Treatment options for primary biliary cirrhosis and primary sclerosing cholangitis

Opinion statement Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are chronic cholestatic liver diseases that affect 0.5 to 40 per 100,000 and 1 to 6 per 100,000 Americans, respectively. Prompt recognition and management of the clinical manifestations of these diseases is essential for the patients’ well-being and ultimate outcome. Ursodeoxycholic acid (UDCA), 13 to 15 mg/kg per day, is the standard therapy for PBC and should be offered to every patient. It has been shown to slow progression of the disease and prevent the need for liver transplantation, which is the last recourse for patients with end-stage disease. However, there is no effective therapy for PSC yet. Patients are managed symptomatically, with surgical or endoscopic interventions as needed in cases of significant biliary obstruction. Complications of chronic cholestasis are seen in both PBC and PSC, with pruritus and fatigue being the most common complaints. The first choice for the treatment of pruritus is still cholestyramine, starting at 4 g/d. The pathogenesis of fatigue is poorly understood in this population; unrecognized hypothyroidism should be excluded. The use of antidepressants is currently under evaluation, but there is no specific therapy for fatigue as of yet. For prevention of severe osteoporosis, we recommend supplementation with 800 IU vitamin D and 1500 mg calcium/d. In patients with PBC and established osteoporosis, the use of alendronate and vitamin K appears to cause an increase in bone mineral density. Further studies are necessary before either of these drugs is routinely recommended. Finally, fat-soluble vitamin deficiencies are noted with more advanced disease. We recommend that serum levels be checked in high-risk patients, and that vitamins are replaced as appropriate with water-soluble supplements. However, other causes of malabsorption must be ruled out, including pancreatic insufficiency and celiac sprue.     

Treatment of primary sclerosing cholangitis

Opinion statement Aims of treatment for primary sclerosing cholangitis are as follows: prevention of progression of hepatobiliary disease, reduction of symptoms and consequences of cholestasis (pruritus, osteoporosis), and prevention of complications (colorectal cancer, hepatobiliary cancer). Ursodeoxycholic acid (UDCA) improves biliary secretion and laboratory parameters of cholestasis, but its effects on liver histology and survival are not clear. It reduces the incidence of dysplasias and carcinomas of the colon in patients with colitis and possibly has a beneficial effect on the incidence of bile duct carcinomas. At present, UDCA represents the most promising therapeutic option. Immunosuppressive treatment has not been proven to be effective; it appears to be indicated in the overlap syndrome with autoimmune hepatitis but may be harmful in bacterial cholangitis. Bacterial cholangitis is common in patients with dominant stenoses and requires antibiotic treatment. Endoscopic treatment of dominant stenoses improves cholestasis and prolongs survival in comparison to predicted survival. Pruritus represents a problem in some patients, and cholestyramine represents the first-line treatment. If ineffective, opioid antagonists, rifampin, or ondansetron may be tried. For treatment of osteoporosis and osteopenia, calcium and vitamin D supplementation are recommended, and in selected cases, bisphosphonates may be indicated. In patients with severe cholestasis and coagulation defects, parenteral supplementation of vitamin K may be indicated. During treatment, all patients should be regularly screened for colonic and bile duct carcinomas. Patients with cirrhosis of the liver and its complications are treated accordingly, and in end-stage disease, liver transplantation is indicated.     

Review: Treatment of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a slowly progressive chronic cholestatic disease of the liver thought to be caused by immune destruction of the interlobular bile ducts. One-third of patients are asymptomatic and one-third of these develop symptoms within 5 years. Therapeutic regimens should be directed at the control of symptoms, prevention of complications and specific therapy aimed at controlling progression of the disease. Symptoms may be secondary to cholestasis or due to other associated diseases. The cause of pruritus secondary to cholestasis remains unknown; the anion exchange resin cholestyramine generally brings relief. In patients resistant or intolerant to this therapy, rifampin may be helpful, as well as ultraviolet light without sunblock. Liver transplantation may rarely be the only option for uncontrollable pruritus. Clinical manifestations of keratoconjunctivitis sicca and xerostomia need constant attention to prevent corneal ulcers and dental caries. Preventative therapy includes regular screening for thyroid dysfunction and replacement therapy when necessary and the administration of the fat soluble vitamins A, D and K once hyperbilirubinaemia is present. Osteoporosis is a complication of all cholestatic liver disease. There is no satisfactory preventative therapy. It may be appropriate to give hormone replacement therapy to all post-menopausal women with PBC to reduce osteoporosis. Liver transplantation is the best option for those with fractures. Oesophageal varices may develop early in the course of PBC, non-selective beta-blocker therapy should be used as prophylaxis against variceal haemorrhage. The only specific therapy shown to cause both a biochemical and survival benefit in patients with PBC is ursodeoxycholic acid (UDCA). Treatment with UDCA delays progression, but does not result in a cure of this disease. Currently, liver transplantation is the only definitive treatment available for end-stage disease.     

