The Pathophysiology of Cholestasis and Its Relevance to Clinical Practice (2024)

Short abstract

Key Learning Points

• Cholestasis is evident when the formation or excretion of bile is impaired.

• Serum liver tests usually demonstrate raised values of alkaline phosphatase and/or gamma‐glutamyltransferase (GGT), disproportionate to other serum markers of liver injury.

• There are many causes of cholestasis, some acute and others chronic; the severity and duration of cholestatic liver injury associates with the risk for development of biliary cirrhosis.

• Usually benign, often self‐limiting, cholestatic syndromes can be seen during pregnancy and after some drug injuries.

• A proportion of cholestasis has a strong heritable component notably in childhood; in adult patients, autoimmune disease (e.g., primary biliary cholangitis [PBC] and primary sclerosing cholangitis [PSC]) more frequently cause chronic cholestatic syndromes.

• Treatments for nonobstructive cholestasis are not usually specific to single pathophysiological mechanisms, for example, the non‐specific hydrophilic bile acid ursodeoxycholic acid. Molecular‐based therapies such as the licensed farnesoid X receptor (FXR) agonist obeticholic acid and a variety of peroxisome proliferator‐activated receptor (PPAR) agonists are increasingly being used and studied.

Cholestasis is evident when there is impaired formation or excretion of bile, and this is the case when the underlying disease process, acute or chronic, leads to impaired hepatobiliary function. In most hepatobiliary disease there will be a degree of cholestasis, but in diseases that target the biliary tree more specifically, cholestasis becomes a dominant feature.

Cholestasis is often subclassified as intrahepatic (hepatocyte injury, bile canaliculi, or intrahepatic bile ducts) or extrahepatic (extrahepatic ducts, the common hepatic duct, or the common bile duct). Biliary disease severity will often relate to the site of injury, and the capacity of the liver to compensate for biliary damage will inevitably be greater in diseases that are restricted to small bile ducts as compared with large duct diseases. The consequences of cholestatic liver injury are varied, and reflect the severity and duration of injury, as well as the efficacy of reparative processes. Although triggers for cholestatic liver disease are frequently very different, therapies continue to focus on commonality in downstream mediators of liver injury.

What is Bile for?

Bile is an emulsificant produced by the liver that is necessary to mediate the absorption of fatty acids and fat‐soluble vitamins from the small intestine; bile acids are equally important signaling molecules that are critical to maintaining a healthy liver‐gut axis. The appreciation of this axis and the importance of bidirectional interactions between the liver and the gut, via the microbiome, as well as enterohepatic signaling, are continuing to be better appreciated.

Bile acids are the principal solutes secreted into the canaliculi and are the primary drivers of bile formation and flow. Bile acids can be synthesized de novo in the hepatocytes or taken up from sinusoidal blood. They are transported and then secreted into biliary canaliculi, from where bile flow carries them to the gallbladder and, in the postprandial state, to the intestine. Bile acids are actively reabsorbed from the terminal ileum and taken up from the portal blood in the hepatic sinusoids at the basolateral membranes of hepatocytes. They are then secreted into the canaliculus again; bile acids undergo enterohepatic circulation approximately five times daily.

What Defines Cholestasis?

When there is impaired formation, or excretion of bile, one consequence is an accumulation of biliary constituents beyond the limits of the normal cellular architecture of the liver, contributing to cellular damage to the hepatic parenchyma, toxic injury to the biliary tree, and circulation peripherally of noxious chemicals, including bile acids. The relevant disease pathology may impair cellular function of hepatocytes or biliary epithelium, or, because of benign or malignant processes, cause intrinsic or extrinsic obstruction to biliary flow; injury thereby may span any point from the basolateral (sinusoidal) membrane of the hepatocyte to the ampulla of Vater. The pathophysiology of disease is very broad and overlapping. It may be a result of very specific changes to molecular transporters that are key to biliary homeostasis, a reflection of inflammatory and obstructive biliary disease, or a nonspecific response to a systemic insult such as prolonged sepsis.

How do Patients Present?

Clinically, patients can range from being asymptomatic to having severe symptoms including pruritus, fatigue, abdominal pain, and systemic upset. Laboratory indices are focused on changes to serum liver tests, particularly alkaline phosphatase and GGT. Depending on the speed of onset, however, acute cholestasis may at times be evident only by raised serum aminotransferase activity (direct hepatic injury from bile acids). Bile acid values, although very sensitive, are not largely used diagnostically. Mechanistically, serum alkaline phosphatase activity increases are a result of increased hepatic synthesis, with consequent release of liver alkaline phosphatase in sinusoidal blood. There is a correlation between bile acid concentration and alkaline phosphatase activity; it seems with less bile acid canalicular secretion and secondary bile acid retention, liver alkaline phosphatase synthesis increases. GGT is a very sensitive laboratory index, but not purely of cholestasis; when elevated in the context of cholestasis, however, this is associated with damage to the apical membranes of bile ducts and disruption of intercellular junctions because of high concentrations of biliary bile acids. In some rare genetic cholestasis syndromes, synthesis or canalicular secretion of bile acids is largely absent, with no significant release of membrane GGT from damaged cholangiocytes, or leakage of bile into the extracellular space, and subsequently the blood. In these scenarios, GGT can be characteristically normal or even low. With greater severity and/or bile duct loss or obstruction, clinically significant jaundice becomes evident. In view of a close association between bile acid metabolism and lipid metabolism, cholestasis is often associated with lipoprotein abnormalities. These may be evident as skin xanthelasma, as well as elevated serum cholesterol values.

