Cholestasis: treatment

Drug treatment for cholestasis

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

Treatment of pruritus

Drainage of biliary tract. Itching in patients with biliary obstruction disappears or decreases significantly 24-48 hours after external or internal drainage of the biliary tract.

Cholestyramine. When this ion-exchange resin is used in patients with partial biliary obstruction, the itching disappears after 4-5 days. It is suggested that cholestyramine reduces itching by binding salts of bile acids in the lumen of the intestine and removing them with feces, but this mechanism of action is only conjectural, since the cause of pruritus with cholestasis remains unclear. When taking cholestyramine in a dose of 4 g (1 sachet) before and after breakfast, the appearance of the drug in the duodenum coincides with the contractions of the gallbladder. If necessary, further increase in the dose (4 g before dinner and dinner) is possible. The maintenance dose is usually 12 g / day. The drug may cause nausea and aversion to it. The use of the drug is especially effective in combating itching in patients with primary biliary cirrhosis, primary sclerosing cholangitis, atresia and stricture of the bile duct. There is a decrease in the level of bile acids and cholesterol in the serum, a decrease or disappearance of the xanth.

Cholestyramine increases the fat content in feces even in healthy people. It is necessary to use the drug in minimum effective doses. Possible development of hypoprothrombinemia due to deterioration of absorption of vitamin K, which is an indication for its intramuscular injection.

Cholestyramine can bind calcium, other fat-soluble vitamins and medicines involved in enterohepatic circulation, especially digitoxin. Cholestyramine and other drugs should be taken separately.

Ursodeoxycholic acid (13-15 mg / kg per day) can reduce itching in patients with primary biliary cirrhosis due to choleretic action or a decrease in the formation of toxic bile acids. The use of ursodeoxycholic acid is accompanied by an improvement in biochemical indices in drug-induced cholestasis, but the antipruritic effect of the drug for various cholestatic conditions has not been proven.

Medication of pruritus

Traditional	Cholestyramine
Non-permanent effect	Antihistamines; ursodeoxycholic acid; phenobarbital
Needs caution	Rifampicin
Efficiency is being studied	Naloxone, nalmefene; ondansetron;

S-adenosylmethionine; propofol

Antihistamines are used only because of their sedative effect.

Phenobarbital can reduce itching in patients who are resistant to other types of treatment.

The naloxone opiate antagonist , according to a randomized controlled trial, reduced itching with intravenous administration, but the drug is not suitable for long-term use. Encouraging results were obtained with the oral antagonist of nalmefene opiates. The results of further controlled studies are expected; there are currently no commercial forms of the drug.

A 5-hydroxytryptamine receptor antagonist, type 3 ondansetron, led to a reduction in pruritus in a randomized study. Side effects include constipation and changes in functional liver samples. Further studies of this drug are needed.

The hypnotic drug for intravenous administration of propofol reduced itching in 80% of patients. The effect was studied only with a short application.

S-adenosyl-L-methionine, improving fluidity of membranes and giving antioxidant and many other effects, is used to treat cholestasis. The results of the treatment are contradictory, the use of the drug does not currently go beyond experimental studies.

Rifampicin (300-450 mg / day) reduces itching for 5-7 days, which can be due to induction of enzymes or inhibition of the capture of bile acids. Possible side effects include the formation of gall bladder stones, a decrease in the level of 25-OH-cholecalciferol, the effect on the metabolism of drugs and the emergence of antibiotic-resistant microflora. The safety of long-term use of rifampicin has not yet been established, therefore careful treatment of patients and observation is necessary for treatment with this drug.

Steroids. Glucocorticoids reduce itching, but this significantly worsens the condition of bone tissue, especially in postmenopausal women.

Methyltestosterone at a dose of 25 mg / day sublingually reduces itching for 7 days and is used in men. Anabolic steroids, such as stanazolol (5 mg / day), have less virilizing effect at the same efficacy. These drugs increase jaundice and can cause intrahepatic cholestasis in healthy people. They do not affect liver function, but they should be used only with refractory skin itching and in minimal effective doses.

