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Chronic Immune-Mediated Liver Disease

Chronic Immune-Mediated Liver DiseaseChronic hepatitis refers to a condition of hepatic inflammation, necrosis, and fibrosis that is present for at least 6 months. There are numerous causes of chronic hepatitis. The natural history and response to therapy depend on the etiology and the age and condition of the patient. However, the end stage of all forms of chronic hepatitis, cirrhosis, and its complications, is the same for all causes.

Forms of chronic hepatitis. Histologically, chronic hepatitis has been subdivided into three forms:

  • Chronic mild hepatitis refers to mild disease in which the inflammation is confined to the portal tracts. Serum transaminases may be near normal or moderately elevated.
  • Chronic active hepatitis  refers to symptomatic chronic hepatitis in which the liver tests and histology are compatible with active inflammation, necrosis, and fibrosis, which may lead to cirrhosis. On histology, there is active inflammation spilling out of the portal tracts into the parenchyma with piecemeal necrosis and fibrosis.
  • Chronic lobular hepatitis refers to lobular inflammation with spotty necrosis.

The histologic classification emphasizes the importance of liver biopsy in the diagnosis, management, and prognosis of the disease. Any of the causes described in section B can take any of these forms in histologic appearance; hence histology alone is not sufficient for diagnosis and proper management of these patients.

The causes of chronic hepatitis can be classified into several basic groups: viral, metabolic, autoimmune, and drug-induced chronic hepatitis. It is also important to exclude Wilson’s disease, О±1-antitrypsin deficiency, and hemochromatosis in these patients.

Viral hepatitis B, C, and D have been shown to progress to chronic hepatitis.

Autoimmune chronic hepatitis is a progressive inflammatory liver disease in which immune reactions against host antigens are believed to be the major pathogenic mechanism. The clinical syndrome occurs in both sexes and all ages with a predominant occurrence in women. Autoimmune chronic hepatitis is frequently associated with other autoimmune disorders. The abnormalities of the immune system include autoantibodies; polyclonal hypergammaglobulinemia associated with HLA-A1, -B8, -DR3, and -DW3; increase of the peripheral CD4:CD8 ratio; and a suppressor-T-cell defect. The cause of Autoimmune chronic hepatitis is unknown.

Diagnosis

Clinical presentation

Type I: lupoid. The patient is typically a young woman who presents with malaise, fatigue, anorexia, arthralgias, oligomenorrhea, fluctuating jaundice, and a cushingoid appearance with striae, hirsutism, and acne. Cutaneous manifestations of chronic liver disease and other autoimmune diseases such as Coombs-positive hemolytic anemia and thyroid disease may be present. Occasionally a patient with Autoimmune chronic hepatitis presents with acute hepatitis and jaundice, which represent an episode of activation of an underlying chronic process that was previously silent. Few patients present with fulminant hepatic failure. At the other end of the spectrum are patients with advanced Autoimmune chronic hepatitis and cirrhosis who present with ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, or bleeding from esophagogastric varices. In current practice, due to routine laboratory testing for liver chemistries, patients are detected much earlier in the course of the disease.

TABLE. CAUSES OF CHRONIC HEPATITIS
Viruses
Hepatitis B virus
Hepatitis C virus
Hepatitis D virusDrugs
Alpha-methyldopa
Oxyphenacetin
IsoniazidAlcoholic liver disease

Nonalcoholic steatohepatitis

Metabolic causes
Primary biliary cirrhosis
Sclerosing cholangitis
Alpha1-antitrypsin deficiency
Wilson’s disease
HemochromatosisAutoimmune hepatitis
Type I (antiactin)
Type II (anti-KLM)
Type III (anti-SLA)Cryptogenic
KLM, kidney-liver-microsomal; SLA, soluble liver antigen.

Type II: anti-KLM (kidney-liver-microsomal) antibody-positive. Type II is less prevalent than type I and has been described most often in Continental Europe. It tends to present predominantly in the pediatric age group and is more often associated with other autoimmune diseases, such as insulin- dependent diabetes mellitus, autoimmune thyroid disease, and vitiligo. The presentation is often acute, even fulminant, and has a propensity to progress rapidly to cirrhosis.

