Keywords
cholestasis - pruritus - Chinese medicine - Western medicine - research progress
Cholestatic liver disease refers to a series of liver and biliary system diseases
caused by various factors leading to the obstruction of bile generation, secretion,
and excretion. Pruritus is one of the most common symptoms in patients with cholestatic
liver disease, with over 80% of cholestatic patients experiencing pruritus, especially
in patients with primary biliary cholangitis (PBC), primary sclerosing cholangitis
(PSC), intrahepatic cholestasis of pregnancy (ICP).[1]
[2]
[3] Compared with pruritus caused by other diseases, pruritus in cholestatic liver disease
often persists long term and is difficult to relieve. In severe cases, it can lead
to insomnia and even suicide.[1] However, due to the complex and incompletely understood pathogenesis of pruritus
in cholestatic liver disease, the pruritus inducers are diverse, and there are still
challenges in effective treatments. According to traditional Chinese medicine (TCM),
the liver governs dredging and regulating. Cholestasis is a common pathological manifestation
of liver and bile dysfunction in dredging and regulating, with dampness, heat, stasis,
and toxicity as the main pathological mechanism. It is mostly caused by damp heat
and epidemic toxins transforming into excessive fire, and the accumulation of heat
and toxins.[4]
[5] From the perspective of conveyance and dispersion, patients with cholestasis have
dysfunction in conveyance and dispersion, and dampness, heat, fire, and toxins cannot
be relieved, which can overflow onto the skin and easily lead to symptoms such as
jaundice and skin itching.[4] TCM has a long history of treating pruritus, with numerous therapies and medications
for relieving itch. This article provides an overview of the pruritus inducers and
the progress in the treatment of cholestatic liver disease-related pruritus in TCM
and Western medicine.
Cholestatic Liver Disease-Related Pruritus and Pruritus Inducers
Cholestatic Liver Disease-Related Pruritus and Pruritus Inducers
Currently, majority of the studies suggest that the factors causing cholestatic liver
disease-related pruritus may be bile acids and lysophosphatidic acid (LPA) formed
in the liver or intestines. These inducers accumulate in the systemic circulation
and stimulate the skin, transmitting itch signals through combining with the receptors
in the dorsal root ganglion (DRG) or trigeminal ganglion. These signals then reach
the central nervous system, leading to the perception of itching.[6]
[7] The specific pruritus inducers related to cholestatic liver disease-related pruritus
are expounded as follows.
Steroids and Steroid Metabolites
Clinical research has found that during the pruritic episodes of cholestatic liver
disease, levels of certain hormone metabolites in the plasma of patients with ICP
significantly increase. Some of these metabolites, such as progesterone sulfate, can
modulate bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and induce
scratching behavior in wild mice, suggesting that certain concentrations of progesterone
metabolites can trigger pruritus.[8]
[9]
[10] Numerous studies, including clinical trials, have also confirmed the involvement
of estrogen in the regulation of pruritus, although the specific mechanism is not
yet clear.[11]
[12] It has been observed that estrogen can reduce nociception by modulating intracellular
calcium ion concentration in DRG neurons. In acute and chronic pruritus models, high
estrogen levels may play a role in inhibiting itch signal transmission by regulating
Mas-related G protein-coupled receptors.[13]
[14]
Cytokines
During normal pregnancy, the levels of type 1 cytokines decrease, while type 2 cytokines
increase to protect the fetus.[15]
[16] However, in ICP, patients undergo a shift from Th0 cells to Th1 cells, resulting
in the proliferation and secretion of cytokines such as interferon-γ (IFN-γ) and tumor
necrosis factor-α (TNF-α) and leading to increased inflammatory reactions.[17]
[18] Since inflammation is closely associated with pruritus and plays a significant role
in the pathogenesis of inflammatory skin diseases involving pruritus, it is likely
that cytokines participate as pruritus inducers in the occurrence of ICP and other
cholestatic liver diseases with pruritus.[19]
Bile Acid and Bile Salt
Bile acid is the marker of cholestasis and plays a critical role in various cholestatic
liver diseases. It is closely related to the occurrence of pruritus. For years, bile
acid and bile salt have been considered as one of the inducers in cholestatic pruritus.
In clinical observations, the elevated level of bile acid is found during cholestasis
and can further activate a series of receptors, including TGR5 and farnesoid X receptor,
which are all associated with pruritus.[20]
[21]
[22] Alemi et al[23] found that TGR5 is expressed in neurons of the DRG in mice and overlaps with the
expression of transient receptor potential cation channel subfamily V member 1 (TRPV1)
and gastrin-releasing peptide. Mice with high expression of TGR5 show increased scratching
activity, suggesting its involvement in itch signal transmission. However, Yu et al[20] questioned this finding in 2019. They injected a TGR5-specific agonist into the
forearms of human subjects, but it did not cause itching. They also found that hTGR5
is selectively expressed in satellite glial cells and not expressed in hDRG neurons.
