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==Signs and symptoms==
==Signs and symptoms==
The signs and symptoms of cholestasis vary according to the cause. In case of sudden onset, the disease is likely to be acute, while the gradual appearance of symptoms suggests chronic pathology.<ref name=":03">{{Citation|last=Shah|first=Rushikesh|title=Cholestatic Jaundice|date=2021|url=http://www.ncbi.nlm.nih.gov/books/NBK482279/|work=StatPearls|place=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=29489239|access-date=2021-12-02|last2=John|first2=Savio}}</ref> In many cases, patients may experience pain in the abdominal area. Localization of pain to the upper right quadrant can be indicative of cholecystitis or choledocholithiasis, which can progress to cholestasis.<ref>{{Cite journal|last=Brady|first=Patrick|date=2016|title=Commentary on “Prospective Evaluation of the Clinical Features of Choledocholithiasis: Focus on Abdominal Pain”|url=http://dx.doi.org/10.14423/smj.0000000000000462|journal=Southern Medical Journal|volume=109|issue=5|pages=294–295|doi=10.14423/smj.0000000000000462|issn=0038-4348}}</ref><ref>{{Cite journal|last=Schirmer|first=Bruce D.|last2=Winters|first2=Kathryne L.|last3=Edlich|first3=Richard F.|date=2005|title=Cholelithiasis and Cholecystitis|url=http://www.dl.begellhouse.com/journals/1bef42082d7a0fdf,69622d0e4ea6cf4b,07f88f8255346b09.html|journal=Journal of Long-Term Effects of Medical Implants|language=en|volume=15|issue=3|pages=329–338|doi=10.1615/JLongTermEffMedImplants.v15.i3.90|issn=1050-6934}}</ref>
* Itchiness ([[pruritus]]). Pruritus is the primary symptom of cholestasis and is thought to be due to interactions of serum bile acids with opioidergic nerves.<ref>{{cite journal | vauthors = Sanjel B, Shim WS | title = Recent advances in understanding the molecular mechanisms of cholestatic pruritus: A review | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1866 | issue = 12 | pages = 165958 | date = December 2020 | pmid = 32896605 | doi = 10.1016/j.bbadis.2020.165958 | s2cid = 221542039 }}</ref> In fact, the opioid antagonist [[naltrexone]] is used to treat pruritus in cholestasis.

* [[Jaundice]]. Jaundice is an uncommon occurrence in intrahepatic (metabolic) cholestasis, but is common in obstructive cholestasis.
Pruritus or itching is often present in many patients with cholestasis.<ref>{{Cite journal|last=Bergasa|first=Nora V.|date=2015-04-13|title=The pruritus of cholestasis: Facts|url=http://dx.doi.org/10.1002/hep.27582|journal=Hepatology|volume=61|issue=6|pages=2114–2114|doi=10.1002/hep.27582|issn=0270-9139}}</ref> Patients may present with visible scratch marks as a result of scratching.<ref name=":03" /> Pruritus is often misdiagnosed as a dermatological condition, especially in patients that do not have jaundice as an accompanying symptom.<ref name=":03" /> In a typical day, pruritus worsens as the day progresses, particularly during the evening time.<ref name=":12">{{Cite journal|last=Langedijk|first=Jacqueline A. G. M.|last2=Beuers|first2=Ulrich H.|last3=Oude Elferink|first3=Ronald P. J.|date=2021|title=Cholestasis-Associated Pruritus and Its Pruritogens|url=https://www.frontiersin.org/article/10.3389/fmed.2021.639674|journal=Frontiers in Medicine|volume=8|pages=224|doi=10.3389/fmed.2021.639674|issn=2296-858X}}</ref> Overnight, pruritus dramatically improves. This cycle can be attributed to an increase in the concentration of biliary elements during the day due to food consumption, and a decline at night.<ref name=":03" /> Pruritus is mostly localized to the limbs, but can also be more generalized.<ref name=":12" />
* [[Human feces#Color|Pale stool]].<ref name="Hilscher_2020" /> This symptom implies obstructive cholestasis.

