Liver and biliary tract
Jetra i bilijarni traktARCH GASTROENTEROHEPATOL 2001; 20 ( No 3 – 4):
Lecenje primarne bilijarne ciroze urzodeoksiholnom kiselinom
( accepted December 17th, 2001 )
Rada Ješić, 1Ivan Boričić, Miodrag N. Krstić, Dragan Tomić, Aleksandra Pavlović, Djordje Ćulafić, Radmila Šarenac, Vladislava Bulat, Tanja Cvejić
Institute of Digestive Diseases, Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia, Belgrade, 1Institute of Pathology, School of Medicine, University of Belgrade.
Address correspondence to: Professor Dr Rada Jesic
Clinic for Gastroenterology and Hepatology
Institute of Digestive Diseases
Clinical Center of Serbia
Koste Todorovica 6 St.
YU-11000 Belgrade, Serbia,
Yugoslavia
……………………… ……………………………
Ursodeoxycholic acid in PBC Gastroenteroloska sekcija SLD-
01716, 2001.
Primary biliary cirrhosis is chronic cholestatic liver disease of middle-aged women which laboratory hallmark is serum antimitochondrial antibody positivity. Although the aetiology of disease is not fully eludicated, genetic and immunologic factors appear to play a role. The signs and symptoms of cholestasis develop as disease progress. The diagnosis should be considered in every patient with cholestasis of undetermined origin and/or serum alkaline phosphatase increase. In order to confirm the diagnosis and to determine the prognosis, percutaneous liver biopsy is mandatory. Although there is no proven curative medical therapy, ursodeoxycholic acid appears to be promising agent and its use is associated with liver histology improvement in some patients.
We are presenting our 5- year experience with 32 cases of primary biliary cirrhosis diagnosed at the Institute of Digestive Diseases and treated for with ursodeoxicholic acid. The majority were females ( 27 ). Ursodeoxicholic therapy led to improvement of all laboratory indices of cholestasis: serum bilirubin, alkaline phosphatase, serum cholesterol, and antimitochondrial antibody titer. During the observation period symptomatic improvement was recorded as well. Liver histology demonstrated slowing of the disease progression in almost 50% of cases. We therefore confirmed that in primary biliary cirrhosis ursodeoxycholic is usful and safe treatment modality, and might be recomended.
Key words: primary biliary cirrhosis, ursodeoxycholic acids
Primarna bilijarna ciroza je hronična holestatska bolest jetre koja se uglavnom javlja u žena srednje dobi. Premda je uzrok bolesti i dalje nepoznat, genetski i autoimuni faktori igraju značajnu ulogu u njenom nastanku. Antimitohondijalna antitela su prisutna u serumu u vecine bolesnika. Znaci i simptomi se razvijaju sa progresijom bolesti. Biohemijski pokazatelji holestaze i patohistološki nalaz potvrđuju dijagnozu i određuju prognozu bolesti. Poslednih godina se u lecenju primarne bilijarne ciroze sa velikim uspehom koristi hidrofilna žučna kiselina-ursodeoksiholna kiselina.
Prikazujemo rezultate lečenja urzodeoksiholnom kiselinom 32 pacijenta sa primarnom bilijarnom cirozom koji su u periodu od 5 godina praćeni u Klinici za gastroentrologiju i hepatologiju KC Srbije. Žena je bilo 27. Nakon ovog perioda lečenja, došlo je do statistički signifikantnog smanjenja biohemijskih indikatora holestaze, bilirubina, holesterola kao i pada antimitohondrijalnih antitela. Većina prisutnih simptoma i znakova se povukla. Patohitološka analiza tkiva jetra pokazala je u manje od polovine pacijenata lako-stepenu progresiju bolesti. Zaključili smo da rana i dugotrajna terapija sa ursodeoksiholnom kiselinom može da se preporuči kao korisna i bezopasna.
Ključne reči: primarna bilijarna ciroza, ursodeoksiholna kiselina
INTRODUCTION
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease, which primarily affects middle-aged woman, and is associated with positive serum antimitochondrial antibodies (AMA) (1 ). It is associated with variety of different autoimmune disorders and syndromes. Their relationship is further supported by the presence of the haplotypes HLA DR 7, HLA DR 8, HLA DQB1 and HLADRW 52 in PBC, which are characteristic for autoimmune diseases as well. The signs and symptoms of PBC are due to cholestasis. The earliest disease symptom is pruritus, which tends to increase during the disease course. Hepatic histology demonstrates granulomatous destruction of the interlobular and septal bile ducts, portal and periportal fibrosis and finally, development of biliary cirrhosis.
In PBC, an effective treatment modality must reduce clinical manifestations of cholestasis, decelerate progression of the disease, improve quality of life and increase survival rate (1, 2). Ursodeoxycholic acid (UDCA) was proved so far to be the most effective medical treatment of PBC.