Bone disorders in chronic liver disease

Osteomalacia rarely occurs in adult patients with chronic liver disease despite a low serum vitamin D level being reported in up to two-thirds of patients with cirrhosis. In contrast, osteoporosis, which increases the risk of vertebral fractures, occurs in 12%-55% of patients with cirrhosis. Although the prevalence is probably falling, as shown by a fall from 57%-26% in patients with biliary disease requiring liver transplantation over the last 2 decades, it still accounts for significant patient morbidity. Bone density also falls in the first 3 months after liver transplantation, and pretransplant fractures are predictive of posttransplant fractures. Many of the known risk factors for postmenopausal osteoporosis exist in the cirrhotic population, such as excess alcohol intake, steroid use, poor nutrition, and hypogonadism. There is also an increased risk of osteoporosis in patients without cirrhosis, particularly those with hemochromatosis and biliary disease. The diagnosis is made with bone density measurements. The effective treatment is largely based on evidence from postmenopausal osteoporosis as there have been only a few small clinical trials of patients with chronic liver disease. Bisphosphonates are the mainstay of treatment; they have been shown to be effective in biliary disease and are well tolerated.     

A Review of the Challenges Associated with the Diagnosis and Therapy of Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic and progressive cholestatic liver disease that often leads to the development of cirrhosis. Complications of PSC include pruritus, fatigue, vitamin deficiencies, metabolic bone disease, dominant biliary strictures, gallstones, and hepatobiliary malignancies, most commonly cholangiocarcinoma (CCA). Despite the presumed autoimmune etiology of PSC, a clear benefit from immunosuppressive agents has not yet been established, and their use is limited by their side effects. Endoscopy is required in evaluation of biliary strictures in PSC to rule out the possibility of CCA. Liver transplantation is currently the only life-extending therapy for patients with end-stage disease. However, disease recurrence can be a source of morbidity and mortality as transplanted patients survive longer. Further studies are needed to develop an optimal therapeutic strategy for patients with PSC to decrease the incidence of complications of the disease, to decrease the need for transplantation, and to extend life expectancy.     

Vitamin D replacement for cirrhosis-related bone disease

The osteoporotic fracture rate in patients with chronic liver disease is approximately twice that of age-matched, control individuals. About 66% of patients with moderately severe cirrhosis and 96% of patients awaiting liver transplantation have vitamin D deficiency. Studies have shown a strong correlation between vitamin D deficiency and bone density, particularly in the hip. Previous studies of vitamin D therapy in cirrhosis-related bone disease have had major design flaws. Most reports and guidelines on the treatment of hepatic bone disease have concluded that vitamin D deficiency does not have a significant pathogenetic role in the development of osteoporosis in cirrhosis, and that there is no evidence for a therapeutic effect of vitamin D supplementation. Conversely, it is generally recommended that patients with cirrhosis and low bone density should receive calcium and vitamin D supplementation; yet there is a paucity of reliable data on the optimal doses to use, as well as a lack of clearly demonstrated benefit. We believe that clinical trials of vitamin D therapy in these patients with liver disease are warranted. As low-dose oral supplementation often will not normalize vitamin D levels or suppress parathyroid hormone activity in cirrhotic patients, high-dose, parenteral vitamin D might be preferable, but further long-term studies are required to assess the benefits and safety of this approach.     

Management of osteoporosis in primary biliary cirrhosis.

Osteoporosis is not a significant problem in the majority of patients with primary biliary cirrhosis (PBC). However, substantial bone-related morbidity may occur in patients with advanced disease, in particular after liver transplantation. The cause of osteoporosis in PBC is multifactorial, and pathophysiological mechanisms specifically related to PBC have not been defined. In general, the principles of management followed in post-menopausal osteoporosis also apply in chronic liver disease. Dual energy X-ray absorptiometry is currently the method of choice for monitoring bone mineral density. Avoidance of conditions with potential negative effects on bone mass, and maintaining adequate serum vitamin D levels and calcium intake form the cornerstone in preventing osteoporosis. Bisphosphonates are the most logical choice when specific medical treatment of PBC-associated osteoporosis is indicated, as well as for preventing bone loss during glucocorticoid treatment and after liver transplantation. Recent studies suggest that active vitamin D analogues are effective alternatives in the post-transplant setting.     