* [[Urine#Color|Dark urine]]<ref name="Hilscher_2020">{{cite journal | vauthors = Hilscher MB, Kamath PS, Eaton JE | title = Cholestatic Liver Diseases: A Primer for Generalists and Subspecialists | language = English | journal = Mayo Clinic Proceedings | volume = 95 | issue = 10 | pages = 2263–2279 | date = October 2020 | pmid = 33012354 | doi = 10.1016/j.mayocp.2020.01.015 | s2cid = 222154067 }}</ref>
Many patients may experience jaundice as a result of cholestasis.<ref>{{Cite journal|last=Gordon|first=Stuart C.|date=1991-09-15|title=Jaundice and cholestasis|url=http://dx.doi.org/10.1080/00325481.1991.11701060|journal=Postgraduate Medicine|volume=90|issue=4|pages=65–71|doi=10.1080/00325481.1991.11701060|issn=0032-5481}}</ref> This is usually evident after physical examination as yellow pigment deposits on the skin, in the oral mucosa, or conjunctiva.<ref name=":03" /><ref>{{Cite journal|last=Fargo|first=Matthew V.|last2=Grogan|first2=Scott P.|last3=Saguil|first3=Aaron|date=2017-02-01|title=Evaluation of Jaundice in Adults|url=https://pubmed.ncbi.nlm.nih.gov/28145671/|journal=American Family Physician|volume=95|issue=3|pages=164–168|issn=1532-0650|pmid=28145671}}</ref> Jaundice is an uncommon occurrence in intrahepatic (metabolic) cholestasis, but is common in obstructive cholestasis. The majority of patients with chronic cholestasis also experience fatigue.<ref>{{Cite journal|last=Kumar|first=D|date=2002-07-01|title=Fatigue in cholestatic liver disease--a perplexing symptom|url=http://dx.doi.org/10.1136/pmj.78.921.404|journal=Postgraduate Medical Journal|volume=78|issue=921|pages=404–407|doi=10.1136/pmj.78.921.404|issn=0032-5473}}</ref> This is likely a result of defects in the corticotrophin hormone axis or other abnormalities with neurotransmission.<ref name=":03" /> Some patients may also have xanthomas, which are fat deposits that accumulate below the skin.<ref>{{Cite journal|last=Pearson|first=Hadley J.|last2=Mosser|first2=Joy L.|last3=Jacks|first3=Stephanie K.|date=2017|title=The triad of pruritus, xanthomas, and cholestasis: Two cases and a brief review of the literature|url=http://dx.doi.org/10.1111/pde.13306|journal=Pediatric Dermatology|volume=34|issue=6|pages=e305–e308|doi=10.1111/pde.13306|issn=0736-8046}}</ref> These usually appear waxy and yellow, predominantly around the eyes and joints.<ref>{{Cite journal|last=Zak|first=Ales|last2=Zeman|first2=Miroslav|last3=Slaby|first3=Adolf|last4=Vecka|first4=Marek|date=2014-06-23|title=Xanthomas: Clinical and pathophysiological relations|url=http://dx.doi.org/10.5507/bp.2014.016|journal=Biomedical Papers|volume=158|issue=2|pages=181–188|doi=10.5507/bp.2014.016|issn=1213-8118}}</ref> This condition results from an accumulation of lipids within the blood.<ref>{{Cite journal|last=Parker|first=Frank|date=1985|title=Xanthomas and hyperlipidemias|url=https://linkinghub.elsevier.com/retrieve/pii/S0190962285701399|journal=Journal of the American Academy of Dermatology|language=en|volume=13|issue=1|pages=1–30|doi=10.1016/S0190-9622(85)70139-9}}</ref>

Bile is required for the absorption of fat-soluble vitamins.<ref>{{Cite book|url=http://doi.wiley.com/10.1002/9780470691861|title=Textbook of Hepatology|date=2007-06-18|publisher=Blackwell Publishing Ltd|isbn=978-0-470-69186-1|editor-last=Rods|editor-first=Juan|location=Oxford, UK|language=en|doi=10.1002/9780470691861|editor-last2=Benhamou|editor-first2=Jean-Pierre|editor-last3=Blei|editor-first3=Andres T.|editor-last4=Reichen|editor-first4=Jrg|editor-last5=Rizzetto|editor-first5=Mario}}</ref> As such, patients with cholestasis may present with a deficiency in vitamins A, D, E, or K due to a decline in bile flow.<ref>{{Cite journal|last=Sokol|first=Ronald J.|date=1994|title=FAT-SOLUBLE VITAMINS AND THEIR IMPORTANCE IN PATIENTS WITH CHOLESTATIC LIVER DISEASES|url=http://dx.doi.org/10.1016/s0889-8553(21)00165-5|journal=Gastroenterology Clinics of North America|volume=23|issue=4|pages=673–705|doi=10.1016/s0889-8553(21)00165-5|issn=0889-8553}}</ref> Patients with cholestasis may also experience pale stool and dark urine.<ref name="Hilscher_2020">{{cite journal|vauthors=Hilscher MB, Kamath PS, Eaton JE|date=October 2020|title=Cholestatic Liver Diseases: A Primer for Generalists and Subspecialists|journal=Mayo Clinic Proceedings|language=English|volume=95|issue=10|pages=2263–2279|doi=10.1016/j.mayocp.2020.01.015|pmid=33012354|s2cid=222154067}}</ref>


==Causes==
==Causes==

Revision as of 04:15, 2 December 2021

Cholestasis
Micrograph showing bile (yellow) stasis in liver tissue, i.e. cholestasis. H&E stain.
SpecialtyGastroenterology

Cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system that can occur from a gallstone or malignancy, and metabolic types of cholestasis which are disturbances in bile formation that can occur because of genetic defects or acquired as a side effect of many medications. Classification is further divided into acute or chronic and extrahepatic or intrahepatic.

Signs and symptoms

The signs and symptoms of cholestasis vary according to the cause. In case of sudden onset, the disease is likely to be acute, while the gradual appearance of symptoms suggests chronic pathology.[1] In many cases, patients may experience pain in the abdominal area. Localization of pain to the upper right quadrant can be indicative of cholecystitis or choledocholithiasis, which can progress to cholestasis.[2][3]

Pruritus or itching is often present in many patients with cholestasis.[4] Patients may present with visible scratch marks as a result of scratching.[1] Pruritus is often misdiagnosed as a dermatological condition, especially in patients that do not have jaundice as an accompanying symptom.[1] In a typical day, pruritus worsens as the day progresses, particularly during the evening time.[5] Overnight, pruritus dramatically improves. This cycle can be attributed to an increase in the concentration of biliary elements during the day due to food consumption, and a decline at night.[1] Pruritus is mostly localized to the limbs, but can also be more generalized.[5]