Here we report our results with the long-term treatment of PBC with UDCA.
MATERIal and methods
Thirty-two patients with PBC who were diagnosed and regularly followed-up at the Institute of Digestive Diseases, Clinical Center of Serbia, enrolled this study. The age of the patients ranged between 31 and 68 years, mean years; male to female ratio was 5:27. At the time of diagnosis, clinical features were as follow: pruritus (18 patients,56%), fatigue (23 patients, 71%), pain below the right costal margin (9 patients,28%), jaundice (14 patients,43%), skin hyperpigmentation that resembles sun tanning (8 patients,25%), xanthelasma and xantomata (13 patients,40%).
All patients underwent routine biochemical examinations including liver function tests, immunological testing, hepatitis viruses studies, abdominal ultrasonography including Doppler examination of lieno-portal system, and liver biopsy.
The diagnosis PBC was based on the following criteria: 1) chronic cholestatic liver disease lasting at least 6 months, 2) positive AMA, 3) liver biopsy confirming PBC or consistent with PBC and 4) exclusion of other liver diseases.
The following patients were withdrawn from the study: 1) patients who proved to be pregnant, 2) those who were considered candidates for liver transplantations within a year, with less chance than 80% for one year survival without liver transplantation, 3) those with cirrhosis-associated complications such as repeated variceal bleeding, encephalopathy, ascites resistant to diuretics, and 4) patients who received corticosteroid therapy or some other experimental treatment six months before initiation of the study.
UDCA was administered in doses: 10-15-mg/kg body weight/day. Changes of biochemical parameters before and after UDCA are presented on Table 1.
Table 1.Results of five years treatment of PBC with ursodeoxycholic acid
|
Biochemical parameters |
Ursodeoxycholic acid |
||
|
Before treatment |
After treatment |
P |
|
|
ALT |
138.2 + 51.48 |
92.72 + 11.78 |
< 001 |
|
AST Bilirubin |
121.3 + 43.0 48 + 5.75 |
81.3 +9.7 37.98 +10 |
< 001 |
|
Alkaline phosphatase |
471 + 91.7 |
301.6 + 61.8 |
< 001 |
|
GGT |
251 + 61.5 |
141 + 31.1 |
< 001 |
|
Cholesterol |
8.97 + 1.51 |
5.83 + 0.39 |
< 001 |
|
Gamma globulin |
22.53 + 1.39 |
18.79+ 1.01 |
< 001 |
|
AMA |
> 640 |
> 320 |
< 001 |
The intensity of skin itching was reduced within 2-3 weeks after the initiation of UDCA treatment. Alkaline phosphatase (AP) and GGT levels were significantly reduced during the observation period. The same occur with serum bilirubin and cholesterol level. In 2/3 of the patients AMA values were slightly lowered. Xanthelasma developed in 10 patients. Malaise and fatigue were markedly less prominent in more than 50% of cases after one year of UDCA treatment.
Repeated liver biopsy was performed in 12 patients. In more than 50% of cases milder degree of disease progression was recorded.
Primary biliary cirrhosis is disease which caracterise small intrahepatic ducts progressive destruction, probably by an immunological process. This results in slowly progressive cholestasis. The major diagnostic hallmark is the antimitochondrial antibody (AMA), but it is uncertain whether AMA is involved directly in the pathogenesis of this disease. (2,3,5) Presentation nowadays tends to be early, and the patient is usually asymptomatic (2,5,6). She may be found to have a raised level of serum alkaline phosphatase and/or total serum cholesterol discovered at the routine check (2,3,5). The diagnosis may be made in patients under investigation for a condition known to be associated with PBC, such as Hashimoto, s thyroiditis, scleroderma, rheumatoid arthritis, or Sjogren, s syndrome etc (2,3,5,6). Osteoporosis may be an initial observation (2). The serum antimitochondrial antibody is always positive in a titer exceeding 1:40 (2,5,6). The most frequent symptom of patients with PBC is fatigue which cause remains unknown (2,5,6). It does not correlate with the severity of disease (2,5,6). The second most common symptom, namely pruritus starts insidiously (2,3,5). Jaundice may never develop but, without treatment, it appears in most patients within 2 years of the onset of disease (2,3,6).
Follow-up studies of patients with PBC indicate that the median survival for symptomatic disease is 8 years, and for asymptomatic disease 16 years (3). On the contrary, there are some opinions that the rate of progression is unpredictable. It is possible that some asymptomatic patients will never progress to symptomatic disease (2,6). Therefore one may conclude that asymptomatic disease does not necessarily means presymptomatic disease (2).
