Cholestasis is a disease of the liver.
It occurs when your liver's bile flow is
restricted or blocked. Your liver produces bile, a fluid that aids in the digestion of
food, particularly fats. A buildup of bilirubin can occur when bile flow is altered.
Your liver produces bilirubin, a pigment that is eliminated from your body through
bile. Cholestasis is divided into two forms: extrahepatic and intrahepatic
cholestasis, as shown in Figure 1. The liver is where intrahepatic cholestasis gets
its start. It can be brought on by: disease, infection, drug use, genetic flaws, and
hormonal influences on bile flow are all factors. The signs and symptoms of both
types of cholestasis are the same: jaundice is characterized by a yellowing of the
skin and eyes, dark urine, light-colored stools, abdominal pain, exhaustion,
nausea, and excessive itching. PBD, PSC, and other liver diseases are additional
forms of cholestasis that can affect people of all ages. At the end of the day,
timely diagnosis and treatment are helpful. Adults with chronic cholestasis
frequently do not experience symptoms, and not everyone with cholestasis
experiences symptoms.
Bile flow, in contrast to urine production, is driven by the osmotic pressure of
solutes secreted across the apical membrane of hepatocytes and bile duct
epithelial cells rather than by hydrostatic forces. A collection of primary active
transporters act as mediators in this secretory process, pumping solutes against
the concentration gradient through ATP hydrolysis. Electrolytes, organic anions,
bile salts, and lipids are the bile's most important solutes. Cholestasis, or
impaired bile flow, is the direct result of the osmotic mechanism of bile formation,
which causes these pumps to malfunction. Numerous inherited cholestatic
diseases are caused by mutations in these genes, which highlight the function of
these pumps. Not only was it important for diagnosing these diseases to find the
molecular defect, but it also highlighted the pathological consequences of
impaired transporter function. To be sure, it is currently turning out to be certain
that impeded or downregulated carrier capability is likewise associated with the
pathogenesis of obtained cholestatic conditions.
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Figure 1. Illustration of two
forms of cholestatic liver disease. (Vibhute, 2021).
In Pathogenesis of Cholestatic Liver Disease and Therapeutic Approaches,
Hirschfield, Heathcote, and Gershwin (2010) provide a review of the
characteristics of bile acid transport, tissue repair and regulation, apoptosis,
vascular supply, immune regulation, and cholangiocytes that are associated with
cholestatic liver disorders.
Inadequate hepatobiliary production and excretion of bile, which allows bile components to enter the
bloodstream, are the root causes of cholestasis. In these conditions, injuries to bile ducts or hepatocytes
can result in a variety of clinical manifestations, including liver failure or hepatobiliary malignancy,
isolated abnormalities in liver biochemistry, and more; Disease can be caused by congenital,
immunologic, structural (obstructive/vascular), and toxic factors (Figure 1).Proliferation of mature
cholangiocytes and hepatocytes in response to injury may result in cirrhosis, biliary fibrosis, and
periductular fibrosis. The individual's response to injury and the etiology of the disease play a role in
disease progression and repair efficacy. With a focus on primary sclerosing cholangitis (PSC) and primary
biliary cirrhosis (PBC), we examine the mechanisms and biliary pathophysiology of cholestatic liver
disease.
Cholangiocytes make up about 5% of the liver's cells; The biliary tree, an intricate network of
interconnected bile ducts that expand in diameter from the Hering ducts to the extrahepatic bile ducts,
is lined by these ciliated epithelial cells. While cholangiocytes that line smaller bile duct branches,
cholangioles, and ducts of Hering play roles in inflammatory and proliferative responses, those that line
the large interlobular and major ducts are primarily responsible for secretory functions. Each
cholangiocyte has a primary cilium that controls mechanosensory, osmosensory, and chemosensory
functions and extends from the apical plasma membrane into the ductal lumen. Changes in osmolality
and bile flow are detected and signaled by cilia.
Figure 1. Cholestasis and hepatobiliary injury The location of the hepatobiliary insult is linked to the
etiology of cholestatic liver disease. (Left panel) Bile formation is coordinated by a number of different
bile acid transporters, with various cell surface receptors on cholangiocytes that regulate cholangiocyte
secretion and function. (Middle panel) Histologic representation of cholestatic liver disease
demonstrating bland hepatic cholestasis due to drug injury, PBC's small bile duct lymphocytic
cholangitis, ductopenia as shown by keratin immunostaining, the classic large bile duct involvement
seen in PSC (obliterative cholangitis), and immunochemical staining demonstrating IgG4-positive plasma
cells Cholestasis develops when hepatocytes and small and large bile ducts are damaged.
As depicted in Figure 3, bile flow abnormalities can be caused by a variety of factors. Antigenic stimuli,
exotoxins, endotoxins, xenobiotics, and microorganisms can elicit a cholangiocyte reaction that leads to
cholestatic state, despite the fact that the majority of environmental triggering factors are unknown.
Bile transport deterrent is another inclining factor. Intrahepatic and extrahepatic deterrent can happen
because of extraneous harmless pressure (cystic illnesses), threatening mass impact
(cholangiocarcinomas), and furthermore as an outcome of cholelithiasis development or movement all
through the biliary tree. Additionally, elevated levels of bile acid (BA) promote a cholestatic state when
biliary flow is slowed. The main characteristics of BA may be altered, resulting in a more cytotoxic BA
component, as may sepsis, hyperestrogenic states (like pregnancy), congestive heart failure, and
dysfunction of BA transporter genes.
Figure 3. Core pathogenic mechanism of cholestatic liver diseases.
Heidari, R., & Niknahad, H. (2019). The Role and Study of Mitochondrial Impairment and Oxidative
Stress in Cholestasis. Methods in Molecular Biology, 117–132. https://doi.org/10.1007/978-1-4939-
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Copple, B., Jaeschke, H., & Klaassen, C. (2010). Oxidative Stress and the Pathogenesis of Cholestasis.
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Carey, E. J., & Lindor, K. D. (2012). Current pharmacotherapy for cholestatic liver disease. Expert
Opinion on Pharmacotherapy, 13(17), 2473–2484. https://doi.org/10.1517/14656566.2012.736491.
Vilas-Boas, V., Gijbels, E., Jonckheer, J., De Waele, E., & Vinken, M. (2020).
Cholestatic liver injury induced by food additives, dietary supplements and
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https://doi.org/10.1016/j.envint.2019.105422.