Many patients may experience jaundice as a result of cholestasis.[6] This is usually evident after physical examination as yellow pigment deposits on the skin, in the oral mucosa, or conjunctiva.[1][7] Jaundice is an uncommon occurrence in intrahepatic (metabolic) cholestasis, but is common in obstructive cholestasis. The majority of patients with chronic cholestasis also experience fatigue.[8] This is likely a result of defects in the corticotrophin hormone axis or other abnormalities with neurotransmission.[1] Some patients may also have xanthomas, which are fat deposits that accumulate below the skin.[9] These usually appear waxy and yellow, predominantly around the eyes and joints.[10] This condition results from an accumulation of lipids within the blood.[11]

Bile is required for the absorption of fat-soluble vitamins.[12] As such, patients with cholestasis may present with a deficiency in vitamins A, D, E, or K due to a decline in bile flow.[13] Patients with cholestasis may also experience pale stool and dark urine.[14]

Causes

Possible causes:

Drugs such as gold salts, nitrofurantoin, anabolic steroids, sulindac, chlorpromazine, erythromycin,[16]: 208  prochlorperazine, cimetidine, estrogen,[17] and statins can cause cholestasis and may result in damage to the liver.[citation needed]

Drug-induced cholestasis

Cholestasis can be caused by certain drugs or their metabolites. Drug-induced cholestasis (DIC) is a category of drug-induced liver injury (DILI), the other two being hepatocellular and mixed hepatocellular and cholestatic.[18][19] Cholestatic and mixed DILI are generally more severe than hepatocellular alone and account for ~50% of cases.[18] While some drugs (e.g., acetaminophen) are known to cause DILI in a predictable dose-dependent manner (intrinsic DILI), it is far more common for cases to be idiosyncratic, meaning affecting only a small minority of individuals taking the offending medication.[19][20] Seventy-three percent of DIC cases can be attributed to a single prescription medication, the common categories being antibiotics & antifungals, anti-diabetics, anti-inflammatory, & cardiovascular drugs, psychotropic drugs.[18][21] The exact pathomechanism may vary for different drugs and requires further elucidation.[21]

Typical symptoms of DIC include pruritus and jaundice, nausea, fatigue, and dark urine, which usually resolve after discontinuation of the offending medication.[18][22]

DIC can be divided into acute, chronic (lasting more than 3 months), drug-induced cholangiopathy, and drug-induced sclerosing cholangitis.[23][24][16]: 17  Acute DIC may manifest as either pure/bland cholestasis or cholestatic hepatitis.[23] Bland cholestasis is characterized by obstruction of bile flow in the absence of inflammation or biliary and hepatic injury, whereas these features are present in cholestatic hepatitis.[23][16]: 17  Bland cholestasis is almost always caused by anabolic steroids or estrogen contraceptive use,[25] while drugs associated with cholestatic hepatitis include penicillins, sulfonamides, sulfonylureas, rifampin, cephalosporins, fluoroquinolones, tetracyclines, and methimazole, among others.[22][23]

Among antibiotics and antifungals, common drugs implicated in DIC are penicillins, macrolides, trimethoprim/sulfamethoxazole, and tetracyclines.[23] The penicillin amoxicillin-clavulanate is the most common culprit of cholestatic liver injury, which occurs as a result of the clavulanic acid component.[23] Flucloxacillin, which is commonly prescribed in the UK, Sweden, and Australia, is another penicillin frequently involved. Cholestasis induced by penicillins usually resolves after withdrawal.[23] Macrolides with the potential to cause DIC include erythromycin, clarithromycin, and azithromycin; prognosis is likewise favorable.[23] Trimethoprim/sulfamethoxazole, due to its sulfonamide component, is the fourth most common antibiotic responsible for DILI in North America. DIC is comparatively less common for low-dose tetracyclines (e.g., doxycycline).[23] Other antimicrobials include the antifungal terbinafine, notable for its potential to cause life-threatening cholestatic injury, and quinolones (ciprofloxacin, levofloxacin), which have been linked to cholestatic hepatitis and vanishing bile duct syndrome.[23] Among psychotropic drugs, chlorpromazine is well-known to cause cholestatic hepatitis, as can tricyclic antidepressants (imipramine, amitriptyline) and SSRIs (duloxetine).[23] Anti-inflammatory drugs with cholestatic potential include the immunosuppressant azathioprine, reported to cause fatal cholestatic hepatitis, and the NSAID diclofenac.[23]

Rare causes of cholestasis

The causes of cholestasis are diverse, and some feature more prominently than others. Some rare causes include primary sclerosing cholangitis, primary biliary cholangitis, familial intrahepatic cholestasis, Alagille syndrome, sepsis, total parenteral nutrition-based cholestasis, benign recurrent intrahepatic cholestasis, biliary atresia, and intrahepatic cholestasis of pregnancy.