Plasmapheresis is used for refractory itching, combined with hypercholesterolemia and xanthomatous neuropathy. The procedure gives a temporary effect, it is expensive and time consuming.

Phototherapy. UV irradiation for 9-12 minutes daily can reduce itching and pigmentation.

Liver transplantation may be the only treatment for some patients with refractory skin itching.

Biliary Decompression

Indications for surgical or conservative treatment are determined by the cause of obstruction and the condition of the patient. With choledocholithiasis resort to endoscopic papillosphincterotomy and removal of the stone. When obstructing the biliary tract with a malignant tumor, operative patients are judged to be resectable. If surgical treatment is impossible and the tumor is removed, the bile ducts are drained with an endoprosthesis, which is installed by the endoscopic or, if not successful, by a percutaneous route. An alternative is the imposition of bioliodigestive anastomoses. The choice of method of treatment depends on the patient's condition and technical capabilities.

Preparation of a patient for any of these types of treatment is important from the standpoint of preventing complications, including renal failure, observed in 5-10% of patients, and sepsis. Violations of blood coagulation are subject to correction by parenteral administration of vitamin K. To prevent dehydration and arterial hypotension, which can lead to acute tubular necrosis, intravenously injected liquids (usually 0.9% sodium chloride solution) and monitor the water balance. Mannitol is used to maintain kidney function , but before it is used, the patient should not be dehydrated. The results of recent studies raise doubts about the effectiveness of mannitol. Abnormal kidney function after the operation can partly be due to the circulation of endotoxin, which is intensively absorbed from the intestine. To reduce the absorption of endotoxin, deoxycholic acid or lactulose is administered inside, which, apparently, prevents damage to the kidneys in the postoperative period. These drugs are ineffective in cases where renal failure was present before surgery.

To reduce the risk of septic complications after surgery and medical-diagnostic manipulations, prescribe antibiotics. The length of treatment after the manipulations depends on how marked the signs of septic complications and how successful the biliary decompression was.

Important factors that determine the high postoperative mortality and the incidence of complications are the initial hematocrit index of 30% and below, the level of bilirubin is more than 200 μmol / l (12 mg%) and the obstruction of the biliary tract by a malignant tumor. To reduce the expressed jaundice in the preoperative period is possible by percutaneous external drainage of the biliary tract or endoscopic endoprosthesis, but the effectiveness of these procedures has not been confirmed in randomized controlled trials.

[6], [7], [8], [9], [10], [11], [12],

Diet with cholestasis

A particular problem is the deficiency of bile salts in the lumen of the intestine. Dietary recommendations include adequate intake of protein and maintenance of the necessary caloric intake of food. In the presence of steatorrhea, the intake of neutral fats that are poorly tolerated, insufficiently absorbed and impaired calcium absorption, is limited to 40 g / day. An additional source of fats can be triglycerides with an average chain length (TCS) in the form of an emulsion (for example, a milkshake). TCS is digested and absorbed as free fatty acids even in the absence of bile acids in the lumen of the intestine. A significant amount of TCS is contained in the preparation "Scientific Hospital Supplies Ltd, Great Britain" and coconut oil for frying and salads. An additional calcium supplement is also needed.

[13], [14], [15], [16]

Treatment of chronic cholestasis

• Dietary fats (in the presence of steatorrhea)
• Restriction of neutral fats (40 g / day)
• Additional admission TSTS (up to 40 g / day)
• Fat-soluble vitamins *
  • Inside: K (10 mg / day), A (25,000 IU / day), D (400-4000 IU / day).
  • intramuscularly: K (10 mg once a month), A (100,000 IU 3 times a month), D (100,000 IU once a month).
• Calcium: skim milk, calcium inside.

