Rev.  Gastroenterol. Perú.        Vol. 19 • Nº 3 • 1999


Treatment of Cholestasis

Jürgen Schölmerich*

 

RESUMEN

La colestasis incluye una amplia variedad de causas. Cuando se excluyen las causas extrahepáticas un número de trastornos que producen colestasis intrahepática son definidos. El mecanismo celular de la colestasis aún no esta completamente entendido. El diagnóstico puede hacerse utilizando la historia, examen clínico, algunos parámetros de laboratorio, serología y también la PCRE. El tratamiento principalmente depende de la causa de la colestasis. Las causas mas importantes de colestasis intrahepática, la cirrosis biliar primaria y la pericolangitis esclerosante primaria tienen en el ácido ursodeoxicólico, en ocasiones asociadas a terapia inmunosupresora, al tratamiento de elección. El trasplante hepático se mantiene como una importante opción terapéutica. Todos los demás tratamientos deben evaluarse, comparándose a estas medidas estándar.

Palabras clave: Colestasis, Cirrosis biliar primaria, colangitis esclerosante, ácido biliares, ácido ursodeoxicólico.


SUMMARY

Cholestasis includes a wide variety of causes. When extrahepatic causes are excluded a number of disorders causing intrahepatic cholestasis are defined at this time. The cellular mechanisms of cholestasis have as yet to be completely understood. Diagnosis can be made using history, physical examination, a few laboratory parameters, serology and also ERCP. Treatment depends largely on the cause of the cholestasis. Regarding the leading disorders such as PBC and PSB, ursodesoxycholic acid and in some instances in addition immunosuppressants are thus far established. Liver transplantation remains an important treatment option. All other treatments need to be evaluated against these standard measures.

Key words: Cholestasis, primary biliary cirrhosis, sclerosing cholangitis, bile acids, ursodeoxycholic acid.


Rev. Perú Gastroenterol.1999; 19 (3): 221-29


INTRODUCTION

Cholestatic liver disorders comprise a number of heterogeneous diseases with different etiology, and morphological, clinical, radiological or physiological definitions (table 1) affecting different structures of the biliary excretory system (figure 1).



Although von Helmont wrote in the nineteenth century "bile - the balsam of life, a noble juice that could not cause disease" it is by now clear that cholestasis and the spillover of bile components into the circulation can lead to a number of severe symptoms and even life threatening problems.

Cholestasis is associated with retention of bile acids and other toxic compounds in the liver. A number of mechanisms has been described for toxic effects on liver cells of these compounds (table 2). These effects have been summarized(1), (figure 2). In particular, apoptosis has been found as an important component of bile salt damage to liver cells(2) including blebbing in electromicroscopy (figure 3).

Table 2

Figure 2

 

However, toxic effects to liver cells are not the only important events occurring in cholestasis. Probably even more important are the lack of bile constituents in the intestinal lumen which explain a number of further symptoms in cholestasis (table 3). Altogether the findings present thus far indicate that cholestasis is a mixed problem of liver cell damage, intestinal dysfunction and some even less well known dysfunctions of extraintestinal organs such as kidney, heart and possibly even the brain.

Pagina_222_Figure 3a.jpg (4894 bytes)

 

Symptoms of cholestasis

The main symptoms of cholestasis described in text books are icterus, pruritus and xantelasmata, which are probably due to retention of substances which are normally excreted via the biliary route. The lack of biliary constituents, in particular bile salts in the intestinal lumen leads to pale stools, malabsorption and vitamin deficiency. Unexplained thus far are symptoms such asbradycardia and renal functional disorders. It is as yet unknown, to what extent immune dysfunction, increased bacteria translocation, disturbed wound healing and other symptoms are really due to the cholestatic syndrome.

Table 3


Laboratory abnormalities in cholestasis

Weil known to most clinicians are the classical laboratory abnormalities of cholestasis such as hyperbilirubinemia, increased alkaline phosphatase, increased g-glutamyl transferase (g-GT) and increased protrombine time (table 4).

Pagina 223 Table 4.jpg (14381 bytes)

 

Diseases leading the cholestasis

According to the anatomical structure of the biliary excretory tract diseases can be classified (figure 4). Depending on the cause of the disorder influences on hepatocellular functions, canalicular disturbances, bile duct proliferation and large biliary duct dysfunction can be distinguished. A large list of disorders of cholestasis in adults can therefore be made (table 5).

Figure 4

 

Table 5 Primarily, the extrahepatic causes of cholestatis (obstruction) have to be distinguished from non-obstructive disorders. This can be done with a correctness of 85 % by history and physical examination and some basal laboratory tests. Furthermore, abdominal ultrasound is well suitable to perform this distinction (figure 5) (3). Since extrahepatic causes of cholestasis are not the subject of this review it will further on focus only on intrahepatic cholestasis.


