinical manifestations that allow an experienced specialist to correctly establish a diagnosis already at the initial contact with a patient with cholestasis, there is a certain algorithm for examining this category of patients. All laboratory-instrumental techniques used in this situation are aimed not so much at diagnosing cholestasis, but rather in identifying the cause of its occurrence. So, carrying out ultrasound examination or cholangiography in most cases allows to establish the exact localization of mechanical blockade in the lumen of the structures of the hepato-biliary system. If there is a suspicion that the patient has an intrahepatic version of cholestasis, provided that there is no information in other instrumental techniques, a puncture biopsy is recommended.
Cholestasis in pregnant women
The prevalence of this pathology among the general population of pregnant women is 1: 500 and such a high rate is determined by the family type of inheritance. In addition, cholestasis during pregnancy is prone to recurrent course, so the subsequent pregnancy in 80-90% of cases also occurs with signs of cholestasis. The fatal mortality rate for cholestasis in a pregnant woman is no more than 10% and in the majority of cases is caused by massive uterine bleeding due to vitamin K deficiency.
Pathogenetic mechanisms of development of cholestasis in a woman during pregnancy are explained by a violation of the metabolism of estrogens, which have an inhibitory effect on the process of formation and secretion of bile. In a situation where there is a significant deposition of bile acids and other components of bile in the placenta, the risk of provoking premature births in the early stages of fetal development incompatible with life is significantly increased. Among gastroenterologists, there is an opinion that pregnancy acts as a provoking factor in the development of genetic defects of production and bile secretion that have been born since birth.
The risk group for the development of this pathology is women who are in the third trimester of pregnancy and in most cases the only clinical manifestation of cholestasis is a painful common skin itch. The predominant localization of skin manifestations of cholestasis during pregnancy is the upper half of the trunk and especially the palms of the hands. In most situations, itching is self-leveling after the delivery of the woman no later than two weeks.
The greatest information about the diagnosis of the cholestatic syndrome during pregnancy has a biochemical blood test, in the study of which there is a significant increase in the direct fraction of bilirubin and activity of alkaline phosphatase under the condition of normal ALT and AST. When carrying out a specific analysis of the content of bile acid fractions in the blood of a pregnant woman with cholestasis, there is a significant increase in their concentration exceeding the normal values by 100 or more.
Despite the fact that cholestasis in pregnancy at a late period is a frequent pathology even in absolutely healthy women, when identifying its signs, it is necessary to carefully examine the patient for the presence of other diseases having a similar clinical and laboratory picture (parenchematous and mechanical jaundice, hereditary diseases with metabolic disorders, acute fatty hepatosis ).
Subject to slightly expressed clinical and laboratory criteria for cholestasis, the treatment of a pregnant woman consists exclusively in the use of symptomatic drugs (Promethazine in a daily dose of 75 mg, Phenobarbital in a daily dose of 45 mg orally). In a situation when a pregnant woman has a significant excess of bile acid levels and there is no indication for routine delivery, it is recommended to use drugs whose action is aimed at reducing the level of serum bile acids (cholestyramine in a daily dose of 12 g) with simultaneous application of Phytomenadione in 10 mg subcutaneously once a week and Folic acid in a daily dose of 1 mg.
In connection with the increased risk of uterine bleeding diet with cholestasis of pregnant women is of great importance. A woman should eat enough food containing a high concentration of vitamin K, and also limit the consumption of fatty foods.
Cholestasis in children
The frequency of occurrence of cholestasis in children during the newborn period and in the breast period varies considerably in the populations of different countries and regions, but there is a certain tendency to increase the incidence of cholestasis of extrahepatic origin in this category of patients. Do not also overlook the transient variants of the course of the cholestatic syndrome of newborns, even though it does not bring significant harm to the health and development of the child.
Determination of the etiopathogenetic variant of cholestasis in children is of paramount importance, since the further tactics of treating the patient depend on this. At present, most of the variants of extrahepatic cholestasis in infants is an absolute indication for the use of surgical intervention, since modern methods of surgical treatment of extrahepatic bile duct atresia allow to achieve good results in eliminating the signs of cholestasis.
Common signs characteristic of both etiopathogenetic variants of cholestasis are the appearance of clinical and laboratory signs of a violation of bile outflow. Clinical criteria in this case is the appearance of icteric staining of the skin and mucous membranes, discoloration of stool and darkening of urine. The most important diagnostic sign of cholestasis in the newborn period is the staining of the feces, since its change allows one to assess the dynamics of cholestasis. For newborns, the appearance of severe itching is not typical, and in the older age, severe itching of the skin is observed with intrahepatic cholestasis. It should be borne in mind that during the newborn period, cholestasis always flows with jaundice, which is a specific pathognomonic clinical marker of this pathology.
In children, in addition to severe clinical symptoms, cholestasis is accompanied by significant changes in laboratory indicators in the form of an increase in the conjugated bilirubin index, an increased total cholesterol index and an increase in the activity of alkaline phosphatase.