Primary sclerosing cholangitis

Main article: Primary sclerosing cholangitis

Chronic cholestasis is a feature in primary sclerosing cholangitis (PSC). PSC is a rare and progressive cholestatic liver disease characterized by narrowing, fibrosis, and inflammation of intrahepatic or extrahepatic bile ducts, leading to reduced bile flow or formation (i.e., cholestasis).[26][27] The pathogenesis of PSC remains unclear but probably involves a combination of environmental triggers and genetic predisposition.[27] Notably, 70-80% of patients with PSC also have an inflammatory bowel disease (e.g., ulcerative colitis or Crohn’s colitis), suggesting a link between the two.[26][28]

PSC predominantly affects males (60-70%) of 30-40 years of age.[27] With an incidence of 0.4-2.0 cases/100,000 and a prevalence of 16.2 cases/100,000, PSC qualifies as a rare disease.[29][27] Nonetheless, it accounts for 6% of liver transplants in the US due to its eventual progression to end-stage liver disease, with a mean transplant-free survival of 21.3 year.[27]

Outside the 40-50% of patients who are asymptomatic, commonly reported symptoms include abdominal pain in the right upper quadrant, pruritus, jaundice, fatigue, and fever.[26][27] The most common signs are hepatomegaly and splenomegaly.[26] Prolonged cholestasis in PSC may additionally cause fat-soluble vitamin deficiency which may predispose to osteoporosis[26] PSC is diagnosed based on elevated serum alkaline phosphatase persisting for at least 6 months and the presence of bile duct strictures on cholangiogram.[26][27] Unlike primary biliary cholangitis, PSC lacks a diagnostic autoantibody or reliable biomarker of disease progression.[27][26] Although a liver biopsy is not required for diagnosis, the characteristic histological finding is concentric periductal fibrosis resembling onion skin.[27]

PSC is associated with increased risk of several cancers, most notably, a 400 times greater risk for cholangiocarcinoma compared to the general population.[26] Patients with PSC also face elevated risk of pancreatic and colorectal cancer.[27] Therefore, regular screening is recommended.[26]

No drugs are currently approved for treating PSC specifically.[30] Although commonly given, moderate dose ursodeoxycholic acid failed to improve transplant-free survival in randomized controlled trials.[27][26] 40% of patients eventually require liver transplantation due to disease progression, following which survival is excellent (91% at 1 year, 82% at 5 years, and 74% at 10 years).[27] However, disease recurs in at least 25% of transplant recipients, particulary in those with IBD and an intact colon.[26]

Clinical trials of several novel therapies are underway, including obeticholic acid (a bile acid analogue), simtuzumab (a monoclonal antibody), 24-4nor-ursodeoxycholic acid (a synthetic bile acid), and LUM001 (an ASBT inhibitor).[26] 

Although the pathogenesis of PSC is poorly understood, three dominant mechanisms have been proposed: 1) aberrant immune response, 2) increased intestinal permeability, and 3) dysbiosis of gut microbiota. The first mechanism postulates that chronic immune activation damages the bile ducts. It is thought that in PSC, cholangiocytes and hepatocytes abnormally express endothelial adhesion molecules usually limited to the gut (e.g., MAd-CAM-1, CCL25, VAP-1). This allows T cells activated by intestinal antigens or inflammation to home to the bile ducts and liver, where they cause immune-mediated damage. Additionally, intestinal microbiota may produce pathogen-associated molecular patterns (PAMPs) that stimulate cholangiocytes and hepatic macrophages to produce proinflammatory cytokines, which promote recruitment immune cells to the bile ducts, fibrosis, and cholangiocyte apoptosis and senescence, culminating in obliteration of the bile ducts. In support of T cell involvement, certain human leukocyte antigen (HLA) variants (e.g., the HLA-B*08, HLA-DRB1 alleles on chromosome 6p21) are strongly associated with PSC risk. Further evidence for genetic predisposition include the identification of 23 non-HLA susceptibility loci and the higher risk among siblings, though environmental factors appear to play a much larger pathogenic role.

Another possible mechanism is increased intestinal permeability. Tight junctions normally seal the gap between enterocytes comprising the intestinal epithelium but may become disrupted by inflammation. Leaky tight junctions allow commensal bacteria and toxins to translocate paracellularly into portal circulation and reach the liver, where they can trigger inflammation and fibrosis.

The intestinal dysbiosis theory hypothesizes that yet unidentified environmental triggers (e.g., diet, medication, inflammation) reduce microbiota diversity and/or alter the population of specific species. An imbalance between primary and secondary bile acids results, leading to PSC via the gut-liver axis. The primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) are synthesized in the liver and conjugated with glycine and taurine before being released into the small intestine to aid with digestion. In the distal ileum, 95% of conjugated BAs are actively reabsorbed via ASBT but 5% enter the colon and undergo conversion by gut microbes into deconjugated secondary bile acids, predominantly deoxycholic acid (DCA) and lithocholic acid (LCA). DCA and LCA are then reabsorbed into portal circulation and reach the liver, where they serve as signaling molecules in bile acid homeostasis. Specifically, DCA and LCA and potent agonists of farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5), the activation of which produces anti-inflammatory and cholangioprotective effects. On cholangiocytes, TGR5 activation induces CFTR to secrete chloride into bile ducts, which then drives chloride-dependent secretion of bicarbonate by AE2. Bicarbonate protects the apical surface of cholangiocytes from damage by bile acids. On macrophages, activation of FXR and TGR5 inhibits NF-κB, thereby reducing production of proinflammatory cytokines. Therefore, it is hypothesized that a reduction in secondary bile acid production, as a result of dysbiosis, could lead to bile duct damage by these mechanisms. Indeed, lower levels of secondary bile acids were found in PSC patients, but a causal relationship remains to be confirmed.

