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Cholestyramine binds anions in the small bowel. It decreases the enterohepatic
circulation of compounds, including bile acids, increasing their fecal excretion [97].
It is reported on the LiverToxNIH website that leunomide induced DILI should be
treated with cholestyramine to enhance drug clearance [98], in addition to the dis-
continuation of the drug.
Valproic acid treatment can be associated with hepatotoxicity [99]. Carnitine is
essential in the beta-oxidation of fatty acids. Carnitine depletion is associated with
impaired transport of long-chain fatty acids into the mitochondrial matrix, leading
to decreased β-oxidation, acetyl-CoA, and ATP production. A decrease in β-oxidation
can change the metabolism of valproic acid towards predominantly peroxisomal
ω-oxidation, which is associated with an increase in the production of ω-oxidation
products, including 4-en-valproic acid, a metabolite that is incriminated in valproic
acid induced hepatotoxicity. The intravenous administration of carnitine is recom-
mended for patients with valproic acid induced DILI [99, 100]
The use of N-acetylcysteine has been extended to all forms of DILI [94].
The treatment of DILI of the autoimmune phenotype is steroids, either at presen-
tation or if a resolution is not noted within one to two weeks of diagnosis after dis-
continuation of the drug or if there is any evidence of hepatic synthetic dysfunction
[101]. The treatment duration has not been conrmed in controlled studies; how-
ever, treatment has been suggested in doses of 20 to 60mg orally per day to be
decreased in association with improvement for three to 6 months and vigilant follow
up. DILI of the autoimmune hepatitis phenotype tends not to relapse at least in a
follow up of a few years after discontinuation of steroids, which supports the diag-
nosis of this phenotype [102].
Prevention ofDrug-Induced Liver Injury
Prevention of DILI requires vigilant monitoring to identify early liver injury and to
discontinue the agent involved. Idiosyncratic DILI cannot be prevented [103].
Information about the likelihood of a drug or classes of drugs to cause DILI is very
useful and can help build a DILI surveillance schedule during treatment. Knowledge
regarding the documented latency to DILI in association with a newly prescribed
drug reported to cause liver injury is an excellent practice to incorporate for the
clinician to establish a monitoring schedule. In patients with liver disease, the author
monitors liver tests two weeks after initiation of any therapy, and subsequently, in
an individualized manner, depending on the drug and the patient.
The American Thoracic Society has provided guidelines to detect hepatotoxicity.
However, the frequency of monitoring has not been established. Every two to four
weeks at the start with spaced out testing subsequently was suggested. Its recom-
mendation is that “Treatment should be interrupted and …. a modied or alternative
regimen used for those with ALT elevation more than three times the upper limit of
normal (ULN) in the presence of hepatitis symptoms and/or jaundice, or ve times
the ULN in the absence of symptoms” [104].
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The importance of accessing the NIHLiverTox.gov website [2] and the recently
upgraded Drug-induced liver injury severity and toxicity list cannot be overempha-
sized [105]. A genetic, cellular, organoid, and human-scale evidence testing plat-
form to identify drugs associated with DILI has been developed [106]. Its use in
drug development and clinical trials may facilitate the production of safe
medications.
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of Springer Nature 2022
N. V. Bergasa (ed.), Clinical Cases in Hepatology,
https://doi.org/10.1007/978-1-4471-4715-2_15
Chapter 15
Complications ofLiver Disease
NoraV.Bergasa
Pruritus
The pruritus or itch of liver disease is considered to be secondary to cholestasis.
Cholestasis is dened as impaired secretion of bile [1]. Cholestasis is a complica-
tion of all types of liver diseases; however, pruritus is more prevalent in conditions
primarily due to cholangiopathies, where cholestasis can be profound.
The etiology of the pruritus of cholestasis is unknown. The ideas that have pre-
vailed concern the accumulation of bile acids and increased opioidergic tone [2]. A
role of autotaxin and lysophosphatidic acid in the pruritus of cholestasis has been
proposed [2].
Pruritus is always annoying. The pruritus of cholestasis can be mild, without major
interference with regular activities, moderate, prompting patients to seek therapeutic
intervention, and severe and intractable, leading to sleep deprivation. The pruritus of
cholestasis is not readily relieved by scratching; this characteristic stimulates the
patients to scratch with abrasive objects such as forks, knives, and hairbrushes. It can
be generalized or localized to particular parts of the body, particularly the palms of the
hands and the soles of the feet where the symptom is often rst perceived. The percep-
tion of pruritus of cholestasis varies considerably among patients, and it does not
appear to correlate with serum biochemical parameters of liver disease. This form of
pruritus can be persistent or intermittent. The perception of pruritus may be inu-
enced by various factors, such as changes in mood and distractions. It can be exacer-
bated by normal physiologic changes such as the premenstrual state in women;
therefore, it is essential to obtain this information during the clinical interview.
N. V. Bergasa (*)
Department of Medicine, H+H/Metropolitan, New York, NY, USA
New York Medical College, Valhalla, NY, USA
Hepatology, H+H/Woodhull, Brooklyn, NY, USA
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The treatment of pruritus secondary to cholestasis can be classied according to
the presumed antipruritic mechanism of the intervention.