Additionally, pruritus usually occurs in the initial stage of cholestasis, and the
itching symptom often disappears when bile acid and salt concentrations reach the
highest levels, indicating that bile acid does not appear to play a crucial role in
cholestatic pruritus.[24]
Lysophosphatidic Acid
Lysophosphatidic Acid (LPA) is an important active compound found in the serum of
patients with cholestatic liver disease-related pruritus. The levels of LPA in the
serum of these patients are higher compared with normal individuals, which may be
related to significantly increased autotaxin (ATX) activity.[24]
[25] ATX can hydrolyze the precursor molecule lysophosphatidylcholine (LPC) to form LPA.[26] Macias' research also confirmed this finding, showing a correlation between elevated
levels of ATX and LPA in the serum of patients with cholestatic pruritus. Moreover,
Kittaka et al[27] discovered that LPA can bind to LPAR5, activate TRPV1 within cells, and induce pruritus.
This confirms the pruritic effect of LPA and suggests that LPA may be an important
itch inducer in cholestatic liver disease-related pruritus.
Endogenous Opioids
The endogenous opioid system plays an important role in central neurogenic pruritus.
Düll and Kremer[28] found that in both animal experiments and clinical studies, the use of morphine
and other opioid receptor agonists or antagonists can reduce scratching behavior in
animals and improve itching symptoms in patients and the use of some opioid receptor
antagonists can prevent pruritus. In addition, the use of opioid receptor antagonists
such as naloxone and naltrexone can not only relieve pruritus in patients with cholestasis
but also induce opioid withdrawal-like reactions in patients with cholestasis.[29] These studies suggest that endogenous opioids may be one of the important causes
of cholestatic liver disease-related pruritus such as PBC/PSC. More clinical and basic
research studies are needed to confirm the role of the endogenous opioid system in
patients with cholestatic liver disease-related pruritus.
Gut Microbiota
Multiple studies have found that the gut microbiota plays an important role in the
pathogenesis of PBC and PSC by regulating metabolism and immune response.[30] A recent study linked the gut microbiota to secondary pruritus of PBC, showing that
pruritus score decreased in PBC patients after treatment with an apical sodium-dependent
bile acid transporter (ASBT) inhibitor (GSK2330672), indicating a certain correlation
between gut microbiota and cholestatic liver disease-related pruritus. By comparing
the gut microbiota of PBC pruritus patients with asymptomatic PBC patients and healthy
volunteers, no significant difference was found, suggesting that although there is
a certain connection between gut microbiota and cholestatic liver disease-related
pruritus, it does not play a major role.[31]
Lysophosphatidylcholine
A recent study found that a high concentration of LPC in the skin may cause pruritus.
Subcutaneous injection of LPC in wild-type mice can activate the TRPV4 receptor in
mice and induce frequent scratching behavior.[25] Chen et al[32] further linked LPC-mediated activation of keratinocytes with the secretion of miR-146a
and found that this microRNA can activate TRPV1, which is closely involved in itching
signal transduction. However, there is currently no direct evidence to indicate the
role of LPC in cholestatic liver disease-related pruritus. Some researchers have also
studied the relationship between LPC and cholestatic liver disease-related pruritus
in patients in clinical experiments. By comparing the levels of LPC with 13 different
acyl chain types in PBC patients with and without pruritus, they found a relatively
small difference between the two groups. Therefore, the role of LPC in causing cholestatic
liver disease-related pruritus remains to be determined.[25]
Progressive Treatment of Cholestatic Liver Disease-Related Pruritus
Progressive Treatment of Cholestatic Liver Disease-Related Pruritus
Western Medicine Treatment for Cholestatic Liver Disease-Related Pruritus
Medication Treatment
In terms of medication treatment, anion exchange resins such as cholestyramine and
its analogs are currently considered the first-line drugs for treating cholestatic
liver disease-related pruritus.[33] Cholestyramine, as a bile acid sequestrant, can improve the enterohepatic circulation
of bile acid in patients with cholestasis, reduce pruritus by decreasing the levels
of pruritus inducers, and achieve the goal of treating pruritus. However, some patients
may develop tolerance to cholestyramine, resulting in a lack of therapeutic effects.[1] Moreover, cholestyramine can cause gastrointestinal adverse reactions such as abdominal
distension and discomfort.