Type III: anti-SLA (soluble liver antigen). These patients constitute a small group of Autoimmune chronic hepatitis patients who are, in general, negative for antinuclear antibody (antinuclear antibody) and KLM antibodies.

However, up to 30% of these patients may have smooth muscle antibody and liver membrane antibody, rheumatoid factor, antithyroid antibodies, or antimitochondrial antibody. Nevertheless, there is no evidence that these patients differ in any significant respect from those with type I Autoimmune chronic hepatitis.

Anti-liver specific protein (anti-LSP) and anti-asialoglycoprotein receptor (ant-ASGP-R) are found in virtually all Autoimmune chronic hepatitis patients with positive antinuclear antibody or smooth muscle antibody and KLM-I. Anti-LSP is found in a number of chronic liver disorders, primarily those with an underlying immunopathology and in which periportal inflammation is a feature. Titers of anti-LSP and anti-ASGP-R correlate with histologically assessed disease severity and fluctuate in response to immunosuppressive therapy.

TABLE. CLINICAL AND IMMUNOLOGIC COMPARISON OF THE THREE TYPES OF AUTOIMMUNE CHRONIC HEPATITIS
Characteristic Type I (Lupoid) Type II Type III
anti-SM (Antiactin) anti-KLM-I anti-SLA
Age at presentation (y) 10-30 and 40-70 <17 30-40
Other autoimmune disorders 10% 15%-20%
Autoantibodies (%)
Anti-SM 100 40-60* 35%
antinuclear antibody 30-90 1-5
antimitochondrial antibody 10-20 1-5
LE cells 10-50
Gamma globulins (g/L) 30-100 20-30
IgG 20-50 20-30
IgA 3-5 1-3
IgM 1-2 2-5
SM, smooth muscle; KLM, kidney-liver-microsomal; SLA, soluble liver antigens; antinuclear antibody, antinuclear antibody; antimitochondrial antibody, antimitochondrial antibody; LEZ, lupus erythematosus.

The distinction between Autoimmune chronic hepatitis and primary biliary cirrhosis is not always clearcut; histologic, clinical, and immunologic overlaps have been well described. In some young patients, the disease may progress to sclerosing cholangitis.

Viral hepatitis (A, B, C, D, E) should be excluded initially. The frequent finding of false- positive anti-Hepatitis C virus in patients with Autoimmune chronic hepatitis should be confirmed with Hepatitis C virus viral titer determination by the polymerase chain reaction (polymerase chain reaction). The disease runs a slow course in most patients. In some cases, however, a dramatic acute episode may develop, which may result in sudden death.

Diagnostic studies. The serum aspartate aminotransferase (aspartate aminotransferase) is usually more than ten times normal and the serum gamma-globulin concentration is grossly elevated, often in the range of 50 to 100 g/L.

Liver biopsy is recommended in these patients before the initiation of therapy. The histologic features of Autoimmune chronic hepatitis represent the entire spectrum of chronic hepatitis with variable inflammatory activity ranging from mild hepatitis to severe chronic active hepatitis. In some patients, bridging fibrosis may be present and lead to cirrhosis. In contrast to chronic viral hepatitis, there may be broad hypocellular areas of collapse and microacinar transformation of hepatocytes with hydropic swelling. The cellular infiltrate may be predominantly plasma cells, although this is not a consistent feature. The different subgroups of Autoimmune chronic hepatitis are not distinguishable by histologic examination of the liver biopsy specimens by light microscopy.

Treatment

In early studies, patients with Autoimmune chronic hepatitis were diagnosed with histologic features showing chronic active hepatitis, and the disease was noted to be progressive and fatal within 4 to 5 years. In current practice, most patients come to medical attention in the earlier stages of the disease before the development of cirrhosis; thus, the life expectancy is improved. The mortality figures in the placebo groups of the major controlled trials all showed that more than half of the untreated patients died within 3 to 5 years. There is considerable evidence that immunosuppressive therapy that includes corticosteroids leads to a decrease in mortality. The goals of therapy are to diminish hepatic inflammation and fibrosis and prevent the progression of the chronic hepatitis to cirrhosis.