Biliary tract inflammatory disorders: Primary sclerosing cholangitis and primary biliary cirrhosis

Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are chronic progressive cholestatic diseases that frequently lead to biliary cirrhosis. The exact pathogenesis of these diseases remains elusive but is likely immunologically based. Complications range from fatigue and pruritus to end-stage liver disease. The risk of developing hepatocellular carcinoma is low for patients with PBC, whereas cholangiocarcinoma is common in PSC and carries an ominous prognosis. Although ursodeoxycholic acid is effective in slowing the progression of PBC, no effective medical therapy exists for PSC. Liver transplantation is the only option for patients with end-stage liver disease and yields excellent long-term survival in both groups.     

Treatment of cholestatic liver diseases; the role of ursodeoxycholic acid]

Ursodeoxycholic acid (UDCA) allows symptomatic treatment of cholestatic liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, intrahepatic biliary atresia, and cholestasis of cystic fibrosis. Patients should be treated at an early stage of the disease in order to prevent progression to cirrhosis. Since UDCA has no toxic effects longterm treatment with this substance is possible without the risk of undesired side effects. In patients with primary biliary cirrhosis and rapid progression of the disease, UDCA may be combined with an immunosuppressive substance (i.e. cyclosporin). In primary sclerosing cholangitis, biliary atresia and cholestasis of cystic fibrosis, UDCA at present seems the only treatment of which a benefit for the patients can be expected. In endstage disease liver transplantation is indicated. The role of UDCA in chronic hepatitis and alcohol induced liver disease needs to be clarified in further studies. Whether the improvement of laboratory tests in such patients indicates amelioration of the course of disease, still is unclear.     

Hepatic Osteodystrophy in Primary Biliary Cirrhosis: Effects of Medical Treatment

Objectives : Osteoporosis is a frequent extrahepatic complication of primary biliary cirrhosis. Although histologically similar to the osteoporosis commonly seen in postmenopausal females, the pathogenesis and management of bone disease in patients with primary biliary cirrhosis is poorly understood. The experience with a subgroup of patients with primary biliary cirrhosis treated with vitamin D, calcium, and estrogen supplementation was reviewed to determine the effects of medical treatment on hepatic osteodystrophy. Methods : The records of 203 women with the diagnosis of primary biliary cirrhosis were reviewed retrospectively for lumbar spine bone mineral density, menopausal status, and supplementation with vitamin D, calcium, and estrogen. Results : The 16 postmenopausal patients treated with estrogen replacement had a statistically significant increase in the lumbar spine bone mineral density at 1 yr (+ 0.014 ± 0.049 vs. -0.03 ± 0.046 g/cm² p < 0.038), without a significant change in the serum bilirubin or alkaline phosphatase. In treated patients, vitamin D and calcium supplementation did not lead to significant improvement in lumbar spine bone mineral density. Conclusions : Calcium and vitamin D supplementation, even in the presence of vitamin D deficiency, do not improve lumbar spine bone mineral density in patients with primary biliary cirrhosis. Estrogen replacement in postmenopausal patients, however, does appear to improve lumbar spine bone mineral density without increasing clinical or biochemical cholestasis, a potential complication reported in animal studies. This study should serve as an impetus for a controlled trial of estrogen replacement in postmenopausal patients with primary biliary cirrhosis.     

Biliary tract inflammatory disorders: Primary sclerosing cholangitis and primary biliary cirrhosis

Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are chronic progressive cholestatic diseases that frequently lead to biliary cirrhosis. The exact pathogenesis of these diseases remains elusive but is likely immunologically based. Complications range from fatigue and pruritus to end-stage liver disease. The risk of developing hepatocellular carcinoma is low for patients with PBC, whereas cholangiocarcinoma is common in PSC and carries an ominous prognosis. Although ursodeoxycholic acid is effective in slowing the progression of PBC, no effective medical therapy exists for PSC. Liver transplantation is the only option for patients with endstage liver disease and yields excellent long-term survival in both groups.     