Specic treatment of liver disease associated with cure should resolve the pruri-
tus because cholestasis would decrease or disappear. For example, in cases of pruri-
tus from biliary obstruction, e.g., common duct stone, the removal of the obstruction
is associated with the relief of pruritus. However, cholestasis from liver inamma-
tion and ductopenia from cholangiopathies including primary biliary cholangitis
(PBC), primary sclerosing cholangitis (PSC), and cholestasis from congenital con-
ditions are chronic and can be associated with intermittent or chronic pruritus in a
substantial proportion of patients; thus, specic treatments for pruritus are neces-
sary, in the absence of a cure of the primary liver disease. Treatments of pruritus
have evolved based on what is believed to be its cause. Often, however, there is no
clear rationale supporting the use of certain interventions. In addition, the exclusive
use of subjective methodology to assess the effect of therapeutic interventions on
pruritus makes it difcult to interpret data from clinical studies, including those that
are placebo-controlled, as the placebo effect is strong.
Pruritus is a perception, and, as a perception, it cannot be directly measured; in
contrast, scratching activity, the behavioral manifestation of pruritus, can be
recorded independently from gross body movements. Thus, the inclusion of behav-
ioral methodology in clinical trials of pruritus offers the opportunity to obtain objec-
tive, analyzable data, and it should be part of the design of clinical studies.
The development of effective treatments for pruritus is desperately needed. In
this chapter, some of the interventions used to treat the pruritus of cholestasis are
described according to their presumed aim.
Therapies that Aim at theRemoval ofthePruritogenic
Substances(s) fromtheBody
Cholestyramine is a nonabsorbable resin used to treat hypercholesterolemia [3]. It
is believed that the pruritogenic substances or cofactors to the pruritogens are made
in the liver and excreted in bile, and as a result of cholestasis, accumulate in tissues.
The presumed aim of resins, which also include colestipol and colesevelam, is to
increase the excretion of pruritogen(s) in feces, that may include bile acids; how-
ever, many patients with pruritus from cholestasis who report relief on cholestyr-
amine at the start of treatment report recurrence of pruritus after some time on the
medication. This observation tends to suggest some tolerance to the drug, which
may be a form of receptor-mediated tachyphylaxis.
In a single-blind, open-label, placebo-controlled crossover trial of 6–32months
duration cholestyramine at doses between 3.3 and 12g orally per day was associ-
ated with relief of pruritus in 23 of 27 patients as compared to an observational
control group that did not receive cholestyramine, but that received norethandrolone
or no treatment [4]. There is a clinical consensus supporting that the administration
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of cholestyramine is associated with the amelioration of pruritus in many patients
with cholestasis, including patients with PBC [4, 5]. The maximum recommended
dose of cholestyramine is 16g per day, 4g per dose. In patients with the gallbladder
in situ, there is a rationale to administer the resins immediately before and after
breakfast because it is inferred that the pruritogen(s) is excreted in bile and that it
accumulates in the gallbladder during the overnight fast; extra doses with lunch and
dinner may be added if there is no satisfactory effect with the rst two doses. In
general, cholestyramine is well tolerated, although some patients report bloating,
constipation, and diarrhea. It is recommended that other prescribed medications be
taken at least 2hours apart from the resins, as they can interfere with the absorption
of other drugs. The administration of cholestyramine interferes with the absorption
of fat-soluble vitamins, which are malabsorbed in cholestasis; thus, assessing for
deciencies of these vitamins and coagulation prole, a reection of vitamin K
deciency (i.e., prothrombin time) is prudent during long-term treatment with
cholestyramine.
In a meta-analysis that addressed the efcacy and safety of bile acid-binding
agents [6], the inclusion criteria of the identied studies were described as hetero-
geneous, not allowing for combination and proper analysis of the data [6].
GSK2330672 is a selective inhibitor of human ileal bile acid transporter (IBAT),
preventing the enterohepatic circulation of bile acids. GSK2330672 was studied in
22 patients with pruritus from PBC in a phase 2a, double-blind, randomized,
placebo- controlled, crossover study. The drug was reported to be associated with a
signicant decrease in baseline “itch scores” of −57% (95% Condence Interval
(CI), −73 to −42, p<0·0001), a−31% (−42 to −20, p<0·0001) decreased in the
itch domain of the PBC 40 questionnaire, suggestive of improvement, and a−35%
(−45 to −25, p<0·0001) decrease in the 5-D itch scale, which includes ndings in
physical examination pertinent to excoriations from scratching. There was a signi-
cant reduction in the serum total bile acid concentrations in association with the
drug. Diarrhea was reported as a limiting factor in the long-term use of this medica-
tion [7]. Odevixibat is a drug reported to be associated with a decrease in pruritus in
children with progressive familial intrahepatic cholestasis, recently approved for
this clinical indication [8].
Invasive procedures have been used to treat patients with intractable pruritus. A
transient relief from pruritus has been reported in association with anion adsorption
and plasma separation [9], and the extracorporeal liver support systems Prometheus
™ and MARS ™ [10–14]. These interventions may never be submitted to con-
trolled clinical trials because of their nature; however, the tremendous need to pro-
vide relief to patients with severe pruritus supports the use of this type of intervention
by experienced operators in a controlled environment. The placebo effect of these
interventions may be substantial and the relief provided temporary [11].
Reports of relief of the pruritus have also been published in association with
nasobiliary drainage [15], partial internal diversion of bile in patients with progres-
sive familial intrahepatic cholestasis [16] (see above), and partial external diversion
of bile [17, 18] and ileal diversion in children with cholestasis [19], in whom an
improvement in quality of life was also reported.
15 Complications ofLiver Disease
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