Familial intrahepatic cholestasis

Main article: Progressive familial intrahepatic cholestasis

Familial intrahepatic cholestasis (FIH) is a group of disorders that lead to intrahepatic cholestasis in children.[31] Most often, FIH occurs during the first year of life, with an incidence rate of 1/50,000 to 1/100,000.[32] There are three different versions of FIH, with each causing a different severity of jaundice. Typically, children exhibit recurrent jaundice episodes, which eventually become permanent.[31] Diagnosis usually occurs by analyzing laboratory features, liver biopsy results, DNA/RNA sequences, and biliary lipid analysis.[31] The definitive treatment for FIH is liver transplant which usually results in a high recovery rate.[31] Each type of FIH is a result of a different mutation. The three genes thought to be involved include APT8B1, which encodes for the FIC1 protein.[33] The ABCB11 gene encodes for the PFIC2 protein, and the ABCB4 gene encodes for the MRP3 protein.[33][34]

Alagille syndrome

Alagille syndrome is an autosomal dominant disorder that impacts five systems, including the liver, heart, skeleton, face, and eyes.[31] In the early part of life (within the first three months), patients with Alagille syndrome exhibit conjugated hyperbilirubinemia, severe pruritus, and jaundice.[31] Bile duct obliteration usually worsens over time, causing cirrhosis of the liver and eventual failure.[31] Diagnosis usually occurs using the classic criteria by looking at changes associated with the five systems discussed earlier.[35] Like FIH, the definitive treatment is a liver transplant.[36] Almost all patients with Alagille syndrome have mutations of the genes involved in the Notch signaling pathway. Most have a mutation of the JAG1 gene, while a small minority have a mutation of the NOTCH2 gene.[37][38]

Sepsis

A variety of factors associated with sepsis may cause cholestasis. Typically, patients have conjugated hyperbilirubinemia and alkaline phosphatase (ALP) elevation but not to extreme levels.[39] Sepsis-induced cholestasis may occur due to increased serum lipopolysaccharide levels. Lipopolysaccharides can inhibit and down-regulate bile salt transporters in hepatocytes, thereby leading to cholestasis.[31] As such, in the case of sepsis, cholestasis occurs not as a result of impaired obstruction but rather the disruption of bile flow. Ischemic liver injury resulting from sepsis can also cause cholestasis. Importantly, jaundice is not indicative of cholestasis in all cases. Widespread hemolysis resulting from sepsis may release bilirubin, thereby overwhelming bilirubin reabsorption and excretion mechanism.[31]

TPN-based cholestasis

Total parenteral nutrition (TPN) is given to patients with intestinal failure or a variety of other gastrointestinal problems.[31] Under normal settings, TPN causes a slight elevation of ALP levels. However, this does not indicate cholestasis alone.[31] In the case of TPN-induced cholestasis, there is a excessive elevation of ALP, gamma-glutamyltransferase (GGT), and conjugated bilirubin.[40] Without appropriate intervention, symptoms can quickly exacerbate, leading to liver cirrhosis and failure.[31] Cholestasis arising from TPN has a diverse range of causes, including toxicity to TPN components, underlying disorders, or a lack of enteral nutrition.[31] Without enteral food consumption, gallbladder function is greatly inhibited, leading to gallstone formation, subsequent blockage, and eventually cholestasis.[31] Cholestasis resulting from TPN may also be a result of reduced bile flow from portal endotoxins.[31] With TPN, there is a reduction in gastrointestinal motility, immunity, with an increase in permeability.[31] These changes facilitate bacteria growth and increase the amount of circulating endotoxin. Moreover, given that patients using TPN often have underlying health problems, drugs being used with known liver toxicity may also cause cholestasis. Lipids in TPN may cause cholestasis and liver damage by overwhelming clearage mechanisms.[41] Intravenous glucose can also cause cholestasis as a result of increased fatty acid synthesis and decreased breakdown, which facilitates the accumulation of fats.[42]

Intrahepatic cholestasis of pregnancy (obstetric cholestasis)

Main article: Intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is an acute cause of cholestasis that manifests most commonly in the third trimester of pregnancy.[14] It affects 0.5-1.5% of pregnancies in Europe and the US and up to 28% in women of Mapuche ethnicity in Chile.[43] ICP is characterized by severe pruritus and elevated serum levels of bile acids as well as transaminases and alkaline phosphatase.[44] These signs and symptoms resolve on their own shortly after delivery, though they may reappar in subsequent pregnancies for 45-70% of women.[45] In the treatment of ICP, current evidence suggests ursodeoxycholic acid (UDCA), a minor secondary bile acid in humans, is the most effective drug for reducing pruritus and improving liver function.[44]

The etiology of ICP is multifactorial and likely involves hormonal, genetic, and environmental factors. Several observations suggest estrogen plays a major role: ICP begins in the third trimester, when estrogen levels are highest, resolves after estrogen levels return to normal post-delivery, and occurs with higher incidence in multiple pregnancies, where estrogen levels are more elevated than usual.[45][46] Although estrogen's exact pathomechanism in ICP remains unclear, several explanations have been offered. Estrogen may induce a decrease in the fluidity of the hepatic sinusoidal membrane, leading to a decrease in the activity of basolateral Na+/K+-ATPase.[45][47][48] A weaker Na+ gradient results in diminished sodium-dependent uptake of bile acids from venous blood into hepatocytes by the sodium/bile acid cotransporter.[45][49] More recent evidence suggests that estrogen promotes cholestasis via its metabolite estradiol-17-β-D-glucuronide (E2).[43][45] E2 secreted into the canaliculi by MRP2 was found to repress the transcription of bile salt export pump (BSEP),[50][43][51] the apical ABC transporter responsible for exporting monoanionic conjugated bile acids from hepatocytes into bile canaliculi.[50] E2 was also found to upregulate miR-148a, which represses expression of the pregnane X receptor (PXR).[50] PXR is an nuclear receptor in hepatocytes that senses intracellular bile acid concentrations and regulates gene expression accordingly to increase bile efflux.[52]