There are four principal groups of important disorders of intrahepatic cholestatic liver disease.

i) Genetic cholestasis
ii) Cholestatic hepatitides
iii) Drug induced liver damage
iv) Autoimmune liver disorders
Figure 5

 

Table 6: Genetic cholestatic syndromes
Idiopathic cholestasis of pregnancy
Benign recurrent cholestasis
Familial intrehepatic cholestasis

    Byler syndrome
    Alagille syndrome

Genetic liver disorders include a number of diseases which mainly occur during early childhood (table 6). Treatments include liver transplantation, surgical drainage and rarely application of suitable bile acids(4). Drug induced cholestasis can occur with every class of drugs available on the market (table 7). The impact of these drugs on different structures of the biliary excretory system is different, they all have to be considered in any case of cholestasis. Treatment obviously implies avoiding the
application of the drug candidates identified.

When all these causes are excluded a few major cholestatic disorders remain which are dealt within the following paragraphs.

Table 7: Drugs inducing cholestasis
Steroids
Sedatives
Antidiabetics
Antibiotics
Antimycotics
NSAID
Anticoagulants
Antigout drugs
Antidepressants
Anticonvulsants
Antimitotics
H2-blockers
Antythyroids
Cardiovascular drugs
Diuretics
Lipid lowering drugs
--> All classes of drugs


Primary biliary cirrhosis

Primary biliary cirrhosis (PBC) mainly affects females above the age of 40. The prevalence is between 20 and 240/106 persons, the incidence varies between 4 and 30/l06/year. There is an increase of this disorder in England by a factor of 2 in the eighties. The pathophysiology of PBC has not been completely clarified. A molecular mimicry with bacteria involved in urinary tract disorders and a number of other problems have been discussed. The occurrence of antimitochondrial antibodies does not seem to be related to pathophysiology in general. This has not been changed by identifying the antigens to these antibodies.

Although the name of this disorder suggests cirrhotic changes the earlier stages do not imply cirrhosis but rather a nonsuppurative cholangitis. The diagnosis of primary biliary cirrhosis is made by the clinical symptoms, laboratory abnormalities and serological markers (table 8).

Pagina 225 Table 8.jpg (18528 bytes)

Prognosis of this disorder is also controversial. Some studies showed that asymptomatic PBC does not lead to an excessive number of deaths due to liver disorders (figure 6)(5). This may however be only an effect of a time delay between diagnosis and symptoms occurring. Ultimately PBC seems to lead to cirrhosis with all its consequences.

Pagina 225 Figure 6a.jpg (15996 bytes)

Table 9: treatment of PBC - symptomatic
Pruritus

Colestyramin
Phenobarbital
UDCA
Deficiencies

ADEK
MCT-fat
Zinc

The treatment of PBC consists of symptomatic approaches, where in particular pruritus and malabsorption needs to be handled (table 9). There is an impressive list of possible treatments of pruritus (table 10). Substitution is obviously aimed at deficiencies identified and includes fat soluble vitamins, easily absorbed fat (medium chain triglycerides) and some trace elements.

 

Table 10: Treatment of pruritus in PBC
1. choice Colestyramine
2. choice
Rifampicin
UDCA
3. choice.
Naloxon
Propofol
4. choice

Antihistaminics
Steroids
Phenobarbital
5. choice Plasmapheresis
Bile diversion
No effect SAMe
Phototherapy
Ondansetron

Medical treatment of primary biliary cirrhosis has been attempted with a number of immunosuppressive compounds (including D-penicillamine, chlorambucil, cyclosporine A, colchicin, azathioprine, methotrexate and others. Up to now none of those has demonstrated a reasonable benefit when related to the possible side effects.

The only drug thus far showing an effect on the course of the disease seems to be ursodesoxycholic acid (UDCA).


Effects of UDCA on liver cell damage

A number of possible mechanism of action of UDCA has been described (table 11)(6). Some of them are related to the protective effect of this bile acid against cytotoxic bile acids (tables 12,13)(7). It has been also shown recently, that TUDC is able to inhibit apoptosis induced by dihydroxy bile acids(8). lt is not yet clear, what of this array of effects of UDCA is in particular responsible for the positive effects on the course of PBC in humans. More recent findings indicate that UDCA can actually increase the transit time of bile acids through the liver and increase the amount of bile acids excreted while not affecting the uptake (table 14)(9).

