Liver and cholestasis
- Gastroepato
- Gastroenterology
- Liver and cholestasis
- Anaerobic bacteria
- Helminths
doctor's notes Claudio Italiano
Cholestasis is defined as an altered bile secretion, in the sense that bile
excretion meets an obstacle for which liver disease is characterized by the
accumulation in the plasma of substances that are, under physiological
conditions, excreted in the bile like bile acids , cholesterol and bilirubin.
Normally, the signs of cholestasis are represented by an increase in the AST and
ALT enzymes, by an increase in the alkaline phosphatase and the GT range, as
well as by an increase in direct bilirubin. A special form is cholestasis in
pregnancy, a condition that often manifests itself, apparently due to an
idiosyncratic exaggeration of the normal effects of hormones on the transport of
bile. An intense itch, which is the first manifestation of cholestasis, occurs
in the 2nd or 3rd trimester; sometimes hyperchromic urine and jaundice follow.
There is no hepatic inflammation and there are no systemic symptoms. This
disorder is benign and resolves after childbirth; however, it tends to reoccur
at each subsequent pregnancy and the women who are affected often develop the
same syndrome when they take oral contraceptives. One of the striking signs of
cholestasis is the itching from cholestasis, whose etiology is unknown, but it
seems to be related to the bile salts that pass into the circulation not being
discharged into the digestive tract. It manifests itself as a complication of
some hepatic pathologies that manifest themselves with a tight cholestasis, such
as primitive biliary cirrhosis (PBC) and primitive sclerosing cholangitis (PSC).
However, a cholestasis can also affect other pathologies of minor impact that
are characterized by a moderate alteration of the hepatic serum profile, with
moderate signs of cholestasis (eg, predominantly an increase in the activity of
alkaline phosphatase and v-glutamyl transpeptidase) , as occurs in chronic
hepatitis C, can be associated with itching. It has also been seen that pruritus
depends on cholestasis from an increased opioidergic neurotransmission, so that
drugs that antagonize opioids can decrease cholestasis pruritus.
Treatment to extinguish itching
Interventions to remove pruritogens in cholestasis have not been evaluated in
controlled clinical trials. The most effective drugs are cholestyramine (questran)
and colestipol and, more recently, colesevalam, ie non-absorbable anionic
exchange resins used to lower serum cholesterol, resins are not absorbable,
capture anions in the small intestine and increase fecal excretion of the (i)
pruritogen (i). Cholestyramine is the most widely used and prescribed drug to
treat cholestasis pruritus. Many patients respond to cholestyramine a decrease
in pruritus, but some do not respond at all and others respond transiently.
Based on the fact that the (i) pruritogen (i) is excreted in the bile, the
intake of cholestyramine powder (4 g / dose) mixed with different liquids can be
correctly prescribed before and after breakfast to benefit from the passage of
the content in the small intestine to the interruption of the nocturnal fast.
The first two doses are not associated with remission of pruritus, and the
dosage can be increased by adding 4 g at lunch and dinner. It is recommended not
to exceed 16 g per day, otherwise belly swelling and stubborn constipation may
appear. The malabsorption of fat-soluble vitamins worsens using the resins and
above all the prothrombin activity can be lengthened.
jaundice |
spider nevi |
Antihistamines
Antihistamines. they are frequently given to patients with cholestasis and
pruritus, although there is no evidence to support the role of histamine in this
type of pruritus. The hydroxizine antihistamines do not induce a consistent
improvement from cholestasis. Prescription of antihistamines to patients this
class of drugs does not bring any improvement.
Inductors of liver enzymes
Hepatic enzyme inducers include phenobarbital and rifampicin, used to treat
patients with cholestasis pruritus. The documented improvement of cholestasis
pruritus given by phenobarbital but the benefit is momentary and the risks of
sedation are considerable. Rifampicin improves pruritus in primary biliary
cirrhosis but is toxic to the liver, and the intimate mechanism of action is not
known. At doses between 300 and 450 mg / day or 10 mg / kg, rifampicin improves
cholestasis pruritus.