Genetic predisposition for ICP is suggested by familial and regional clustering of cases.[45][43] Several studies have implicated heterozygous mutations of the genes ABCB11 and ABCB4 in ICP, which respectively encode the canalicular transport proteins BSEP and multidrug resistance protein 3 (MDR3).[53][43] MDR3 is responsible for exporting phosphatidylcholine, the major lipid component of bile, into bile canaliculi where it forms micelles with bile salts to prevent the latter from damaging luminal epithelium. Bile flow requires canalicular secretion of both bile salts and phosphatidylcholine.[53] MDR3 mutations are an established predisposing factor, found in 16% of ICP cases.[43][54] More recently, studies have demonstrated involvement of BSEP mutations in at least 5% of cases.[53] The V444A polymorphism of ABCB11 in particular may lead to ICP by causing a reduction in hepatic BSEP expression and consequently decreased bile salt export.[43] Other notable mutations identified in ICP patients include ones in the farnesoid X receptor (FXR), a nuclear receptor in hepatocytes which activates transcription of MDR3 and BSEP upon binding intracellular bile acids, thereby increasing canalicular bile efflux.[43][55][51]

Mechanism

Bile is secreted by the liver to aid in the digestion of fats. Bile formation begins in bile canaliculi that form between two adjacent surfaces of liver cells (hepatocytes) similar to the terminal branches of a tree. The canaliculi join each other to form larger and larger structures, sometimes referred to as the canals of Hering, which themselves join to form small bile ductules that have an epithelial surface. The ductules join to form bile ducts that eventually form either the right main hepatic duct that drains the right lobe of the liver, or the left main hepatic duct draining the left lobe of the liver. The two ducts join to form the common hepatic duct, which in turn joins the cystic duct from the gall bladder, to give the common bile duct. This duct then enters the duodenum at the ampulla of Vater.

In cholestasis, bile accumulates in the hepatic parenchyma.[56]

Mechanisms of drug-induced cholestasis

Drugs may induce cholestasis by interfering with 1) hepatic transporters, 2) bile canaliculi dynamics, and/or 3) cell structure and protein localization.[18][57] Hepatic transporters are an essential mechanism in the maintenance of enterohepatic bile flow and bile acid homeostasis.[58] Therefore, drugs that directly inhibit these transporters are expected to induce cholestasis. The most relevant transporters that targeted by drugs are BSEP, MDR3, MRP2-4, and NTCP.[18][48]

Competitive inhibition of BSEP is a possible mechanism by which several drugs induce cholestasis, namely cyclosporine A, rifampicin, nefazodone, glibenclamide, troglitazone, and bosentan.[21][57] These drugs inhibit BSEP transport by binding to its ATP-binding site or substrate-binding site of BSEP.[21] BSEP is the main apical transporter by which bile salts are exported out of hepatocytes into bile canaliculi. Therefore, its inhibition should result in accumulation of cytotoxic bile salt accumulation in hepatocytes, leading to liver injury and impaired bile flow.[21] Indeed, a strong association exists between BSEP inhibition and cholestasis in humans, and BSEP inhibitors have been shown to induce cholestasis in vitro.[57] However, hepatocytes have safety mechanisms that can compensate for impaired canalicular efflux.[57] In response to cholestasis, MRP3 and MRP4 on the basolateral membrane are upregulated to protect the hepatocyte by allowing the accumulated bile salts to efflux back into portal blood. MRP2 similarly allows accumlated bile to flow out of hepatocytes across the apical/canalicular membrane.[48][57] These compensatory mechanisms may explain why some BSEP inhibitors do not lead to cholestasis, and suggests that other mechanisms are involved in cholestasis induced by BSEP inhibitors.[21][57]

MDR3 is another vital canalicular efflux transporter inhibited by certain drugs. It is responsible for secreting phosphatidylcholine into bile canaliculi, where it is needed to form micelles with bile salts in order to dissolve cholesterol as well as protect the apical membranes of hepatocyte and cholangiocytes from detergent damage by bile salts.[18] Antifungal azoles such itraconazole have been shown to inhibit both MDR3 and BSEP,  thus increasing their cholestatic potential.[59] When phospholipid concentrations in bile are reduced following MDR3 inhibition, cholestasis can be impaired as a result of damage to cholangiocytes. [59]Other drugs shown to inhibit MDR3 in hepatocytes are chlorpromazine, imipramine, haloperidol, ketoconazole, saquinavir, clotrimazole, ritonavir, and troglitazone.[21]

MRP2, a canalicular efflux transporter, is another target for inhibition by certain drugs. Although MRP2 mainly transports bilirubin glucuronide and glutathione, it is the preferential route of export for certain sulfated conjugated BAs (taurolithocholic acid and glycolithocholic acid), suggesting its inhibition could contribute to cholestasis.[48] Other cholestatic drugs exert dual inhibition on MRP3/4 and BSEP (rifampicin, troglitazone, and bosentan).[48] Since they act as the “emergency safety valves” for BAs that have accumulated inside hepatocytes, MRP3/4 inhibition increases the risk of liver injury.[21][48] On the hepatocyte basolateral membrane, Na+-taurocholate cotransporting peptide (NTCP) is the major transporter of conjugated bile acids.[57] Enterohepatic bile flow requires the concerted activity of both NTCP and BSEP, as they form the major route by which BAs enter and exit hepatocytes respectively.[48] Therefore, NTCP inhibitors, such as cyclosporine A, ketoconazole, propranolol, furosemide, rifamycin, saquinavir, and ritonavir, should cause cholestasis by increasing serum BA levels.[57] However, no relationship was found between NTCP inhibition and DIC risk.[57] This can be explained by the ability of basolateral sodium-independent OATPs to partially compensate for bile salt uptake.[57] Therefore, NTCP inhibition alone may be insufficient to cause cholestasis.[57] Indeed, the cholestatic effect of cyclosporine A relies on its inhibition of both NTCP and the compensatory OATP1B1.[57][59]