Table 11: Mechanisms of cation of UDCA
Inhibition of resorption of toxic BA
Reduced secretion of toxic BA into canaliculus(?)
Stimulation of choleresis
Improved movilisation of toxic BA from the liver cell
Inmune system downregulation
Influence on calcium metabolism in liver cells
Table 12: Cell necrosis by taurolithocholate-protective effect of tauroursodesoxycholate
Number of cells
(n=625 cells)
%
TLC (8 µM)
TLC + TUDC(8+16µM)
7.2±1.2
2.7±0.5
1.15±0.20
0.40±0.10



 

 

 

Table 13: Comulative effect of TLD on UDC
(GUDC,TUDC)-induced bile flow
UDC GUDC TUDC
TLC:(G)(T) UDC
1:2
1:10

-18.4
-26.2

-7.9
-13.9

+4.3
1.5
Values are µl/g liver/30 minutes


Table 14:  75seHCAT and cholestasis - effect of UDCA in PBC/PSC(9)
Control PBC/PSC
before UDCA
PBC/PSC
after 3 months UDCA
Hepatic uptake(%/min)
Hepatic transit time(min)
Hepatic net excretion(%/min)
17.2
11.6
3.7
19.9
18.7
1.4
18.5
14.7
2.0
Improvement better in stage I/II

However, more than 10 year ago it had been shown that laboratory signs of PBC such as alkaline phosphatase and others can be much improved by the application of a standard dose of UDCA (10 - 15 mg/kg/d) (figure 7). It has furthermore been shown that survival without liver transplantation and the necessity of liver transplantation can be reduced by UDCA as compared to the application of placebo (table 15)(10,11,12,13,14,15).

Treatment can even delay the onset of esophageal varices(16) and seems to be costefficient(17).

Figure 7 New studies have shown that the combination of UCDA with some immunosuppressive drugs might even be more adventageous than UDCA alone(18,19) This is, however, not the case with methotrexate(20).

The final treatment of PBC, however, is still liver transplantation (LTX). There is a clear list of indications for LTX in this disorder (table 16). The survival of patients transplanted due to this disorder is very good when compared to other indications. Recurrence after transplantation is still debated but may not actually hamper success of this treatment.


Primary sclerosing cholangitis

May be observed during ERCP (figure In contrast to PBC primary sclerosing cholangitis (PSC) mostly, affects younger patients, in particular males. The symptoms are relatively similar to PBC (table 17). The diagnosis is made mainly with endoscopic retrograde cholangiopancreatography, histology is only supportive. Different types of PSC 8).

In contrast to PBC, UDCA does not have similar significant effects (21). An improvement of laboratory parameters was found only in 50% of the studies (22), an effect of survival has yetto be shown. The treatment therefore consists of endoscopic dilatation of major stenoses in combination with UDCA (23), supportive therapy such as substitution of fat soluble vitamins and surveillance regarding liver function. An important aspect is that PSC induces a significant number of cholangiocarcinomas which can only be detected via an aggressive diagnostic approach including regular brush cytology or even biopsy of bile ducts. In any suspicious case early transplantation is to be recommended. Longterm results of LTX in PSC are as promising as those in PBC, when carcinoma has not yet developed.

Table 15: Combined analysis of UDCA in PBC (14)
4 years UDCA
(n=273)
Placebo*
(n=275)
Survival without LTX(%)
LTX(%)
82.8
8.0
76.0**
11.6
Effect appears after 2 years, more impressive in patients with bilirubin > 3.5 and advanced disease.
* only 2 years, than UDCA in 2/3 of patients
** = significant

 

Table 16: Indications for LTX in PBC
Estimated survival < 1 year
Bilirubin > 10 mg/dl
Refractory ascites
Encephalopathy
Serum albumin < 30 g/l
Wasting
Recurrent SBP
Progressive osteoporosis
Early HCC
Unacceptable life quality(pruritus, lethargia)
Table 17: Symptoms in PSC
 
Malaise, fatigue
Jaundice
Abdominal pain
Weight loss
Fever
Pruritus
Nausea, vomiting
Cholangitis

%
64
51
43
42
42
40
23
13

 

Table 18: Autoimmune cholangitis - clinical and serological findings (24)
AMA - - + +
ANA
   n
-
24
+
40
-
62
+
74
AP(U/I) 492 631 435 617
ASMA+(%) 27 50 26 41
Histology
   Duct lesions(%)
   Cholestasis(%)

63
96

65
35

60
84

43
86
Overall: No differnces !!!
ANCA´s not analized !
       

 



Pagina 227 Figure 8.jpg (21752 bytes)

 

Autoinmune cholangiopathy

In the more recent years a significant number of reports described overlap syndromes between PBC and PSC, PBC or PSC with autoimmune hepatitis (AIH) (24). This led to the definition of the diagnosis of autoimmune cholangitis or autoimmune cholangiopathy which indeed seems to be an "overlap syndrome" in hepatology similarly to that defined in rheumatology (table 18). The earlier description of AMA-negative PBC does also fit in this scheme.

These overlap disorders need to be treated with immune suppression (steroids and azathioprine) as weIl as with UCDA. Controlled trials are lacking, however.


Rerefencias Bibliográficas