Cholestasis is a pathophysiological process caused by impaired bile secretion and excretion, which manifests as an excessive accumulation of bile components such as bile acids, cholesterol and bilirubin in the liver and body circulation, causing damage to liver cells and the body, and long-term persistent cholestasis will progress to liver fibrosis or even cirrhosis. During biliary stasis, elevated bile acid, bilirubin and other bile components in the body activate nuclear receptors related to bile acid metabolism, up-regulating or down-regulating their related target genes, resulting in reduced bile acid synthesis and increased bile acid output, and enhancing the detoxification of stagnant components by the liver. However, the compensatory effect of the organism itself is limited and cannot completely alleviate biliary stasis, and intervention of related therapeutic measures is still required. In cases of secondary intrahepatic cholestasis with a clear etiology, such as those caused by drug or rejection reactions, treatment of the cause is the most crucial. However, clinical encounters with intrahepatic cholestatic diseases of unknown etiology, without specific treatment or even rare, may be considered for symptomatic treatment by different aspects such as stimulating the expression or enhancing the activity of defective transporter proteins.
Ursodeoxycholic acid
Ursodeoxycholic acid (UDCA) is currently the only FDA-approved drug widely used for the treatment of cholestasis and is a hydrophilic dihydroxycholic acid first isolated from the bile of Chinese black bears. It is a 7b-isomer of goose deoxycholic acid formed by the action of colonic bacteria. Oral administration of UDCA enhances its absorption by dissolution of bile acids, so it is recommended to take it with meals. Concurrent administration of activated carbon, aluminum-containing antacids, colestipol, and other drugs may reduce the intestinal absorption of UDCA because these drugs bind UDCA in the intestine. In addition, the absorption and bioavailability of UDCA may be reduced during progressive cholestasis. After intestinal absorption, UDCA enters the portal circulation and is taken up by the Na+-dependent taurocholate cotransporting polypeptide (NTCP), a specific bile acid transporter protein in the hepatic sinusoidal membrane of hepatocytes, and the organic anion transporter (OAT) into hepatocytes by uptake [1]. In hepatocytes, UDCA is mainly bound to glycine (mostly) or taurine, and then transported to the biliary system via the bile salt export pump (BSEP) in the bile duct membrane, followed by the enterohepatic circulation. UDCA is a ligand for the farnesoid X receptor (FXR), which downregulates cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme of cholesterol metabolism, thereby inhibiting the endogenous synthesis of bile acids, upregulating the bile salt export pump (BSEP) in the capillary and basolateral membranes of hepatocytes, reducing the expression of multiresistance-related protein (MRP ) 2 expression, reducing intrahepatic bile acid burden, and also combining anti-apoptotic and anti-fibrotic effects.
I. Primary biliary cirrhosis (PBC)
PBC is a chronic cholestatic liver disease, which is common in middle-aged and elderly female patients and is characterized by immune-mediated damage to small intrahepatic bile ducts. Persistent damage to the bile ducts results in impaired bile secretion, causing retention of hydrophobic toxic bile acids and leading to hepatocellular damage. Based on placebo-controlled trials and long-term case-control studies, several results suggest that UDCA 13-15 mg/(kg?d) is the treatment of choice for PBC. . In addition, stimulation of biliary alkaline bile and inhibition of bile acid-induced apoptosis in hepatocytes and bile duct cells both facilitate the effective role of UDCA in patients with PBC [4]. early application of UDCA in PBC effectively improves its biochemical indices, such as serum bilirubin, serum alkaline phosphatase (ALP), gamma-glutamyl transpeptidase ( gamma-glutamyhransferase (GGT), cholesterol and immunoglobulin (Ig) M levels, slowing down the histological progression of PBC and reducing the possibility of liver transplantation and death. Although UDCA has achieved some efficacy in the treatment of PBC, it is far from satisfactory, and there are still some patients as well as patients with advanced disease who do not respond well to UDCA.
