Chronic cholestatic liver diseases
Presented at the INASL-EASL Meeting, New Delhi, 31 March−2 April, 2002.
HE Blum, Department of Medicine II, University of Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany. Email: email@example.com
Primary biliary cirrhosis
Etiopathogenesis and natural course
Primary biliary cirrhosis (PBC) is, apart from primary sclerosing cholangitis (PSC), the clinically most important cholestatic liver disease. The etiology and pathogenesis are still unknown. Primary biliary cirrhosis is considered to be an autoimmune disease.1–3 An infective etiology has not been definitively excluded, however,4 and genetic factors appear to also be important in PBC.5,6
Primary biliary cirrhosis is a chronic cholestatic liver disease, also termed ‘non-suppurative destructive cholangitis’. The natural history of PBC is characterized initially by the development of antimitochondrial antibodies (AMA) in nearly all patients. Antimitochondrial antibodies are non-organ and non-species specific and are most frequently directed against four M2 polypeptides that are part of the pyruvate dehydrogenase (PDH) complex localized on the inner mitochondrial membrane. When such patients are followed over the years, the serum alkaline phosphatase level is seen to become elevated, and eventually symptomatic PBC develops.7 Patients with asymptomatic PBC have a reduced long-term survival and progression to liver cirrhosis may occur before the patient becomes clinically symptomatic.8 Asymptomatic patients usually sur-vive more than 10 years. In patients with symptomatic PBC and jaundice, survival is approximately 7 years. Although the prognosis is very variable, prognostic models such as the Mayo Clinic model (age, bilirubin, albumin, prothrombin time and edema) allow an estimation of the approximate expected survival time.
Primary biliary cirrhosis can be associated with almost any other autoimmune disease. Among others, collagenoses (lupus erythematodes, rheumatoid arthritis, dermatomyositis, mixed connective tissue disease), scleroderma, keratoconjunctivitis, sicca complex and autoimmune thyreoiditis are particularly frequent.
Diagnosis is based on physical examination, biochemical tests (alkaline phosphatase, gamma-glutamyl transpeptidase, bilirubin and AMA) and liver biopsy. Histopathologically PBC can be classified into four stages. Stage 1, florid bile duct lesions; stage 2, ductular proliferations; stage 3, septal fibrosis and bridging; and stage 4, cirrhosis.
The differential diagnosis of PBC with the classical clinical features of a female patient includes pruritus, elevated alkaline phosphatase, and AMA positivity. Differential diagnosis includes PSC, cholestatic sarcoidosis, autoimmune cholangiopathy and cholestatic drug reactions.
In addition to general measures in patients with cholestasis aimed at controlling pruritus and steatorrhea, several PBC-specific treatment strategies have been evaluated in clinical studies of different design and quality.9 These therapeutic strategies include ursodeoxycholic acid (UDCA), immunosuppressants such as steroids, including budesonide, azathioprine, methotrexate or cyclosporine A, and other drugs such as colchicine, bezafibrate, d-penicillamine and chlorambucil.
The only drug that is widely used in clinical practice to treat patients with PBC and that is licensed for this indication is UDCA.9–11 Ursodeoxycholic acid has, among others, immunomodulatory properties and appears to protect against the accumulation of cytotoxic dihydroxy bile acids.12–14 Although UDCA (13–15 mg/kg per day as a single dose or in three divided doses) has positive effects on laboratory tests in most patients, with complete normalization of alkaline phosphatase levels in approximately 30%, the effect on liver histology and survival is controversial.9,15,16 Ursodeoxycholic acid monotherapy appears promising in early disease but may not prevent disease progression. Therefore, alternative treatment strategies need to be developed and evaluated in qualified clinical trials.
In advanced symptomatic PBC, liver transplantation is the treatment of choice in patients without contraindications. The long-term results for this indication are excellent, with survival rates of 80–90% at 1 year and 60–70% at 5 years after liver transplantation.
Because UDCA monotherapy may not result in a complete normalization of alkaline phosphatase levels and may not prevent disease progression, alternative treatment strategies have been explored. The combination therapy with steroids, including budesonide, azathioprine or methotrexate appear to be better than UDCA monotherapy.9 The trials performed to date are insufficient, however, to allow a general recommendation. Therefore, these patients should be enrolled in qualified clinical trials. In this context a clinical trial has been initiated comparing UDCA monotherapy with the combination of UDCA and mycophenolate mofetil.17
Primary sclerosing cholangitis
Etiopathogenesis and natural course
Primary sclerosing cholangitis is the second most important chronic cholestatic liver disease. Its etiology and pathogenesis are still unknown. Primary sclerosing cholangitis is also considered to be an autoimmune disease,1–3 also based on its association with ulcerative colitis (UC) and the detection of perinuclear antineutrophilic cytoplasmic antibody (pANCA).5,18 An infective etiology has not been definitively excluded, however,4 and genetic factors appear also to be important in PSC.5,6
The natural history of PSC is characterized by progressive fibrosis and ultimately disappearance of intrahepatic or extrahepatic bile ducts or both. The extent of the involvement of the intrahepatic and extrahepatic bile ducts varies. The prognosis of PSC is variable. Mean survival after diagnosis is approximately 12 years. Patients with intra- and extrahepatic involvement have a worse prognosis than patients with only intrahepatic PSC. The Mayo Clinic model estimates prognosis on the basis of serum bilirubin, histological stage, age and the presence of splenomegaly.
