Cholestasis - Treatment

Drug treatment of cholestasis

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Treatment of itching

Drainage of the biliary tract. Itching in patients with biliary obstruction disappears or is significantly reduced 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, itching disappears after 4-5 days. It is assumed that cholestyramine reduces itching by binding bile salts in the intestinal lumen and removing them with feces, but this mechanism of action is only hypothetical, since the cause of itching in cholestasis remains unclear. When taking cholestyramine at a dose of 4 g (1 sachet) before and after breakfast, the appearance of the drug in the duodenum coincides with contractions of the gallbladder. If necessary, a further increase in the dose is possible (4 g before lunch and dinner). The maintenance dose is usually 12 g / day. The drug can 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 strictures of the bile ducts. A decrease in the level of bile acids and cholesterol in the serum, a decrease or disappearance of xanthomas are noted.

Cholestyramine increases the fat content in feces even in healthy people. It is necessary to use the drug in minimal effective doses. Hypoprothrombinemia may develop due to deterioration of vitamin K absorption, which is an indication for its intramuscular administration.

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

Ursodeoxycholic acid (13-15 mg/kg daily) may reduce pruritus in patients with primary biliary cirrhosis due to its choleretic effect or decreased formation of toxic bile acids. The use of ursodeoxycholic acid is associated with improvement in biochemical parameters in drug-induced cholestasis, but the antipruritic effect of the drug in various cholestatic conditions has not been proven.

Medicinal treatment of itching

Traditional	Cholestyramine
The effect is not permanent.	Antihistamines; ursodeoxycholic acid; phenobarbital
Requires caution	Rifampicin
Efficiency is being studied	Naloxone, nalmefene; ondansetron;

S-adenosylmethionine; propofol

Antihistamines are used only for their sedative effect.

Phenobarbital may reduce pruritus in patients resistant to other treatments.

The opiate antagonist naloxone has been shown to reduce pruritus in a randomized controlled trial when administered intravenously, but is not suitable for long-term use. The oral opiate antagonist nalmefene has shown encouraging results. Results from further controlled trials are awaited; there is currently no commercial formulation available.

The 5-hydroxytryptamine receptor type 3 antagonist ondansetron reduced pruritus in a randomized trial. Side effects include constipation and liver function test changes. Further studies of this drug are needed.

The intravenous hypnotic propofol reduced itching in 80% of patients. The effect was studied only with short-term use.

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

Rifampicin (300-450 mg/day) reduces pruritus for 5-7 days, which may be due to enzyme induction or inhibition of bile acid uptake. Possible side effects include gallstone formation, decreased 25-OH-cholecalciferol levels, effects on drug metabolism, and the emergence of antibiotic-resistant microflora. The safety of long-term use of rifampicin has not yet been established, so careful patient selection and monitoring are necessary for treatment with this drug.

Steroids: Glucocorticoids reduce itching, but they also significantly worsen bone tissue, especially in postmenopausal women.

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

Plasmapheresis is used for refractory itching associated with hypercholesterolemia and xanthomatous neuropathy. The procedure provides a temporary effect, is expensive and labor-intensive.

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 pruritus.

Biliary decompression

Indications for surgical or conservative treatment are determined by the cause of obstruction and the patient's condition. In case of choledocholithiasis, endoscopic papillosphincterotomy and stone removal are used. In case of biliary obstruction by a malignant tumor in operable patients, its resectability is assessed. If surgical treatment and tumor removal are impossible, the bile ducts are drained using an endoprosthesis installed endoscopically or, if unsuccessful, percutaneously. An alternative is the imposition of biliodigestive anastomoses. The choice of treatment method depends on the patient's condition and technical capabilities.

Preparation of the patient for any of these treatments is important to prevent complications, including renal failure, which occurs in 5-10% of patients, and sepsis. Blood coagulation disorders are corrected with parenteral vitamin K. To prevent dehydration and arterial hypotension, which can lead to acute tubular necrosis, intravenous fluids (usually 0.9% sodium chloride solution) are administered, and fluid balance is monitored. Mannitol is used to maintain renal function, but the patient should not be dehydrated before its use. Recent studies have cast doubt on the effectiveness of mannitol. Postoperative renal dysfunction may be partly due to circulating endotoxin, which is intensively absorbed from the intestine. To reduce endotoxin absorption, deoxycholic acid or lactulose are administered orally, which apparently prevent renal damage in the postoperative period. These drugs are ineffective in cases where kidney failure was present before surgery.