Lipids and lipid-activated vitamins in chronic cholestatic diseases

Primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune cholangiopathy are cholestatic liver diseases of unknown cause. Destruction of small to medium bile ducts (in primary biliary cirrhosis and autoimmune cholangiopathy) and large bile ducts (in primary sclerosing cholangitis) leads to progressive cholestasis, liver failure and end-stage liver disease. A variety of abnormalities in lipid metabolism have been described in primary biliary cirrhosis, and range from alterations in serum lipid levels and lipoprotein subsets to deranged metabolism of cholesterol. Progressive cholestasis and, consequently, decreased small intestinal bile acid concentrations in these cholestatic liver disease can also lead to impaired absorption of fats and fat-soluble vitamins, resulting in steatorrhea and deficiencies in vitamins A, D, E, and K. This article focuses on abnormalities in lipid metabolism in primary biliary cirrhosis and primary sclerosing cholangitis, and on lipid-activated vitamin deficiencies in these disorders.     

The timing of liver transplantation in primary biliary cirrhosis.

Primary biliary cirrhosis, the most common chronic cholestatic liver disease in adults, usually progresses to cirrhosis and its complications. Ursodeoxycholic acid therapy delays disease progression, but most patients will ultimately succumb. Liver transplantation is now accepted as the standard treatment for end-stage PBC. Development of major complications of portal hypertension and liver failure, poor quality of life and short survival without transplantation are the major indications for this surgical intervention in patients with primary biliary cirrhosis. Resource use is another key variable to be considered in the timing of liver transplantation. Prognostic models have been developed to predict survival and resource utilization with and without liver transplantation. Prognostic models aid the clinician in the selection and timing of liver transplantation in the patient with primary biliary cirrhosis.     

Prevention and treatment of osteoporosis in primary biliary cirrhosis.

Osteoporosis is not a feature unique to primary biliary cirrhosis (PBC) but is also found in other categories of liver disease. The principles developed for monitoring and treating postmenopausal osteoporosis can also be followed for patients with PBC. Monitoring of dietary intake of calcium and vitamin D serum levels is essential, and the threshold for initiating supplementation should be low. Bisphosphonates can be considered the most rational choice when specific therapy is required.     

Sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease whose aetiopathogenesis is unknown. PSC is frequently associated with inflammatory bowel disease, in particular chronic ulcerative colitis, is most commonly observed in young males and is clinically characterized by fatigue, pruritus and jaundice. The diagnosis is supported by a cholestatic biochemical profile and histological abnormalities, and confirmed by visualization of an abnormal biliary tree. The natural history of the disease is currently being evaluated but is generally recognized to be slowly progressive, leading to complications of chronic cholestasis, portal hypertension and biliary cirrhosis. There is no specific medical treatment, and orthotopic liver transplantation remains the only definitive treatment for patients with end-stage PSC. A more rational approach to medical therapy will ensue upon a better understanding of the aetiopathogenesis of this disease.     

Endoscopy in the management of primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver condition characterized by progressive fibrosis and destruction of the intra-and extrahepatic biliary tree. PSC has a clear association with inflammatory bowel disease and is often progressive, leading to cirrhosis and end-stage liver failure. For many patients, liver transplantation offers the only hope of long-term survival. No effective medical treatment exists, and therapy is often aimed at treating complications of the disorder, including dominant biliary strictures, which may cause symptomatic jaundice, cholangitis, and pruritus. Studies on endoscopic therapy (eg, biliary dilation and/or stent insertion) have shown favorable results, although most studies have been small, retrospective, and uncontrolled. Up to 20% of patients with PSC develop cholangiocarcinoma; however, distinguishing between cholangiocarcinoma and benign strictures can be difficult. Ideally, randomized trials are required to determine the safest and most effective endoscopic management for symptomatic dominant strictures.     

Treatment of primary biliary cirrhosis

Primary biliary cirrhosis is a chronic liver disease of unknown etiology, characterized by inflammation and destruction of the intrahepatic biliary ducts, resulting in chronic cholestasis and eventually cirrhosis. The main clinical manifestations consists of pruritus, jaundice, xanthomas, and the consequences of intestinal malabsorption, including vitamin deficiencies and osteodystrophy. Treatment of PBC is addressed at preventing or relieving the symptoms and clinical consequences of chronic cholestasis, and also at correcting the bile duct abnormalities by specific treatments. Pruritus is treated with cholestyramine, but in some cases other drugs, such as rifampicin or opioid antagonists are needed. Bisphosphanates are effective for increasing bone mass in osteopenic patients. Vitamin D and cAlcium supplements are also recommended, particularly in patients with severe cholestasis. Ursodeoxycholic acid (UDCA) has become the standard treatment (13-15 mg/kg/day), resulting in marked relieving of cholestasis. UDCA also prevents the histological progression of the disease, although the effects on survival are less apparent. Small trials of combination therapy using UDCA with methotrexate, colchicine, or prednisone, have been reported but have not shown any increased efficacy over UDCA therapy. Liver transplantation is the only treatment available when cholestasis progresses, with very good survival rates.     