Primary sclerosing cholangitis affects male subjects more frequently than female subjects. Most patients present without symptoms of liver disease. Frequently, an elevated alkaline phosphatase level is found, particularly when screening patients with UC. Frequent presenting symptoms are jaundice, pruritus, weight loss and right upper quadrant pain. Diagnosis is based on physical examination, biochemical tests (alkaline phosphatase, gamma-glutamyl transpeptidase, bilirubin), liver biopsy and cholangiography, demonstrating generalized beading or stenosis of the biliary tree. Ulcerative colitis should be sought even if patients have no clinical evidence for colitis. Eighty percent of patients with PSC have UC that may be mild or completely asymptomatic. The activity of PSC correlates inversely with that of UC. Further, the coexistence of UC does not affect the natural course of PSC. Cholangiocarcinoma occurs in approximately 10% of PSC patients and should always be considered.
The diagnosis of PSC with the classical clinical features of a male patient includes pruritus, elevated alkaline phosphatase and AMA negativity. The differential diagnosis include PBC, secondary sclerosing cholangitis, due to postoperative bile duct strictures, bile duct neoplasms or choledocholithiasis, and cholangitis caused by various infectious agents.
In addition to general measures in patients with cholestasis aimed at controlling pruritus and steatorrhea, several PSC-specific treatment strategies have been evaluated in clinical studies of different design and quality.9 These therapeutic strategies include UDCA, and immunosuppressants such as steroids, including budesonide, azathioprine, methotrexate, cyclosporine A, tacrolimus, pentoxifylline and other drugs. Another important aspect of the management of patients with PSC is the preferably endoscopic treatment of dominant bile duct strictures and the meticulous treatment of biliary infections.
The only drug that is widely used in clinical practice to treat patients with PSC is UDCA.9 Although UDCA (15–20 mg/kg per day as a single dose or in three divided doses) has positive effects on laboratory tests in most patients, the effect on liver histology and survival is very difficult to assess due to the limited number and quality of clinical studies. Ursodeoxycholic acid monotherapy appears to be promising in early disease but probably does not prevent disease progression. Therefore, alternative treatment strategies need to be developed and evaluated in qualified clinical trials.
In advanced symptomatic PSC, liver transplantation is the treatment of choice in patients without contraindications. The long-term results for this indication in adults are excellent, with a survival rate of 80–90% at 3 years after liver transplantation. After transplantation, strictures in the transplanted bile ducts occur more frequently than in other transplant groups.
Because UDCA monotherapy may not result in a complete normalization of alkaline phosphatsase levels and may not prevent disease progression, alternative treatment strategies have been explored. These patients should be enrolled in qualified clinical trials.
Extrahepatic manifestations of primary biliary cirrhosis and primary sclerosing cholangitis
The major extrahepatic manifestations of PBC and PSC are pruritus, osteoporosis and steatorrhea.
The cause of pruritus is not known. Apart from UDCA, first-line therapeutic strategies include cholestyramine and colestipol. Second-line therapies are naloxone, naltrexone and ondansentron. Third-line therapies are rifampicin, phenobarbital, S-adenosyl-methionine and metronidazole. If pruritus cannot be controlled by these strategies, plasmapheresis treatment by molecular absorbent recirculating system (MARS) and liver transplantation may have to be considered.9
Osteoporosis is a frequent complication of cholestatic liver diseases and is present in almost all patients with end-stage liver disease. Its cause is unknown. Therapy is based on a well-balanced diet as well as regular physical exercise. Calcium (1 g per day) and vitamin D3 (500–5000 units per day) should be given. In postmenopausal women estrogen replacement therapy appears to be safe and effective. For bisphosphonates there are insufficient data to allow a general recommendation.9
In patients with cholestatic liver diseases steatorrhea can occur due to impaired fat absorption, caused by reduced bile acid concentration and micelle formation in the small bowel, due to decreased secretion of pancreatic enzymes in the context of a sicca syndrome and due to coexisting celiac disease. Management is based on reduction of fat intake, use of medium chain triglycerides, substitution of pancreatic enzymes and appropriate correction of vitamin A, D, E and K deficiencies as well as supplementation of electrolytes and trace elements, especially zinc.9
Primary biliary cirrhosis and PSC are the two most important cholestatic liver diseases. Their etiology is not known. The natural course is variable and in general characterized by progression to advanced liver disease or liver cirrhosis with substantial morbidity and mortality. Treatment of patients with PBC is based on monotherapy with UDCA. UDCA treatment of patients with PSC should be combined with preferably endoscopic management of dominant strictures. Ursodeoxycholic acid monotherapy is of benefit only in a minority of patients and in the early stages of PBC and PSC. Therefore, a combination of UDCA with other drugs as well as novel treatment strategies need to be developed and evaluated in qualified clinical trials with the aim to reduce disease progression as well as the morbidity and mortality associated with these cholestatic liver diseases.