Primary sclerosing cholangitis (PSC)
PSC is also a chronic cholestatic liver disease that occurs in young and middle-aged men and involves both intra- and extrahepatic bile duct systems. The disease can lead to irregular bile duct occlusion and the formation of multifocal bile duct strictures that will eventually progress to cirrhosis. Most patients with PSC develop inflammatory bowel disease, with ulcerative colitis (UC) being the most common. According to available studies, higher doses of UDCA [15-20 mg/(kg?d)] have been shown to improve serum biochemical and prognostic parameters in patients with PSC, but no improvement in survival has been demonstrated. The specific mechanism of action of UDCA in slowing the progression of PSC-related liver disease is still unclear, and high doses of UDCA may be detrimental to the regression of advanced PSC. However, recent studies suggest that UDCA has a chemopreventive effect on colonic tumor formation in patients with PSC with UC, and the UDCA-treated group showed a trend toward a reduced risk of abnormal colonic hyperplasia and neoplasia compared with patients with PSC with UC without UDCA treatment. UDCA therapy may be especially considered in high-risk groups of PSC patients with a family history of colorectal cancer, previous colorectal tumors, or long-term extensive colitis.
Intrahepatic cholestasis of pregnancy (ICP)
ICP is the most common idiopathic liver dysfunction disease in the middle and late stages of pregnancy, with clinical manifestations of pruritus, elevated serum bile acid levels and abnormal liver function, mostly occurring between the l6th and 36th weeks of pregnancy. Pregnancy is the only cause of pruritus, jaundice, and abnormal biochemical parameters, without severe vomiting, loss of appetite, debility, psychiatric abnormalities or bleeding, and renal failure. UDCA was first reported for the treatment of ICP in 1992 and is the only first-line recommended drug for ICP with proven efficacy in randomized, double-blind, placebo, controlled studies to date. There have been no published reports of adverse fetal effects with UDCA, and it has a good safety profile for use in mid to late pregnancy.
Progressive familial intrahepatic cholestasis (PFIC)
PFIC is characterized by severe intrahepatic cholestasis and is a rare autosomal recessive disorder. Children with PFIC tend to present with progressive jaundice, pruritus and growth disturbances, eventually progressing to cirrhosis and liver failure. Although UDCA is relatively effective and can improve the clinical symptoms and liver function of children, it cannot fundamentally reverse the disease.
Glucocorticoids and other immunosuppressants
I. Prednisolone
Although prednisolone can improve the serum liver function and liver histology of PBC patients, it significantly damages the bone density of patients, accelerates the occurrence and progression of osteoporosis, and increases the possibility of spontaneous fracture, so it is not suitable for long-term application. Short-term (9 months) prednisolone (10 mg/d) in combination with UDCA 10 mg/(kg?d) improved more significantly all liver histological manifestations in early PBC compared to UDCA monotherapy. combination of UDCA with glucocorticoids is the recommended therapy for the overlapping syndrome of PBC and autoimmune hepatitis. Glucocorticoids and other immunosuppressive agents are not recommended in the treatment of adult PSC patients unless there is evidence of autoimmune hepatitis overlap syndrome.
IgG4-associated sclerosing cholangitis (IAC) occurs mostly in the elderly and is a chronic inflammatory disease characterized by elevated serum IgG4, chronic progressive obstructive jaundice, diffuse or limited IgG4-positive plasma cell and lymphocytic tissue infiltration, fibrosis, and occlusive phlebitis. inflammatory disease, often complicated by autoimmune pancreatitis. The clinical, biochemical and imaging features are similar to those of PSC, bile duct cancer and pancreatic tumors. The immunopathogenesis of IAC is clearly distinct from other immune-mediated cholestatic liver diseases such as PSC and PBC, with significant overexpression of helper T (Th) cytokine type 2 and regulatory T cytokines in patients. After hormone therapy, patients with jaundice and hepatic function recover with the disappearance of biliary strictures or varying degrees of improvement. There is no consensus on the dose and duration of hormone therapy for IAC, but the starting dose in most studies is prednisolone 40 mg/d for 4 weeks, followed by a weekly dose reduction of 5 mg for about 2 to 3 months. Although the sensitivity of IAC to hormonal therapy is high, the recurrence rate after initial treatment is also high (54%); the recurrence rate is not significantly different in those treated with hormones compared with those treated with surgery, while the recurrence rate is higher in proximal biliary strictures (proximal extrahepatic or intrahepatic bile ducts) than in distal biliary strictures. Persistent elevation of IgG4 in those receiving hormonal therapy or its re-elevation after treatment may also predict recurrence. Therefore, the European Society of Hepatology recommends glucocorticoids as an option for initial treatment of IAC. The addition of azathioprine 2 mg/(kg?d) is considered for those patients with proximal and intrahepatic biliary stenosis and recurrence of glucocorticoid therapy. The recommended duration of glucocorticoid therapy is 3 months for primary patients, but when the disease is active or recurrent, long-term low-dose maintenance therapy is required.