Following assessment of alternative causes of chronic hepatitis and of the extent of liver injury by liver biopsy, a therapeutic trial should be initiated. A response should occur within 3 months or will not occur at all. Soon after initiation of corticosteroid therapy, patients with Autoimmune chronic hepatitis feel better with abatement of fatigue, malaise, anorexia, and fever. Serum aspartate aminotransferase, alanine aminotransferase, and bilirubin levels fall, and there is a reduction in serum gamma globulin levels.

Corticosteroids

There is general agreement that the treatment of Autoimmune chronic hepatitis should begin with a corticosteroid. Prednisone and prednisolone are equally effective. An acceptable regimen is prednisone or prednisolone 30 to 40 mg per day for 2 to 4 weeks. If the patient has a good response, the dose of the corticosteroid is reduced every 2 weeks according to serum alanine aminotransferase and aspartate aminotransferase levels. Once remission is obtained, some patients do remarkably well at low doses (2.5-7.5 mg per day) only to relapse if the drug is discontinued. In most (about 75%) of the patients, lifelong treatment is required. When a patient is in remission, a trial of drug withdrawal may be reasonable. If relapse occurs, however, treatment should be instituted promptly and continued indefinitely.

Azathioprine

azathioprineCorticosteroids have well-established, predictable dose-related side effects including hypertension, cataracts, diabetes mellitus, osteoporosis, and a predisposition to a variety of infections and weight gain. Most of these side effects are manageable if the dose is kept at less than 10 to 15 mg per day. The use of azathioprine 50 to 100 mg per day has been of considerable value in permitting a lower dose of corticosteroids to be used to achieve remission.

It is recommended that azathioprine be started along with the corticosteroid. Although azathioprine alone has not been effective in achieving remission, in some patients its use alone has been sufficient in maintaining remission. Long-term, low-dose azathioprine therapy does not appear to be associated with an increased frequency of lymphoma or other malignancies. Thrombocytopenia is the only significant side effect of azathioprine therapy. Few patients have myelosuppression and pancreatitis; these side effects are rarely seen with doses of 50 to 75 mg per day.

Alternative therapeutic approaches

Cyclosporine has been reported to be effective in treating patients with Autoimmune chronic hepatitis in whom there has been no response to corticosteroids and in whom drug sensitivity prevents the use of azathioprine. Other drugs such as thymic extract, cyanidanol, and D-penicillamine so far have not been effective.

Liver transplantation

Chronic Immune-Mediated Liver DiseasePatients with Autoimmune chronic hepatitis in whom cirrhosis develops are candidates for liver transplantation. It is recommended that patients with Autoimmune chronic hepatitis be considered for liver transplantation at early stages of disease, before severe complications of cirrhosis develop.

Primary Biliary Cirrhosis

Primary sclerosing cholangitis

Definition. Primary sclerosing cholangitis is a chronic, fibrosing inflammation of the biliary ductal system leading to cholestasis, bile duct obliteration, and cirrhosis of the liver.

Large-duct Primary sclerosing cholangitis. Involvement of the larger bile ducts can be identified by cholangiography. In the classic manifestation of the disease, large-duct Primary sclerosing cholangitis may be accompanied by small-duct Primary sclerosing cholangitis.

Small-duct Primary sclerosing cholangitis (pericholangitis). Involvement of microscopically identifiable bile ducts may be the major manifestation of Primary sclerosing cholangitis. Changes in large bile ducts may accompany small-duct Primary sclerosing cholangitis.

In clinical practice, the term primary sclerosing cholangitis still refers to the classic, large- duct disease but does not make clear whether small-duct disease identified by liver biopsy is also present.

Pathogenesis

The etiology of Primary sclerosing cholangitis has remained unclear. Injury from infection of the bile ducts due to portal bacteremia, viremia, toxins, or ischemia from hepatic arterial damage has been proposed but not substantiated. There is a close relation between Primary sclerosing cholangitis and inflammatory bowel disease. Approximately 70% to 95% of all patients with Primary sclerosing cholangitis have coexisting ulcerative colitis or Crohn’s enterocolitis. Primary sclerosing cholangitis is the most common form of chronic liver disease accompanying ulcerative colitis; about 5% to 10% of all patients with ulcerative colitis eventually have Primary sclerosing cholangitis. Immunologic injury may be the most likely cause of the disease.