Antagonists of opiates
Continuous infusion of the naloxone opioid antagonist (0.2 micrograms / kg / hr),
preceded by intravenous (iv) administration of 0.4 mg bolus and oral nalmefene
administration, has been shown to be associated with a significant reduction of
scratching, the behavioral manifestation of pruritus, and its perception. These
findings support the hypothesis that cholestasis pruritus is mediated, at least
in part, by a mechanism involving the endogenous opioid system and provides a
rationale for the use of opioid antagonists in the treatment of these forms of
pruritus. A concern regarding the use of opioid antagonists in patients with
cholestasis and pruritus is the similar reaction to the opiate withdrawal
reaction that these drugs may precipitate in such patients. The only opioid
antagonist available in the United States for oral administration is naltrexone,
in 50 mg capsules, which may be elevated at the start of treatment in some
patients.
Antagonists of serotonin
The itch is mediated by the serotonergic system being a nociceptive stimulus.
Oral ondansetron was associated with a small but significant reduction of
pruritus.Following the theory of serotonergic neurotransmission, a retrospective
review of the published literature in abstract form determined that patients
with PBC reported improvement of pruritus associated with the administration of
sertraline, a selective serotonin reuptake inhibitor (SSRI). As an SSRI (ie,
sertraline), or a serotonin type 3 receptor antagonist (ie, ondansetron) can
alleviate pruritus from cholestasis is not known. If these reports are confirmed
in controlled clinical trials, studies on the action of the serotonin system in
cholestasis will be needed. Three patients with cholestasis experienced
remission of pruritus after administration of drotiabinol, a cannabinoid
receptor agonist. Experimental data suggest that the endocannabinoid system
participates in the mediation of nociception, but how this is related, in the
end, with itching, is not known.
Modalities of antipruritic interventions that are beyond a classification
Propofol is an anesthetic with some anti-opioid activity. At sub-hypnotic doses,
it was reported in an open-label and double-blind placebo controlled study that
included 10 patients, that propofol improves cholestasis pruritus.It has been
reported that S-adenosylmethionine (SAME) has improved cholestasis pruritus. in
a group of patients. This agent has antidepressive properties. If the
anti-itching effect of SAME was real, it would be a drug's effect on improving
mood at the central level, which could have a significant impact on how pruritus
is experienced or could change the central component of pruritus, playing a role
in antipruritogenic actions. Some doctors use ultraviolet (UV) B light therapy.
Treatment with UV B at erythematous doses is one of the treatments for psoriasis.
There is no obvious rationale for the use of this intervention in the treatment
of cholestasis pruritus. The effect of UV B treatment on this type of pruritus
is largely debatable. It is not possible to provide general suggestions on the
use of the treatments described in the last paragraph due to the limited data
available. Other therapeutic modalities that have been used to treat cholestasis
pruritus include flumecinol, lignocaine, antioxidants and androgens.
Ursodeoxycholic acid (UDCA) is a drug approved to treat PBC. Treatment with UDCA
may be associated with some improvement in pruritus due to the impact it has on
liver disease and excretion of the pruritogenic bile substance.
Cholestasis asthenia
Patients with cholestasis may suffer from asthenia, which can also be very
pronounced. The presence of this symptom, measured in a questionnaire, has been
associated with poor quality of sleep and depression; this suggests that
asthenia is mediated centrally. The increase in serotonergic tone by the
administration of paroxetine was associated with a worse performance of male
athletes in the cycle ergometer. Asthenia is mediated by the increase in
serotonergic neurotransmission, so in one study, a patient who took ondansetron,
ie a serotonin antagonist, had an improvement towards the symptom. Finally, it
seems that even the increase of the opioidergic tone in cholestasis could
contribute to asthenia. The use of ondansetron at doses of 4 mg orally 3 times a
day in patients with PBC was associated with a decrease in asthenia scores,
assessed by the Fisk Fatigue Impact Score (FFIS), as published in the form of
abstracts. Headaches and constipation, however, are the most common side effects
of ondansetron.
Aerobic exercises
Aerobic training increases maximum work capacity and reduces asthenia.
Hypercholesterolemia
Hypercholesterolemia is a complication of cholestasis. Moreover, in patients
with PBC, xanthomas and xanthelasms can be identified in the skin of patients
with hypercholesterolemia. The available data tend to suggest that high density
lipoproteins constitute the most represented lipid fraction in the serum of
patients with PBC and hypercholesterolemia. In patients with cholestasis, the
Apo (a) lipoproteins in the plasma of patients with PBC (see lipids) are
increased compared to those in the control group. It seems that this is a sort
of defense of the organism against secondary complications such as
atherosclerosis, which appears to be a complication not present in patients with
cholestasis.
malabsorption
Cholestasis results in a diminished concentration of bile acids in the
intestine. This results in the malabsorption of fat and fat-soluble vitamins
when the bile acid concentration falls below a critical micellar concentration.