Budesonide
Combination therapy with budesonide and UDCA in early stage PBC patients who do not respond well to UDCA therapy can delay or stop the progression of the disease, but it is not effective in advanced PBC. Some studies have even shown that the formation of portal vein thrombosis in patients with stage 4 PBC in the presence of portal hypertension may be associated with the short-term application of budesonide. Therefore, budesonide should not be used in patients with cirrhosis [19].
III.Dexamethasone
Dexamethasone in ICP patients can reduce the secretion of fetal adrenal dehydroepiandrosterone through the placenta, decrease estrogen levels, reduce cholestasis and promote fetal lung maturation to avoid respiratory distress syndrome in preterm infants. However, in view of the effects on maternal metabolism, immunity and fetal neurodevelopment, it is now mainly used to promote fetal lung maturation in ICP patients before 34 weeks of gestation, or in those estimated to be at risk of preterm delivery within 7 d, and in those with severe conditions who are planning to terminate their pregnancies.
Other immunosuppressive agents such as azathioprine, cyclosporine, methotrexate, azathioprine phenylbutyrate, and mescaline may be effective, ineffective, or potentially harmful when used long-term, and are therefore not recommended as standard of care for PBC and PSC.
S-adenosylmethionine
S-adenosylmethionine (SAM) is a sulfur-containing amino acid analog that regulates the fluidity of hepatic cell membranes, accelerates the inactivation of estrogen metabolites, and increases the synthesis of glutathione through transsulfuration, with detoxifying and cytoprotective effects, mainly in the liver by methylating plasma membrane phospholipids, thereby reducing intrahepatic bile It also has detoxifying and cytoprotective effects by increasing glutathione synthesis through transsulfurylation, thereby reducing intrahepatic biliary stasis and restoring damaged hepatocyte function. Since endogenous SAM synthesis is reduced in liver lesions, supplementation with exogenous SAM is helpful in the prevention and treatment of intrahepatic cholestasis. The drug significantly reduces pruritus symptoms and lowers serum conjugated bilirubin, bile acid and transaminase levels in ICP patients. However, its therapeutic effect may be inferior to that of UDCA, so it is often used in combination with UDCA in clinical practice.
Bile acid metabolism-related nuclear receptors
Recent studies have found that the FXR agonist, 6-ethyl chenodeoxycholic acid ( 6-ECDCA) derivative INT-747, is expected to be a new generation of drug for the treatment of cholestasis in PBC patients with poor UDCA response. Administration of 12 weeks of 6-ECDCA in combination with UDCA significantly improved serum ALP and GGT [22]. further studies and clinical trials are still needed to determine whether 6-ECDCA can be used alone and in the long term in patients with PBC. Before the discovery of the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), their agonists rifampicin and phenobarbital were used to treat refractory pruritus caused by severe cholestasis, upregulate MRP2 expression, and enhance hepatic detoxification of bile acids and bilirubin detoxification and increase their excretion. The peroxisome proliferator-activated receptor (PPAR) α agonist betablockers improve the biochemical parameters and histological manifestations of transaminases and cholestasis in patients with PBC with poor UDCA response [23]. In addition, other nuclear receptor-related drugs are under continuous investigation. The use of nuclear receptors as targets for the treatment of cholestatic diseases has a broad research potential and important clinical value. The regulatory network of nuclear receptors on target genes in vivo is quite complex, and various types of nuclear receptors interact with each other and influence each other, and their agonists as therapeutic drugs inevitably produce a series of adverse effects while regulating the balance of bile acid metabolism. The combination of specific nuclear receptor agonists and different nuclear receptor agonists can improve clinical efficacy and reduce adverse effects, and will be a new direction for the treatment of cholestasis.