Genetic factors. A close association has been found between the HLA-B8 phenotype and Primary sclerosing cholangitis in 60% to 80% of patients with or without ulcerative colitis. Also, HLA- DR3 has been found in 70% of patients with Primary sclerosing cholangitis. It appears that a patient with ulcerative colitis who possesses HLA- B8, DR3 haplotype has a 10-fold increase in the relative risk of development of Primary sclerosing cholangitis. Of patients who do not possess HLA-B8, DR3, an association with HLA- DR2 has been found in 70%. HLA-B8, DR3 and HLA-DR2 are equally distributed in patients with Primary sclerosing cholangitis, with or without ulcerative colitis. It appears that HLA- DR3, HLA-DR2, and ulcerative colitis are separate, independent risk factors for the development of Primary sclerosing cholangitis.

Humoral immune abnormalities. As in primary biliary cirrhosis, adult patients with Primary sclerosing cholangitis usually have hypergammaglobulinemia and increased levels of IgM. High levels of IgG are found in all children with Primary sclerosing cholangitis, and 50% of these children also have elevated IgM levels. Smooth muscle antibody (smooth muscle antibody) and antinuclear antibody (antinuclear antibody) may also be present in patients with Primary sclerosing cholangitis. However, there is no correlation between the presence of circulating autoantibodies and any clinical parameter of the disease.

Circulating anticolonic antibodies have been detected in 60% to 65% of patients with Primary sclerosing cholangitis and ulcerative colitis. The same study also demonstrated another circulating antibody, which reacted with a portal tract antigen that is located in the nuclei of tissue neutrophils. This antineutrophil nuclear antibody (ANNA) was found in sera of 84% of patients with Primary sclerosing cholangitis studied. The ANNA titer appears to correlate with disease activity.

Elevated levels of circulating immune complexes also have been found in both sera and bile of patients with Primary sclerosing cholangitis. Whether this finding is primary or an epiphenomenon is not clear. There is also activation of the complement system via the classic pathway, supporting the involvement of humoral immune mechanisms in Primary sclerosing cholangitis.

Cellular immune abnormalities. A significant reduction in the total number of circulating T cells, especially in the suppressor-cytotoxic (T8) cells, has been noted in Primary sclerosing cholangitis, leading to an increased ratio of helper suppressor (T4/ T8) cells. There is also an increase in the number and percentage of B cells.

In the liver, the portal T4/T8 ratio has been found to be higher in the portal tract than around proliferating bile ductules. Cytotoxic (T8) cells tended to localize in areas of bile duct proliferation and infiltrate the ductal epithelium.

Bile duct expression of HLA-DR. Intra- and extrahepatic bile ducts in normal subjects do not express HLA class II (HLA-DR) antigens. It has been shown that most intrahepatic bile ducts in patients with Primary sclerosing cholangitis express HLA-DR antigens on the surface cell membrane of the bile duct epithelial cells. This aberrant expression may play a role in the pathogenesis of bile duct damage in Primary sclerosing cholangitis.

Conclusion. There is strong evidence that genetic and immunologic factors are important in the pathogenesis of Primary sclerosing cholangitis. The immunologic destruction of bile ducts seems to be triggered in genetically predisposed individuals, possibly by viruses, bacteria, or toxins. The association with Inflammatory bowel disease and ulcerative colitis may be explained by the passage of these microorganisms or toxins across the damaged colonic epithelial barrier into the portal circulation.

The prevalence of Primary sclerosing cholangitis in the United States is approximately 5 cases per 100,000 persons. It affects predominantly young males with an age range of 15 to 75+ years. At the time of diagnosis, most patients are younger than 45 years. Primary sclerosing cholangitis has been reported in children 4 to 14 years old.

Associated disorders. Primary sclerosing cholangitis may be associated with a variety of autoimmune disorders. These include SjГ¶gren’s syndrome, retroperitoneal and mediastinal fibrosis, thyroiditis, myasthenia gravis, and type I diabetes mellitus.