To reduce the risk of septic complications after operations and treatment and diagnostic manipulations, antibiotics are prescribed in advance. The duration of treatment after manipulations depends on how pronounced the signs of septic complications are and how successful the biliary decompression was.

Important factors determining high postoperative mortality and complication rates include a baseline hematocrit of 30% or less, bilirubin levels greater than 200 μmol/L (12 mg%), and biliary obstruction by a malignant tumor. Severe preoperative jaundice can be reduced by percutaneous external biliary drainage or endoscopic endoprosthetics, but the efficacy of these procedures has not been confirmed in randomized controlled trials.

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Diet for cholestasis

A separate problem is the deficiency of bile salts in the intestinal lumen. Dietary recommendations include adequate protein intake and maintaining the required caloric content of food. In the presence of steatorrhea, the intake of neutral fats, which are poorly tolerated, insufficiently absorbed and impair calcium absorption, is limited to 40 g/day. An additional source of fats can be medium-chain triglycerides (MCTs) in the form of an emulsion (e.g., a milkshake). MCTs are digested and absorbed as free fatty acids even in the absence of bile acids in the intestinal lumen. A significant amount of MCTs is contained in the drug "Liquigen" (Scientific Hospital Supplies Ltd, UK) and coconut oil for frying and salads. Additional calcium intake is also necessary.

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Treatment of chronic cholestasis

• Dietary fats (if steatorrhea is present)
• Limitation of neutral fats (40 g/day)
• Additional intake of MCTs (up to 40 g/day)
• Fat-soluble vitamins*
  • orally: 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 taken orally.

* Initial doses and route of administration depend on the severity of hypovitaminosis, severity of cholestasis, 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 within 1-2 days.

In chronic cholestasis, prothrombin time and serum vitamin A and D levels should be monitored. If necessary, vitamin A, D, and K replacement therapy should be administered orally or parenterally, depending on the severity of hypovitaminosis, the presence of jaundice and steatorrhea, and the effectiveness of treatment. If serum vitamin levels cannot be determined, replacement therapy is administered empirically, especially in the presence of jaundice. Easy bruising suggests prothrombin and vitamin K deficiency.

Impaired twilight vision is better corrected by oral administration of vitamin A than by intramuscular administration. Vitamin E is not absorbed, therefore, children with chronic cholestasis require parenteral administration of tocopherol acetate at a dose of 10 mg/day. In other cases, oral administration at a dose of 200 mg/day is possible.

Treatment of bone lesions in cholestasis

Osteopenia in cholestatic diseases is manifested mainly by osteoporosis. Impaired absorption of vitamin D with the development of osteomalacia is less typical. Monitoring of the level of 25-hydroxyvitamin D in the serum and densitometry, determining the degree of osteopenia, are necessary.

If hypovitaminosis D is detected, replacement therapy is prescribed 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 level of vitamin D in the serum is not normalized with oral administration, an increase in the dose or parenteral administration of the vitamin is necessary. In the presence of jaundice or a long course of cholestasis without jaundice, prophylactic administration of vitamin D is advisable; if it is impossible to determine the concentration of the vitamin in the serum, prophylactic 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 the oral route.

In the treatment of symptomatic osteomalacia, the treatment of choice is oral or parenteral administration of 1,25-dihydroxyvitamin D ₃, a biologically extremely active metabolite of vitamin D with a short half-life. An alternative is la-vitamin D ₃, but its metabolic activity is only apparent 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 calcium supplementation. 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 drink skim milk, and to have dosed exposure to the sun or UV radiation. It is necessary to increase physical activity, even in severe osteopenia (in these cases, moderate loads and special exercise programs are recommended).

Corticosteroids, which worsen osteoporosis, should be avoided. In postmenopausal women, estrogen replacement therapy is advisable. In a small group of patients with primary biliary cirrhosis, estrogen therapy did not increase cholestasis, and there was a tendency to reduce bone loss.

There is no established benefit of bisphosphonates and calcitonin in treating bone disease in patients with cholestasis. In patients with primary biliary cirrhosis, a small study showed an increase in bone density with fluoride treatment, but larger studies have not shown a reduction in fractures in postmenopausal osteoporosis, and the efficacy of these drugs remains controversial.

For severe bone pain, intravenous calcium (15 mg/kg per day as calcium gluconate in 500 ml of 5% glucose solution over 4 hours) daily for about 7 days is effective. If necessary, the course of treatment is repeated.

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

There is currently no specific treatment for pain due to periosteal reaction. Analgesics are commonly used. Physiotherapy may be effective in cases of arthropathy.