* The initial dose and route of administration depend on the severity of hypovitaminosis, the severity of cholestasis, the presence of complaints; maintenance doses - on the effectiveness of treatment.

In acute cholestasis, an increase in prothrombin time may indicate the presence of hypovitaminosis K. Parenteral administration of vitamin K at a dose of 10 mg / day for 2-3 days is recommended; Prothrombin time usually normalizes after 1-2 days.

In chronic cholestasis control prothrombin time, as well as the level of vitamins A and D in the serum. If necessary, substitution therapy with vitamins A, D and K should be done orally or parenterally, depending on the severity of hypovitaminosis, the presence of jaundice and steatorrhea, and the effectiveness of treatment. If it is not possible to determine the level of vitamins in the serum, substitution therapy is carried out empirically, especially if there is jaundice. Easy formation of bruising involves a deficiency of prothrombin and vitamin K.

Disturbance of twilight vision is better amenable to correction with oral intake of vitamin A than with intramuscular administration. Vitamin E is not absorbed, in this regard, children with chronic cholestasis need parenteral injection of tocopherol acetate at a dose of 10 mg / day. In other cases, oral administration in a dose of 200 mg / day is possible.

Treatment of bone lesions in cholestasis

Osteopenia with cholestatic diseases is manifested primarily by osteoporosis. Disturbance of absorption of vitamin D with the development of osteomalacia is less typical. It is necessary to control the level of 25-hydroxyvitamin D in the serum and densitometry, which determines the severity of osteopenia.

When hypovitaminosis is diagnosed, D is prescribed replacement therapy at a dose of 50,000 IU of vitamin D orally 3 times a week or 100,000 IU intramuscularly once a month. If the oral vitamin D level in the serum is not normalized, an increase in the dose or parenteral administration of the vitamin is necessary. In the presence of jaundice or a prolonged course of cholestasis without jaundice, a preventive intake of vitamin D is advisable; if it is impossible to determine the concentration of vitamin in the serum, preventive treatment is prescribed empirically. In conditions where the level of vitamin D in the serum is not controlled, the parenteral route of administration is preferable to oral administration.

In the treatment of osteomalacia with the presence of symptoms, the choice method is oral or parenteral administration of 1,25-dihydroxyvitamin D ₃, a biologically extremely active metabolite of vitamin D, which has a short half-life. As an alternative, la-vitamin D _{3 is used}, but its metabolic activity is manifested only after 25-hydroxylation in the liver.

The problem of preventing osteoporosis in chronic cholestasis has been studied in a small number of studies. The diet should be balanced with the addition of calcium. The daily dose of calcium should be at least 1.5 g in the form of soluble calcium or calcium gluconate. Patients are recommended to take skimmed milk, dosed stay in the sun or UV irradiation. It is necessary to increase physical activity, even with severe osteopenia (in these cases moderate loads, complexes of special exercises) are recommended.

You should avoid taking corticosteroids, which worsen the course of osteoporosis. In postmenopausal women, estrogen replacement therapy is advisable. In a small group of patients with primary biliary cirrhosis, compared with treatment with estrogens, there was no increase in cholestasis, and a tendency to decrease bone loss was observed.

The advantages of using bisphosphonates and calcitonin in bone lesions in patients with cholestasis have not been established. In patients with primary biliary cirrhosis, a small study showed an increase in bone density in fluoride treatment, but in larger studies, a decrease in the incidence of fractures in postmenopausal osteoporosis has not been noted, and the efficacy of these drugs remains controversial.

For severe pain in the bones, intravenous calcium administration (15 mg / kg per day in the form of calcium gluconate in 500 ml of a 5% glucose solution for 4 hours) is effective daily for about 7 days. If necessary, repeat the treatment.

After liver transplantation, bone tissue damage is aggravated, so it is necessary to continue treatment with calcium and vitamin D.

At present, there is no specific treatment for pain caused by periosteal reaction. Typically, analgesics are used. With arthropathy, physiotherapy can be effective.