Cholangiocarcinoma. Clinical experience and pathologic evidence strongly support an association between Primary sclerosing cholangitis and cholangiocarcinoma. Cholangiocarcinoma arises in 5% to 10% of patients with preexisting Primary sclerosing cholangitis and can present in a synchronous fashion with Primary sclerosing cholangitis. The most frequent location is the bifurcation of the common right and left hepatic ducts (Klatskin’s tumor); however, it can be multifocal. It is usually heralded by rapid clinical deterioration with progressive jaundice, weight loss, and abdominal discomfort. Regardless of therapy, including transplantation, the prognosis for patients with cholangiocarcinoma complicating Primary sclerosing cholangitis has been poor. Active smoking and alcohol abuse may increase the risk of developing cholangiocarcinoma in patients with Primary sclerosing cholangitis. Primary sclerosing cholangitis may also be an independent risk for colorectal carcinoma.

Diagnosis. The diagnosis of Primary sclerosing cholangitis is based on clinical,biochemical, radiologic, and histologic criteria. The disease is suspected in patients with a cholestatic biochemical profile for longer than 3 to 6 months.

Clinical presentation

History. Most patients are initially asymptomatic but have a chronic indolent form of the disease, which may remain quiescent for many years. When fatigue, pruritus, and jaundice develop, patients typically have advanced disease. Weight loss, abdominal pain, and sometimes complications of cirrhosis or portal hypertension such as variceal bleeding, ascites, or encephalopathy may be the presenting findings.

Approximately 15% of patients with Primary sclerosing cholangitis present with an acute relapsing type of disease with fever, chills, night sweats, recurrent upper quadrant pain, and intermittent episodes of jaundice. This «cholangitic» group of patients may have self-limited, recurrent episodes of bacterial cholangitis caused by biliary sludge, which may intermittently obstruct strictured bile ducts.

The distinction between these two presentations of Primary sclerosing cholangitis may merge with progression of disease. In both types intrahepatic bile duct obstruction may develop with sludge or pigment stones and recurrent symptoms of bacterial cholangitis.

Physical examination. Many patients, especially asymptomatic ones have a normal physical examination. However, with advanced disease, patients may have jaundice and hepatosplenomegaly, xanthomas, signs of portal hypertension, and stigmata of chronic liver disease.

The differential diagnosis should include extrahepatic bile duct obstruction; drug-induced cholestasis; primary biliary cirrhosis; chronic active hepatitis, autoimmune hepatitis, and alcoholic hepatitis with a cholestatic profile; cholangiocarcinoma and secondary sclerosing cholangitis arising in patients with choledocholithiasis; and congenital or postsurgical abnormalities of the biliary tract such as Caroli’s disease, choledochal cyst, or strictures. In immunodeficient patients, infections with human immunodeficiency virus, cytomegalovirus, and Cryptosporidium should be considered. Vascular damage to the hepatic arterial tree by cytotoxic drugs, chemotherapy, and graft-versus-host disease after liver transplantation may mimic Primary sclerosing cholangitis.

Diagnostic studies

Laboratory tests. All patients with Primary sclerosing cholangitis have an elevated serum alkaline phosphatase level (> 2 times normal). Serum transaminases are also usually elevated (2-5 times normal). Serum bilirubin level is variable. Serum albumin and prothrombin time are dependent on the severity of the liver dysfunction. CA-19-9 levels more than 100 u/ml may raise the suspicion for the presence of cholangiocarcinoma.

Hepatic copper concentration is elevated in most of these patients due to cholestasis; however, serum ceruloplasmin levels are also elevated. Serum gamma globulin and IgM levels are elevated in half of the patients with Primary sclerosing cholangitis.

Radiologic visualization of the biliary tree is necessary for the diagnosis of Primary sclerosing cholangitis. Endoscopic retrograde cholangiopancreatography (endoscopic retrograde cholangiopancreatography) is the preferred technique over percutaneous endoscopic cholangiography (percutaneous transhepatic cholangiography) since the intrahepatic ducts are not dilated. Cholangiography typically shows the presence of multifocal stricturing and irregularity of intra- or extrahepatic biliary ducts, or both, giving a «beaded» appearance. There are bandlike short strictures and diverticulumlike outpouchings in the biliary tree in one fifth of patients. Up to 20% of patients have an abnormal pancreatic duct resembling that seen in chronic pancreatitis. The cystic duct and the gallbladder are usually spared but are involved in 5% of the patients. Endoscopic retrograde cholangiopancreatography in addition to defining the extent of ductal disease allows for brushings to be obtained for cytologic examination to rule out malignancy. It also allows therapeutic dilatation and stenting of the abnormal bile ducts when indicated.