The deficiency of the fat-soluble vitamins A, D, E and K tends to be correlated
with the duration and degree of cholestasis. There may also be some degree of
maldigestion in liver disease.
Malabsorption of fats and vitamins
The malabsorption of fats can accompany some chronic liver diseases but the
degree of steatorrhea is modest, with more than 70% of ingested fat being
absorbed. An association with celiac disease is reported in patients with PBC.
In fact, the malabsorption of magnesium or iron is always to be related to
celiac disease. An important malabsorption of fats in patients with cholestasis
can be treated with the administration of medium-chain triglycerides. Vitamin A
is available from animal diet sources such as retinol and from plants such as
P-carotene. Retinol uptake by intestinal cells is regulated by retinol binding
protein. Absorption of P-carotene depends on the availability of bile acids in
the small intestine. In addition to the poor absorption secondary to bile acid
deficiency, the decreased availability of retinol binding protein, resulting
from chronic hepatobiliary disease, contributes to vitamin A deficiency. Vitamin
A deficiency leads to impaired adaptation in the dark, which the patient may not
even be aware of; therefore, an ophthalmologic consultation is generally
necessary for a complete examination in patients at risk for this deficiency.
The activation of retinol in photochemical compound and the hepatic secretion of
retinol binding protein depend on zinc; therefore, it is necessary to monitor
zinc levels and correct deficiency if present. Oral doses of 25,000 Ul / d to
30000 Ul are recommended 3 times a week for vitamin A supplementation. Vitamin A
can be toxic to the liver and other organs; therefore, it must be administered
under strict control so as not to exceed those considered normal levels. The
most important source of vitamin D in men is endogenous production. The
metabolism of vitamin D is normal even in patients with PBC. This has suggested
that low cholesterol exposure due to chronic debilitating disease is the major
cause of vitamin deficiency in cholestasis, in addition to decreased absorption
and renal losses of its metabolites, which may be increased in PBC. . Vitamin D,
parathormone and calcitonin regulate the homeostasis of phosphorus and calcium,
therefore, the levels of the latter can be abnormal in cases of vitamin D
deficiency. The recommended doses for vitamin D supplementation range from 400
to 4000 Ul orally daily or 50,000 Ul oral 3 times a week. Chronic vitamin D
supplementation may result in hypocalcemia and soft tissue calcifications.
Natural tocopherols that require micellar solubilization for absorption are the
most abundant source of vitamin E. Vitamin E inhibits the oxidation of
unsaturated fatty acids, prevents lipid peroxidation and eliminates free
radicals. Vitamin E deficiency manifests with a neurological syndrome
characterized by peripheral neuropathy, cerebellar degeneration and abnormal eye
movements. Retinal degeneration can be attributed to the deficiency of vitamins
E and A alone or combined. Complications of vitamin E deficiency are much more
severe in children than in adults with cholestasis. It is recommended to treat
viticular deficiency. And with doses of α-tocopherol from 2 to 20 μl per os per
day, 100 μg twice a day or from 10 to 25 μl / kg / day. Two forms of vitamin K
contribute to its activity; K1, or phytonadione, which is found in most plants
and K2, a series of menachinones, which is produced by gram-positive bacteria in
the intestine. Vitamin K deficiency manifests with coagulopathy, as can be seen
from a prolonged PT secondary to the deficiency of vitamin K dependent
coagulation factors, or it may be asymptomatic. Vitamin K deficiency
coagulopathy secondary to cholestasis resolves with the administration of the
missing vitamin subcutaneously. Vitamin K deficiency can be corrected with 1 to
10 mg of vitamin K, subcutaneously daily for three consecutive days. In patients
with chronic cholestasis, vitamin K deficiency can be prevented by monthly
administration of 10 mg of vitamin K. Intramuscular administration of vitamin K,
or other drugs, should be avoided in patients with coagulopathy due to the risk
of intramuscular bleeding . If the coagulopathy is caused by the damage of the
hepatocytes, it will not be resolved with treatment with vitamin K.
index of hepatology