The most common cause of development of extrahepatic variant of cholestasis in a child during the newborn period is atresia of extrahepatic biliary tract, observed in one case out of 10,000 newborns. Intrahepatic variant of development of cholestasis in children takes place with direct viral, metabolic and immunological hepatocellular lesions of the hepatic parenchyma.
Medication correction of cholestasis consists in the appointment of drugs that improve the outflow of bile and normalize the parameters of bile acids in the blood serum, and the choice of the drug directly depends on the degree of clinical and laboratory manifestations of cholestasis (Phenobarbital at a calculated dose of 5 mg per 1 kg of the child's weight, cholestyramine in a daily dose of 4 g). The appointment of glucocorticosteroid drugs is considered unjustified for infants due to the complete lack of efficacy and an increased risk of developing infectious complications.
Treatment of cholestasis
Since cholestasis is not an independent nosological form and represents clinical and laboratory support for the main background disease, all the variants of therapeutic measures used in this pathology are classified as symptomatic or etiopathogenetic.
The main goal of the symptomatic component of treatment of cholestasis is the elimination of the main clinical signs of the disease, namely, pruritus. The most effective method of stopping dermal manifestations of cholestasis is the drainage of the bile ducts by external or internal methods, after application of which, itching stops for two days. With the existing contraindications to the use of drainage of the bile ducts, cholestyramine should be used, the use of which makes it possible to level the skin itch for five days. The optimal single dose of Cholestyramine is 4 g with the preferred method in conjunction with breakfast, lunch and dinner. The appearance of signs of hypoprothrombinemia is an indication for the transition to the parenteral route of administration of cholestyramine in the minimum effective dose.
Another drug that has an effective antipruritic effect is Ursodeoxycholic acid. Especially this drug is effective in the treatment of patients suffering from primary biliary cirrhosis at a calculated dose of 10 mg per 1 kg of the patient's weight. Provided that there is no effect from the application of the above mentioned preparations, one should resort to the appointment of sedatives with a short course (Phenobarbital 0,05 g twice a day). A good antipruritic effect is possessed by preparations of the glucocorticosteroid series, but in view of the wide range of negative reactions in the form of deterioration of bone tissue and the increased risk of infectious complications, this treatment is extremely rare.
Provided that the patient has refractory itch combined with critical values of cholesterol in the blood and xanthomatous neuropathy, plasmapheresis should be applied with a short course. However, in most cases, the only method that allows to remove refractory skin itching in cholestasis is liver transplantation.
The use of drugs that have a pronounced hepatoprotective effect is indicated in the intrahepatic version of cholestasis and the drug of choice in this situation is Heptral. The course of hepatoprotective therapy consists in the parenteral administration of Heptral at a dose of 5 ml for two weeks and the subsequent transition to tablet administration of the drug in a daily dosage of 800 mg for at least two months. Rifampicin has a similar effect, which improves the acidic microflora necessary for the normal metabolism of bile acids. The scheme for taking Rifampicin is oral administration of 150 mg per day for three months.
The patient's biliary compression is the basis for the application of surgical techniques. Currently, the concrement in the projection of the common bile duct, which is available in a patient with cholestasis, is successfully eliminated by the method of carrying out papillosphincterotomy by the endoscopic method. In a situation where the obstruction of the bile ducts is caused by the existing tumor substrate, the primary task of the operating oncologist is to assess the resectability of the tumor. If the tumor process is at an inoperable stage, the surgeon must decide to conduct the drainage of the biliary tract with endoscopic access.
The use of any surgical manual for cholestasis requires a careful approach to the issue of preparing a patient for surgical intervention, given the high risk of developing infectious and hemorrhagic complications. In order to prevent possible bleeding, preoperative preparation of a patient suffering from cholestasis provides parenteral administration of vitamin K at a daily dose of 0.03 g. To reduce the risk of infectious complications, the patient should be treated with an adequate antibiotic therapy in the preoperative and postoperative period.
The main link in the treatment of chronic cholestasis is the correction of eating behavior and beriberi. Correction of nutrition consists in enriching the daily menu with products containing vegetable fat and a sharp restriction on the use of neutral fats. In the event that the patient develops minimal manifestations of vitamin A deficiency in the form of a decrease in twilight vision, it is recommended that a course of parenteral administration of an oily solution be administered at a dose of 10,000 IU.
In addition, the chronic course of cholestasis is always accompanied by a violation of the process of bone formation, which is manifested in the development of progressive osteoporosis and the consequences of this pathological condition. When identifying the initial manifestations of osteoporosis in a patient with cholestasis, it is necessary to apply vitamin D replacement therapy according to the scheme: once a month intramuscular injection of 100,000 IU or orally 3 times a week for 50000 IU. The appointment of vitamin D is justified, even if there are no signs of damage to bone tissue as a prophylactic agent for patients with a prolonged course of icteric syndrome.
In some situations, the patient's cholestatic syndrome can occur with the appearance of severe pain syndrome in the projection of the bones, so in this case it is justified to administer intravenous calcium gluconate at a calculated dose of 15 mg per 1 kg of weight with a 5% glucose solution in a volume of 500 ml. Also, the appointment of substitution therapy with calcium and vitamin D preparations is mandatory in the postoperative period after liver transplantation.