Ursodeoxycholic acid (UDCA) is widely regarded as a first-line treatment for ICP and
its secondary pruritus. Studies have found that UDCA, as an effective hepatobiliary
secretagogue, can significantly increase hepatobiliary secretion ability by stimulating
damaged transport proteins and channels in cholestatic conditions, thus improving
liver function indicators and alleviating pruritus symptoms.[34] According to a meta-analysis, UDCA has varying degrees of improvement in pruritus
associated with ICP and does not exhibit toxic reactions even at high doses of 20
mg·kg−1 during pregnancy.[35] However, the effectiveness of UDCA in improving pruritus in patients with PBC and
PSC is not evident.
Another new first-line antipruritic drug is the PPAR agonist bezafibrate. Bezafibrate
is a broad-spectrum PPAR agonist with anticholestatic, anti-inflammatory, and antifibrotic
effects. It can relieve pruritus by reducing cholestasis, improving bile duct inflammation
and injury, and reducing the formation and secretion of pruritus inducers.[36] Bezafibrate was registered in 2015 for the treatment of moderate-to-severe pruritus
in patients with PBC, PSC, and secondary sclerosing cholangitis, and the results of
the FITCH trial clearly showed its short-term improvement in moderate-to-severe pruritus
in PBC and PSC patients.[37] This indicates that bezafibrate can be used as a first-line treatment for moderate-to-severe
pruritus in PBC and PSC patients, but long-term efficacy trials are still needed.
Lifitegrast, a pregnane X receptor (PXR) agonist, is a second-line drug for cholestatic
liver disease-related pruritus. Lifitegrast may reduce the expression of ATX via PXR-mediated
pathways, thereby alleviating pruritus by reducing the metabolism of potential pruritus
inducers. Additionally, as an antibiotic, lifitegrast can also regulate the microbiota
in the intestine and skin.[28] From a clinical perspective, lifitegrast is well-tolerated and is effective and
safe for treating cholestatic liver disease-related pruritus, and it allows long-term
use.[38]
In Phase III clinical trial for pruritus in patients with chronic liver disease, the
selective κ-opioid receptor agonist nalbuphine showed a certain antipruritic effect.[39] However, due to limited efficacy, further research is needed regarding the effects
of nalbuphine and another κ-opioid receptor agonist, butorphanol in the treatment
of cholestatic liver disease-related pruritus.[40]
The 2022 EASL Clinical Practice Guidelines for Primary Sclerosing Cholangitis strongly recommend the use of bezafibrate or lifitegrast for the treatment of moderate-to-severe
pruritus in patients with PSC,[3] while there is limited evidence supporting the use of anion exchange resins, naltrexone,
other opioid antagonists, and sertraline for the treatment of pruritus in PSC.
Other Treatment Methods
For patients who do not respond to the above-mentioned medication treatments, clinical
trial treatments such as ASBT inhibitor, ultraviolet radiation B (UVB) phototherapy,
and plasma exchange can be considered. ASBT is a sodium-dependent bile acid transporter
protein, and the ASBT inhibitor can promote the excretion of bile salt in feces, thereby
reducing the bile acid level in the enterohepatic circulation.[41] Plasma exchange is an effective treatment method, and it has been found in clinical
experiments that patients with ICP or other cholestatic liver diseases who are unresponsive
to medication treatment experience a reduction in the bile acid level and improvement
in itching symptoms after plasma exchange treatment.[42] In addition, UVB phototherapy is a good method for treating pruritus associated
with PBC, and it has good tolerance.[43] However, the clinical trial about the safety of UVB phototherapy is yet to be explored.
For patients with refractory pruritus who do not respond to various treatment methods,
nasobiliary drainage is also an appropriate treatment option that can delay the need
for liver transplantation. When cholestatic liver disease-related pruritus progresses
to the point of severely affecting a patient's quality of life, liver transplantation
can be performed as a last-resort treatment. However, this surgical procedure carries
a high risk and can lead to immune suppression-related adverse reactions.
Traditional Chinese Medicine Treatment for Cholestatic Liver Disease-Related Pruritus
TCM treatment for cholestatic liver disease-related pruritus focuses on syndrome differentiation
and treatment. It deeply explores the etiology and pathogenesis of the disease to
develop targeted treatment plans. Therefore, there are different approaches to treating
cholestatic liver disease-related pruritus using TCM.
Internal Treatment
In clinical research on TCM treatment for cholestatic liver disease-related pruritus,
oral medication is a common treatment method. Yang[44] used a self-formulated prescription based on the principle of syndrome differentiation
and treatment to treat patients with acute jaundice hepatitis. It was found that TCM
treatment can effectively alleviate clinical symptoms and improve liver function indicators.