Magnetic resonance cholangiography and positron emission tomography are noninvasive radiologic techniques which may be used in the diagnosis of Primary sclerosing cholangitis. However, not enough experience has accumulated with these techniques at the present time. Further experience and advances in Magnetic resonance cholangiography and positron emission tomography may allow these modalities to be useful adjuncts in discriminating benign from malignant disease.

Ultrasound. In many patients, an initial ultrasound of the biliary tree may help to rule out choledocholithiasis and ductal dilatation as well as pancreatic pathology.

A liver biopsy is recommended for diagnosis and staging of Primary sclerosing cholangitis. As in Primary biliary cirrhosis, four arbitrary stages have been assigned to describe the severity of Primary sclerosing cholangitis. In the initial stages, the abnormal findings of fibrosis and obliterative cholangitis are confined to the portal tracts. Later, scar formation, ductal obliteration, and parenchymal liver involvement with fibrous piecemeal necrosis and septum formation are seen, leading eventually to cirrhosis.

Complications

Progressive cholestasis may eventually lead to fat malabsorption, steatorrhea, and fat- soluble vitamin (A, D, E, K) deficiencies. Hepatic osteodystrophy, visual abnormalities, and coagulation defects may occur but are uncommon in these patients.

When cirrhosis and portal hypertension develop, patients may present with ascites, hemorrhage from esophageal varices, or encephalopathy.

The prevalence of cholelithiasis, choledocholithiasis, and cholangiocarcinoma is increased in patients with Primary sclerosing cholangitis. Ascending cholangitis may complicate each of these disease entities. Cholangitis may also occur in patients with Primary sclerosing cholangitis without biliary stones. However, it is much more common and recurrent in patients with previous biliary surgery.

Intra- or extrahepatic cholangiocarcinoma in patients with preestablished Primary sclerosing cholangitis is usually multicentric and may be found as carcinoma in situ in areas of fibrous cholangitis. Thus Primary sclerosing cholangitis seems to be a premalignant lesion of the bile ducts.

Treatment

Medical therapy. The medical management of patients with Primary sclerosing cholangitis may be divided into two categories:

Management of complications of chronic cholestasis and bile duct obstruction, such as malabsorption, itching, and recurrent cholangitis.

Malabsorption. Fat-soluble vitamin deficiency should be established with measurement of serum levels of vitamin A and 25-OH vitamin D, and prothrombin time. Vitamin A replacement therapy consists of 15,000 units per day. Vitamin D replacement may be done using doses similar to those used in Primary biliary cirrhosis. The value of calcium supplementation in Primary sclerosing cholangitis is unknown. Steatorrhea may be diminished with the use of medium-chain triglycerides instead of long-chain triglycerides, as recommended for Primary biliary cirrhosis.

Pruritus. Itching appears to present later in the course of Primary sclerosing cholangitis than in Primary biliary cirrhosis. It is worse at night and may result in insomnia and excoriation. The mainstay of therapy is cholestyramine as long as there is adequate bile flow into the intestine. The dose is 4 to 8 g before breakfast and 4 to 8 g after breakfast. If stools are acholic, there is insufficient bile flow for cholestyramine to work. It usually takes 2 to 4 days for the itching to diminish. Once the itching has resolved, the dose may be adjusted downward. However, if itching does not diminish after 2 to 4 days, the dosage may be increased to 8 g three times daily. Additional increases in dosage have not been shown to be effective.

In patients who cannot tolerate cholestyramine, colestipol hydrochloride may be substituted. If constipation occurs with either drug, laxatives and fiber supplements may be added. Activated charcoal capsules also have been used for pruritus. Phenobarbital 60 to 90 mg at bedtime may increase bile flow and act as a sedative. Ultraviolet B light and large-volume plasmapheresis may be helpful in intractable cases. The use of ursodeoxycholic acid is discussed in the next section. Intractable pruritus suggests intensive bile duct scarring and obstruction and is an indication for liver transplantation.