In addition to direct inhibition, drugs can also lead to DIC by causing downregulation and internalization of transporters. For example, cyclosporine A was shown in rats to induce BSEP internalization in addition to inhibiting it. Further, decreased mRNA and protein expression were observed in human hepatocytes following long-term exposure to metformin and tamoxifen, neither of which are direct BSEP inhibitors.[57]

Bile canaliculi dynamics refers to the contractile motion of bile ducts, which is required for bile flow. Drugs that interfere with their constriction and dilation can therefore lead to cholestasis. Drugs causing bile canaliculi constriction include chlorpromazine, nefazodone, troglitazone, perhexiline, metformin, cyclosporin A. These drugs activate the RhoA/Rho-kinase pathway, resulting in inhibition of myosin light chain phosphatase (MLCP), and in turn, increased myosin light chain phosphorylation by MLC kinase, which leads to constriction of bile canaliculi. Drugs that dilate canaliculi work by inhibiting MLCK or inhibiting RhoA/Rho-kinase, and include diclofenac, bosentan, entacapone, tacrolimus, cimetidine, and flucloxacillin.[48][18] Constriction is more serious than dilation, as cell damage and death caused by the former is irreversible.[18]

Possible minor mechanisms of DIC may involve changes to paracellular permeability, membrane fluidity, and transporter localization.[18] Tight junctions normally seal the gap between hepatocytes, preventing bile in canaliculi from diffusing into sinusoids. If a drug causes internalization of hepatocyte tight junctions, as demonstrated by rifampicin in mice, bile flow may be impaired due to paracellular bile leakage.[48] Membrane fluidity is determined by the composition of the plasma membrane and affects the activity of membrane-associated Na+/K+-ATPase, which can in turn impair bile flow since BA uptake by NTCP is dependent on an inwardly directed Na+ gradient.[48][57] In rats, cyclosporine A was found to increase canalicular membrane fluidity, leading to reduced bile secretion. Bile flow was similarly reduced by alterations of basolateral membrane fluidity by ethinylestradiol and chlorpromazine.[48] Lastly, some drugs have been found to hinder proper localization of hepatocyte transporters by interfering with the microtubules required for their insertion into membranes. Rimpaficin and 17β-estradiol are examples of such agents that can alter hepatocyte polarity.[18]

Diagnosis

Cholestasis can be suspected when there is an elevation of both 5'-nucleotidase and ALP enzymes.[60] With a few exceptions, the optimal test for cholestasis would be elevations of serum bile acid levels.[61] However, this is not normally available in most clinical settings necessitating the use of other biomarkers. If 5’ nucleosidase and ALP enzymes are elevated, imaging studies such as computed tomography (CT) scan, ultrasound, and magnetic resonance imaging (MRI) are used to differentiate intrahepatic cholestasis from extrahepatic cholestasis.[60] Additional imaging, laboratory testing, and biopsies might be conducted to identify the cause and extent of cholestasis.[60]

Biomarkers

ALP enzymes are found abundantly within the bile canaliculi and bile. If a duct is obstructed, tight junctions permit migration of the ALP enzymes until the polarity is reversed and the enzymes are found on the whole of the cell membrane.[60] Serum ALP levels exceeding 2-3 times the upper baseline value may be due to a variety of liver diseases.[62] However, an elevation that exceeds 10 times the upper baseline limit is strongly indicative of either intrahepatic or extrahepatic cholestasis and requires further investigation.[62] Cholestasis can be differentiated from other liver disorders by measuring the proportion of ALP to serum aminotransferases, where a greater proportion indicates a higher likelihood of cholestasis.[60] Typically, aminotransferase enzymes are localized within hepatocytes and leak across the membrane upon damage.[63] However, measurement of serum aminotransferase levels alone is not a good marker to determine cholestasis. In up to a third of patients, ALP levels may be elevated without the presence of cholestasis.[62] As such, other biomarkers should be measured to corroborate findings.

Measurement of 5’ nucleosidase levels may be used to identify cholestasis in conjunction with ALP. Levels of ALP may rise within a few hours of cholestasis onset while 5’ nucleosidase levels may take a few days.[64] Many labs cannot measure 5’ nucleosidase and ALP levels so, GGT may be measured in some cases.[60] Abnormal GGT elevation may be attributable to a variety of factors.[65] As such, GGT elevations lack the necessary specificity to be a useful confirmatory test for cholestasis.[60]

Importantly, conjugated hyperbilirubinemia is present in 80% of patients with extrahepatic cholestasis and 50% of patients with intrahepatic cholestasis.[62] Given that many patients with hyperbilirubinemia may not have cholestasis, the measurement of bilirubin levels is not a good diagnostic tool for identifying cholestasis.[60] In a later stage of cholestasis aspartate transaminase (AST), alanine transaminase (ALT) and unconjugated bilirubin may be elevated due to hepatocyte damage as a secondary effect of cholestasis.