Medical treatment of primary biliary cirrhosis and primary sclerosing cholangitis.

Treatment of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) with ursodeoxycholic acid (UDCA) has been in common use since 1985. In PBC, treatment with UDCA improves laboratory data, liver histology, enables a longer transplantation-free interval and prolongs disease survival. Because UDCA is unable to cure the disease newer drugs or combination therapies are still needed. Studies with UDCA and immunosuppressants such as prednisone, budesonide and azathioprine have shown that in selected patients combination therapy may be superior to UDCA monotherapy. PSC is treated successfully with UDCA and endoscopic dilatation of the bile duct strictures. Treatment of extrahepatic manifestations of cholestatic liver disease such as pruritus, fatigue, osteoporosis and steatorrhea can be problematic and time-consuming.     

Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases practice guidelines

Primary biliary cirrhosis (PBC) is a presumed autoimmune disease of the liver, which predominantly affects women once over the age of 20 years. Most cases are diagnosed when asymptomatic (60%). The antimitochondrial antibody is present in serum in most, but not in all, patients with PBC. The disease generally progresses slowly but survival is less than an age- and gender-matched general population. The symptomatic patient may have fatigue, generalized pruritus, portal hypertension, osteoporosis, skin xanthomata, fat soluble vitamin deficiencies, and/or recurrent asymptomatic urinary tract infections. Many nonhepatic autoimmune diseases are found in association with PBC and may prompt initial presentation. To date, immunosuppressive therapy has not been shown to prolong survival in PBC. The hydrophilic bile acid, ursodeoxycholic acid (UDCA), has been shown when given in a dose of 13 to 15 mg/kg daily for up to 4 years to delay the time to liver transplantation or death. This therapy also causes a significant improvement of all the biochemical markers of cholestasis but has no beneficial effects on any of the symptoms or associated disorders. Treatment with UDCA does not obviate the need for liver transplantation. Therapies to prevent complications arising from malabsorption, portal hypertension, and/or osteoporosis are required as well. Good control of pruritus can be achieved in most patients. PBC is diagnosed with increasing frequency, but the agent(s) responsible for this slowly progressive destruction of the interlobular bile ducts remains elusive and hence a specific therapy remains unavailable.     

Bone health and vitamin D status in alcoholic liver disease

Alcohol consumption is harmful to many organs and tissues, including bones, and it leads to osteoporosis. Hepatic osteodystrophy is abnormal bone metabolism that has been defined in patients with chronic liver disease (CLD), including osteopenia, osteoporosis, and osteomalacia. Decreased bone density in patients with CLD results from decreased bone formation or increased bone resorption. The prevalence of osteopenia in alcoholic liver disease (ALD) patients is between 34 % and 48 %, and the prevalence of osteoporosis is between 11 % and 36 %. Cirrhosis is also a risk factor for osteoporosis. The liver has an important role in vitamin D metabolism. Ninety percent of patients with alcoholic liver cirrhosis have vitamin D inadequacy (<80 nmol/L). The lowest serum vitamin D levels were observed in patients with Child–Pugh class C. Bone densitometry is used for the definitive diagnosis of osteoporosis in ALD. There are no specific controlled clinical studies on the treatment of osteoporosis in patients with ALD. Alcohol cessation and abstinence are principal for the prevention and treatment of osteoporosis in ALD patients, and the progression of osteopenia can be stopped in this way. Calcium and vitamin D supplementation is recommended, and associated nutritional deficiencies should also be corrected. The treatment recommendations of osteoporosis in CLD tend to be extended to ALD. Bisphosphonates have been proven to be effective in increasing bone mineral density (BMD) in chronic cholestatic disease and post-transplant patients, and they can be used in ALD patients. Randomized studies assessing the management of CLD-associated osteoporosis and the development of new drugs for osteoporosis may change the future. Here, we will discuss bone quality, vitamin D status, mechanism of bone effects, and diagnosis and treatment of osteoporosis in ALD.