Wu et al[45] believed that the pathogenesis of jaundice-related pruritus is due to wind invasion
of the liver, liver dysfunction in dispersing and regulating, wind and damp-heat pathogenic
factors obstructing the bile collaterals and causing jaundice-related pruritus. In
clinical treatment, the Qufeng Zhiyang decoction functions to expel wind and eliminate
dampness and nourish the liver and blood. In addition, there are numerous TCM clinical
studies on different syndromes of cholestatic liver disease-related pruritus. For
example, the Yigan Zhiyang decoction is used to treat hepatobiliary-derived pruritus
due to wind generation due to liver deficiency, and the Qushi Zhiyang formula is used
to treat jaundice-related pruritus.[46]
[47] During treatment, medication adjustments should be made based on the patient's symptoms,
signs, and syndrome differentiation, and appropriate combinations of herbs can alleviate
itching. For example, Kushen (Sophorae Flavescentis Radix), Baixianpi (Dictamni Cortex),
Difuzi (Kochiae Fructus) can be combined to dispel damp-heat in cases of a predominance
of liver and gallbladder damp-heat. For deficiency syndrome due to yin blood and body
fluid deficiency, Shengdihuang (Rehmanniae Radix), Danggui (Angelicae Sinensis Radix),
and Xuanshen (Scrophulariae Radix) can be added.
External Treatment
Pruritus is common in dermatology, and topical medication is a primary treatment method.
Among various treatment protocols and clinical studies for cholestatic liver disease-related
pruritus, the most common methods include the topical application of Chinese herbal
ointments, local fumigation, and cold compresses. Clinical research has found that
the topical application of Huangqin ointment, a Chinese herbal medicine, can effectively
alleviate cholestatic liver disease-related pruritus symptoms and improve patients'
quality of life.[48] In addition to topical herbal preparations, there is also the method of fumigation
with Chinese herbal decoctions. Self-formulated Chinese herbal fumigation solutions
based on different treatment principles have been shown to effectively improve itching
symptoms in patients with cholestatic liver disease-related pruritus and improve their
quality of life.[49] Cold compress with Chinese herbs is one of the unique treatment methods in TCM and
an important part of external TCM treatment. Some researchers have used cold compresses
with Chinese herbs to treat cholestatic liver disease-related pruritus and have confirmed
its effectiveness through long-term observations, providing definite therapeutic effect.[50]
Characteristic Treatment Methods
In addition to traditional internal and external medications, TCM also includes characteristic
therapies such as acupuncture and cupping. These therapies have played important roles
in the clinical diagnosis and treatment of cholestatic liver disease-related pruritus.
The use of cupping in combination with Western medicine treatment can greatly relieve
skin itching and enhance the therapeutic effect.[51] Besides, therapies such as ear acupressure and bloodletting at the tip of the ear
have also played a certain role in the adjuvant treatment of cholestatic liver disease-related
pruritus.[46]
Summary
Itching is a common clinical symptom in cholestatic liver diseases and often persists
for a long time without easy relief. This article reviews recent research findings
on cholestatic liver disease-related pruritus, indicating that substances such as
steroids and their metabolites, bile acid, and LPA may be potential pruritus inducers
in cholestatic-related diseases. Various treatment methods, including medication and
intervention therapy, have been developed specifically for cholestatic liver disease-related
pruritus. However, there are still some unresolved issues in the study of cholestatic
liver disease-related pruritus: (1) Most experimental studies have only identified
potential pruritus inducers associated with cholestasis, and the complex pathological
mechanism underlying cholestatic liver disease-related pruritus has not been fully
elucidated. (2) Currently, most animal models used in the research studies on cholestatic
liver disease-related pruritus are rodent models, and it is difficult to compare and
analogize the criteria for evaluating pruritus to the human situation. (3) Despite
the existing treatment methods, some patients with cholestatic liver disease-related
pruritus still have a poor treatment response, and effective treatment remains a challenge.
To address these problems, future research works should focus on clinical trials by
conducting comprehensive screening of plasma (and/or bile) samples from a large number
of patients to identify more potential pruritus inducers. Furthermore, the establishment
of humanized organ models can provide a deeper understanding of the itching signaling
pathways in cholestatic liver diseases. In terms of treatment, TCM has shown certain
characteristics and advantages in clinical practice. Based on the etiology, pathogenesis,
and syndrome differentiation and treatment, external applications, internal medications,
and TCM characteristic therapies have achieved good therapeutic effects. Additionally,
the combination of Chinese and Western medicine has also achieved more effective treatment
for patients with cholestatic liver disease-related pruritus. In the future, for patients
who have a poor treatment response to existing methods, a wide range of approaches,
including the combination of Chinese and Western medicine or various novel therapies,
can be adopted to achieve precise and effective treatment.