Imaging

After determination using biomarkers, a variety of imaging studies may be used to differentiate between intrahepatic or extrahepatic cholestasis. Ultrasound is often used to identify the location of the obstruction[66] but, is often insufficient in determining the level of biliary obstruction or its cause because it can pick up bowel gas that may interfere with readings.[60][67] CT scans are not impacted by bowel gas and may also be more suitable for overweight patients.[60] Typically, the cause of cholestasis and magnitude of obstruction is better diagnosed with CT compared to ultrasound.[68] MRI scans provide similar information to CT scans but are more prone to interference from breathing or other bodily functions.[69]

Although CT, ultrasound, and MRI may help differentiate intrahepatic and extrahepatic cholestasis, the cause and extent of obstruction is best determined by cholangiography.[60] Potential causes of extrahepatic cholestasis include obstructions outside the wall of the lumen, those outside the duct, and obstructions found in the duct lumen.[60] Endoscopic retrograde cholangiography may be useful to visualize the extrahepatic biliary ducts.[70] In case of anatomical anomalies, or if endoscopic retrograde cholangiography is unsuccessful, percutaneous transhepatic cholangiography may be used.[60] CT or MRI-based cholangiography may also be useful, particularly in cases where additional interventions are not anticipated.[60]

Histopathology

There is a significant overlap between cholestasis resulting from a hepatocellular origin and cholestasis caused by bile duct obstruction. Due to this, obstructive cholestasis can only be diagnosed after finding additional diagnostic signs that are specific to obstructive changes to the bile ducts or portal tracts.[71] In both non-obstructive and obstructive cholestasis, there is an accumulation of substances that are typically secreted in the bile, as well as degeneration of hepatocytes.[72] The most significant feature from a histopathological perspective includes pigmentation resulting from the retention of bilirubin. Under a microscope, the individual hepatocytes will have a brownish-green stippled appearance within the cytoplasm, representing bile that cannot get out of the cell. Pigmentation can involve regurgitation of bile into the sinusoidal spaces caused by phagocytosis from Kupffer cells, an accumulation of bilirubin within hepatocytes, and inspissated bile in the canaliculi.[71] Most pigmentation and canaliculi dilation occurs in the perivenular region of the hepatic lobule. In chronic cases, this may extend into the periportal area.[71]

Hepatocyte necrosis is not a significant feature of cholestasis; however, apoptosis may often occur.[73] Under the microscope, hepatocytes in the perivenular zone appear enlarged and flocculent.[71] In cases of obstructive cholestasis, bile infarcts may be produced during the degeneration and necrosis of hepatocytes.[73] Bile infarcts are marked by a large amount of pigmented tissue surrounded by a ring of necrotic hepatocytes.[71] In some cases, hepatocyte degeneration is uncommon. E.g., with Alagille syndrome limited degeneration occurs, however, there may be a small amount of apoptosis and enlarged hepatocytes.[74]

Management

Surgical management

In cases involving obstructive cholestasis, the primary treatment includes biliary decompression.[75] If bile stones are present in the common bile duct, an endoscopic sphincterotomy can be conducted either with or without placing a stent.[76] In case of narrowing of the common bile duct, a stent can be placed after dilating the constriction to resolve the obstruction.[77]

The treatment approach for patients with obstructive cholestasis resulting from cancer varies based on whether they are a suitable candidate for surgery. In most cases, surgical intervention is the best option.[76] For patients whom complete removal of the biliary obstruction is not possible, a combination of a gastric bypass and hepaticojejunostomy can be used.[78] This can reestablish bile flow into the small intestine, thereby bypassing the blockage. In cases where a patient is not a suitable candidate for surgery, an endoscopic stent can be placed.[79] If this is not possible or successful, a percutaneous transhepatic cholangiogram and percutaneous biliary drainage can be used to visualize the blockage and re-establish bile flow.[80]

Medical management

A significant portion of patients with cholestasis (80%) will experience pruritus at some point during their disease.[81][82] This is a condition that can severely decrease a patient’s quality of life as it can impact sleep, concentration, work ability, and mood. Many treatments exist, but how effective each option is depends on the patient and their condition. Assessment using a scale, such as a visual analogue scale or a 5-D itch scale will be useful to identify an appropriate treatment.[83] Possible treatment options include antihistamines, ursodeoxycholic acid, and phenobarbital. Nalfurafine hydrochloride can also be used to treat pruritus caused by chronic liver disease and was recently approved in Japan for this purpose.[84]

Bile acid binding resins like cholestyramine are the most common treatment. Side effects of this treatment are limited and include constipation and bloating. Other commonly used treatments include rifampin, naloxone, and sertraline.

In cholestatic liver disease, when bilirubin concentration starts to build up, a deficiency of fat soluble vitamins may also occur.[85] To manage this, doses of vitamin A, D, E, and K are recommended to retain appropriate vitamin levels.

Cholestatic liver disease can impact lipids, and possibly lead to dyslipidemia, which may present a risk for coronary artery disease.[86] Statins and fibrates are generally used as lipid lowering therapy to treat patients with cholestatic liver disease.

For intrahepatic cholestasis in pregnant women, S-adenosylmethionine has proven to be an effective treatment.[87] Dexamethasone is a viable treatment in regards to the symptom of intensive itching.[88]

See also

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