What are Important Pathophysiological Themes in Cholestasis?

Many injuries result in cholestasis (see Fig. ​Fig.11 and Table ​Table1),1), which span congenital and acquired etiologies. Relative frequency is dependent on the population studied, such that in children, important pathophysiology arises from genetic cholestasis syndromes (e.g., progressive familial intrahepatic cholestasis [PFIC] syndromes, Alagille syndrome), as well as biliary atresia. In adults, cholestasis spans a wide array of etiologies. Genetic cholestasis (e.g., benign recurrent cholestasis, biliary disease from damaging variants in the MDR3 gene) is less common, and most frequently cholestasis is acute, that is, in the context of drug‐induced liver injuries, pregnancy (obstetric cholestasis), sepsis, or biliary obstruction (intrinsic or extrinsic to the biliary tree; either benign or malignant in nature). When injury is chronic and persistent, the causes are notably likely to belong to the family of autoimmune biliary diseases, such as PBC, PSC, or immunoglobulin G4 (IgG4) disease. For such diseases, we appreciate genetic and environmental risk factors, but no single etiologic‐specific process.

Cholestasis that is prolonged, severe and chronic, particularly when associated with bile duct loss (ductopenia), will then result in fibrosis and cirrhosis. Different cholestatic syndromes can also have elevated hepatocellular carcinoma or cholangiocarcinoma risks, which may not be linearly related to disease severity and/or duration. Cholangiocarcinoma, for example, can be a presenting manifestation of PSC.

Hepatocyte and biliary epithelial cell regeneration are important in health and disease. Cellular proliferation in response to liver damage, as well as participation in inflammatory responses, is carefully controlled and orchestrated. If the equilibrium between cholangiocyte death (via apoptosis or necrosis) and proliferation is unbalanced, the result is bile duct loss and progressive biliary disease. In advanced biliary disease, cholangiocytes lose the ability to proliferate and may also undergo senescence, with associated secretory phenotypes. In progressive ductopenia, there is more cellular apoptosis than proliferation. Equally in response to inflammation, cholangiocytes further secrete cytokines and chemokines that recruit and activate immune cells, including T cells, macrophages, and natural killer cells. Liver regeneration also involves repopulation of cells via stem cell/progenitor pathways. What stands out, more so perhaps than in parenchymal liver injuries, is that in chronic biliary diseases regenerative hepatocyte “buds” are reduced in association with bile duct loss and cholestatic destruction of nascent buds. The impact of this in chronic biliary disease is that when there is ongoing cholestasis, regenerative capacity is continually impaired; this is then a contributory factor in determining the balance of fibrosis formation and regression. Therapies with the greatest impact on resolving cholestasis have the greatest opportunity to then favor regenerative capacity.

What Therapies are Used and Why?

To date, therapy (beyond relief of obstruction, cessation of injurious drugs, etc.) is often focused on nonspecific amelioration of cholestasis, such as with the hepatoprotective bile acid, ursodeoxycholic acid.

The complex response to injury in the biliary tree is in essence protective, and understanding its molecular nature is thereby an opportunity for development of more specific interventions. For restorative and protective cellular changes to be most effective, resolution of the initial insult is of course the ideal scenario. This may be realistic in acute injuries (e.g., infections, obstruction, drugs), but less so in chronic diseases, such as PBC or PSC, not least because we have insufficient etiological insight. Thus, in such chronic injury, opportunity exists to modulate cellular responses therapeutically, by augmenting already identified biologically active pathways.

Two pathways have increasingly been recognized as physiologically, pathophysiologically, and therapeutically relevant. The first of these is the bile acid receptor, FXR, a ligand‐activated nuclear transcription factor. FXR binds to DNA response elements (either as a monomer or as a heterodimer with the retinoid X receptor) and in so doing regulates expression of genes key to metabolism of bile acids, lipids, and carbohydrates. Bile acid sensing by FXR in ileal enterocytes also induces expression of fibroblast growth factor 19, an enterohepatic hormone that binds a cell surface receptor on hepatocytes, repressing bile acid synthesis and gluconeogenesis, as well as stimulating glycogen and protein synthesis. Fibroblast growth factor 19 also enhances gallbladder filling.

A second nuclear receptor pathway relevant to cholestasis is the PPARs, which are also nuclear hormone receptor, ligand‐activated transcription factors (e.g., subtypes PPARα, PPARγ, and PPARδ; acting on DNA response elements as heterodimers with the retinoid X receptor). Activation by lipid‐derived substrates variously regulates insulin sensitization, glucose metabolism, and fatty acid metabolism. Equally they impact biliary phospholipid secretion (increased MDR3 expression), bile aid metabolism, and synthesis (e.g., repression of synthesis, via CYP7A1 and CYP27A1, uptake via NTCP expression, and detoxification by CYP3A4 expression).

Newer therapies focusing on these two pathways are evident in clinic, as well as early‐ and late‐stage clinical trials. Obeticholic acid is a first‐in‐class semisynthetic FXR agonist approved for patients with PBC, and other non‐bile acid FXR agonists are in development for PBC and PSC (and nonalcoholic steatohepatitis). Existing PPAR targeting therapies have been proposed as repurposed agents for PBC (bezafibrate and fenofibrate), whereas novel data are emerging to support the eventual approval of seladelpar and elafibranor, for example, as licensed therapies in the future.

Notes

Potential conflict of interest: G.M.H. consults for Cymabay and Intercept.

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