Several prognostic models have been developed which give an indication of the outcome of a particular patient with PBC (2). The most often used is Mayo Model (2). This model does not require liver biopsy, but rather utilise age, serum bilirubin, albumin, protrombin time, and the presence or absence of oedema. The common factor in each prognostic model is serum bilirubin. There is recent evidence that bilirubin concentration alone is good prognostic indicator. When bilirubin concentration is >100 mmol/l one may expect survival lesser than 2 years. But no models can yield a precise estimate of survival in the individual patient. They cannot predict life-threatening episodes such as variceal bleeding. Prognostic models are most useful for therapeutic clinical trials and for predicting the timing for liver transplantation (2).
At present, no curative medical treatment can be recommended for PBC (2,3,5,6). Three groups of the drugs have been currently used. The immunomodulators would be expected to be effective in the early stages of disease, whereas the antifibrotics and anticholestatics should be helpful by preventing the progression to cirrhosis and liver failure (2,3,4,5,6).
It appears that treatment strategy for PBC is depending on histological staging of the disease. Stage I encompass asymmetrical destructive lesions of interlobular bile ducts with damaged bile ducts surrounded by dense lympho-mononuclear cells. These lesions are irregularly scattered throughout the portal triads and are often seen only on large surgical liver biopsies. Stage II characterises with more widespread lesions with very reduced number of normal bile ducts within portal triads. Portal fibrosis is pronounced. Stage III is similar to stage II except that fibrous septa extend beyond triads and form portal-to-portal bridges. Stage IV represents the end stage of the lesion with frank cirrhosis. Proposed initial treatment for stage I and II is UDCA plus colchine, for stage II and III UDCA plus colchichine but if liver function tests remain abnormal methotrexate has to be added. For stage III and IV UDCA, methotrexate and, depending of the study group ,colchicine (6).
During the last several years non-toxic, hydrophilic, choleretic bile acid, ursodeoxycholic acid (UDCA) was proved to decrease the toxicity of the retained bile acid in patients with biliary cirrhosis. In PBC, this bile acid modifies the bile acid pool so that it becomes the predominant bile acid of the body. UDCA reduces the progression of disease (PBC) and the probability of death or the need for liver transplantation. Beside choleretic effect, UDCA has cytoprotective, antiapoptotic, immunomodulatory, hypocholesterolemic, lipolytic and other less studied effects (7).
There have been many randomized controlled trials of UDCA in PBC and all included both asymptomatic and symptomatic patients (2,4,5,6,7,8,9,10). Corpehot reported five times slower progression of PBC into the extensive fibrosis or cirrhosis if the drug is introduced in early stage of disease. After four years of treatment with UDCA 76% of patients remains in the early stages (11). However, some authors suggested that symptomatic (loss of pruritus) and laboratory improvements do not necessarily reflect arrest or slowing of histologic progression of the disease (9,10). Heathcote reported that UDCA reduces serum bilirubin levels, but treatment showed little effect on symptoms, liver histology, or survival. It has a variable effect on pruritus, no benefit on osteoporosis, but exerts some benefit on the development of portal hypertension (14).
In spite of the controversial reports seen in the literature, majority of the well controlled studies is consistent in finding that UDCA improves liver function tests, reduces portal inflammation, and prevents histological progression ( 15,16). Prolonged administration of UDCA therapy led to significant delay of the liver fibrosis in 2/3 of PBC patients (17,18). The majority of the published meta-analyses suggest that UDCA is 32% better than placebo in improving survival of the patients with PBC (13,14). Based on the above-mentioned data, early and long-lasting UDCA treatment may be recommended in every PBC patient.
In our study we found an improvement of the quality of life, partial amelioration of deranged liver function tests (particularly bilirubin values), liver histology improvements, and postponing of liver transplantation. We observed unaltered disease progression and ongoing cirrhosis when UDCA is introduced during the advanced disease stages. This confirms already reported data that development of the esophageal varices, variceal hemorrhage, ascites or lethal outcome cannot be considered therapeutic failure if the drug is introduced in the III or IV stage of PBC (17,18,19,20).
Since the single UDCA therapy frequently fails to induce complete laboratory remission, non-responders or partial responders are candidates for combination therapy, e.g. methotrexate and colchicine (6).
In the experimental clinical studies combination of UDCA and silymarin did not show additional benefit in the treatment of PBC patients who are UDCA non-responders (21). Further on, besafibrate (lipid modulating agent) is used with some success in patients with PBC either alone or in combination with UDCA (22). Similarly, promising results are recorded with the combination UDCA and sulindac, nonsteroidal anti-inflammatory drug with choleretic property (23). But before the initiation of such treatment, overlap syndrome (PBC and autoimmune hepatitis) has to be ruled out (18)
For successful treatment of PBC, it is likely that therapy with UDCA has to be started early, at the stage of acute bile-duct inflammation. Since there is no known curative medical therapy, liver transplantation remains the last resort for these patients. The survival after hepatic transplantation in PBC is good; up to 70% of grafted cases survive 10 years. In 17% of transplanted patients recurrence of PBC occur (24). This is difficult to distinguish from chronic graft rejection because both conditions show cholangitic changes with bile duct paucity.
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