Recurrent cholangitis. Antibiotics may be used to treat episodes of ascending cholangitis. Prophylactic antibiotics such as daily doses of ciprofloxacin hydrochloride, amoxicillin, or double-strength trimethoprim/ sulfamethoxazole may decrease the frequency and severity of such episodes.

Treatment of the underlying disease process. A variety of immunosuppressive, antifibrotic, and antiinflammatory drugs have been tried in the treatment of Primary sclerosing cholangitis. The slow progression of Primary sclerosing cholangitis and spontaneous fluctuation in bilirubin levels make it difficult to evaluate treatment. However, no drug has been shown to improve its natural history.

Cyclosporin, azathioprine, penicillamine, colchicine, and prednisone have been studied and found ineffective.

Ursodeoxycholic acid  at 20 mg/kg of body weight per day has given promising results in the long-term treatment of Primary sclerosing cholangitis in several studies. Ursodeoxycholic acid  is postulated to decrease serum aminotransferase by stabilizing hepatocyte membranes rather than by decreasing levels of other bile acids. It also alkalinizes bile and increases the bile flow. Theoretically, the result should be a decrease in the formation of pigment stones in the biliary tract.

Methotrexate. In a small number of patients with Primary sclerosing cholangitis, methotrexate 15mg/kg of body weight per week has resulted in dramatic improvement in symptoms and biochemistry. In several patients, cholangiographic improvement also has been noted with no worsening of liver histologic findings. However, it is not certain that methotrexate is effective in most patients with Primary sclerosing cholangitis.

Tacrolimus decreased the serum bilirubin by 75%, alkaline phosphatase by 70%, and aminotransferase by 83% after 1 year when given to ten patients with Primary sclerosing cholangitis. The dose of tacrolimus was that which kept trough levels between 0.6 and 1.0 mg/mL. There are no data on liver biopsy or endoscopic retrograde cholangiopancreatography findings.

Combination therapy with prednisole, 1mg/kg of body weight per day, azathioprine 1 to 1.5mg/kg of body weight per day, and ursodiol 500 to 750 mg per day in 15 patients has shown promising results with significant improvement in liver enzyme levels and liver histology. Studies using tumor necrosis factor (tumor necrosis factor) inhibitor (etanercept) are under way.

Summary. Because damaged or destroyed bile ducts either lack the capacity to regenerate or do so slowly and ineffectively, diseases such as Primary biliary cirrhosis and Primary sclerosing cholangitis should be treated at early stages before the loss of much of the biliary system and while there are still adequate numbers of functioning bile ducts.

Surgical therapy

Biliary drainage procedures, either percutaneously, endoscopically, or surgically performed, provide only temporary benefit and are riddled with complications such as infection, obstruction, perforation, leakage, and hemorrhage.

Balloon dilatation and stenting. In patients with one or two dominant strictures of the extrahepatic bile ducts or at their bifurcation, balloon dilatation, either by percutaneous or endoscopic approach, and stenting offers a less invasive alternative to surgery; however, a surgical backup is necessary in such cases.

Liver transplantation offers an important, successful therapeutic option, especially in young patients with advanced Primary sclerosing cholangitis in whom any of the following indications exist: (a) clinically significant gastroesophageal varices, (b) persistent bilirubin level greater than 10 mg/dL, (c) spontaneous bacterial peritonitis, (d) repeated bouts of cholangitis, (e) loss of synthetic liver function, and (f) refractory pruritus. Colectomy does not ameliorate Primary sclerosing cholangitis in patients who also have ulcerative colitis.

One-year survival rates after liver transplantation are in the range of approximately 85% to 90%. Previously undiagnosed cholangiocarcinoma has been noted in some of the patients who have undergone transplantation, with a very high incidence of recurrence in the transplanted livers. Increased risk of development of colonic malignancy with long-term immunosuppression in patients with chronic ulcerative colitis who have had a transplant is highly suspected and warrants periodic colonoscopic surveillance. In 20% of patient, Primary sclerosing cholangitis recurs in the new liver.

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