hepatita autoimuna background
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HEPATITA AUTOIMUNA Background
Autoimmune hepatitis is a chronic disease of unknown cause, characterized by continuinghepatocellular inflammation and necrosis and tending to progress to cirrhosis. Immune serum
markers frequently are present, autoantibodies against liver-specific and nonliver-specific
antigens and increased immunoglobulin G (IgG) levels. The disease often is associated withother autoimmune diseases. Autoimmune hepatitis cannot be explained on the basis of chronic
viral infection, alcohol consumption, or exposure to hepatotoxic medications or chemicals.
Clinicians must consider the diagnosis of autoimmune hepatitis in any patient who has acute
hepatitis or acute liver failure (defined by the new onset of coagulopathy). The workup of suchpatients should include testing for serum autoantibodies, serum protein electrophoresis, and
quantitative immunoglobulins. Urgent liver biopsy, transjugular if appropriate, may help to
confirm the clinical suspicion of acute autoimmune hepatitis. (See Workup.)
Rapid institution of treatment with high-dose corticosteroids may rescue patients whose
autoimmune hepatitis ultimately would have progressed to either fulminant hepatic failure orcirrhosis (see Treatment). Other patients continue to deteriorate in spite of immunosuppressant
therapy. Accordingly, a low threshold should exist for transferring patients with acute liver
failure to tertiary care hospitals that are capable of performing emergent liver transplantation.
For patient education information, see theHepatitis CenterandLiver, Gallbladder, and Pancreas
Center, as well asHepatitis A,Hepatitis B,Hepatitis C, andCirrhosis.
Historical background
In 1950, Waldenstrom first described a form of chronic hepatitis in young women.[1] This
condition was characterized by cirrhosis, plasma cell infiltration of the liver, and marked
hypergammaglobulinemia. Kunkel, in 1950, and Bearn, in 1956, described other features of thedisease, including hepatosplenomegaly, jaundice, acne, hirsutism, cushingoid facies, pigmented
abdominal striae, obesity, arthritis, and amenorrhea.[2, 3]
In 1955, Joske first reported the association of the lupus erythematosus (LE) cell phenomenon in
active chronic viral hepatitis.[4] This association led to the introduction of the term lupoid
hepatitis by Mackay and associates in 1956.[5] Researchers currently know that no direct linkexists between systemic lupus erythematosus (SLE) syndrome and autoimmune hepatitis; thus,
lupoid hepatitis is not associated with SLE.
The development of viral serologic tests represented another important step forward. These
permitted hepatologists to differentiate chronicviral hepatitisfrom other types of chronic liverdisease, including autoimmune hepatitis.
Autoimmune hepatitis now is recognized as a multisystem disorder that can occur in males andfemales of all ages. This condition can coexist with other liver diseases (eg, chronic viral
hepatitis) and also may be triggered by certain viral infections (eg,hepatitis A) and chemicals
(eg, minocycline).
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(ie, cytochrome P-450, uridine diphosphate glucuronosyltransferase proteins) are targets of virus-
induced and drug-induced autoimmunity, as well as autoimmune hepatitis.
Pathogenesis
Current evidence suggests that liver injury in a patient with autoimmune hepatitis is the result ofa cell-mediated immunologic attack. Aberrant display of human leukocyte antigen (HLA) class
II on the surface of hepatocytes facilitates the exposure of normal liver cell membraneconstituents to antigen-presenting cells (APCs).
APCs present hepatic antigens to uncommitted helper T lymphocytes (TH 0). APCs and helper Tlymphocytes interact at the ligand-ligand level, which, in turn, activates TH 0. This activation is
followed by functional differentiation into helper T cell 1 (TH 1) or helper T cell 2 (TH 2),
according to the cytokines prevailing in the tissue and the nature of the antigen. T H 1 primarily
secretes interleukin 2 (IL-2) and interferon gamma, which activate macrophages and enhanceexpression of HLA classes I and II, thus perpetuating the immune recognition cycle.
TH 2 cells primarily produce interleukins 4, 5, and 10, which stimulate autoantibody productionby B lymphocytes.[9]
The reasons for the aberrant HLA display are unclear. It may be initiated or triggered by genetic
factors, viral infections (eg, acute hepatitis A or B, Epstein-Barr virus infection),[10] and chemicalagents (eg, interferon, melatonin, alpha methyldopa, oxyphenisatin, nitrofurantoin, tienilic acid).
The asialoglycoprotein receptor and the cytochrome mono-oxygenase P-450 IID6 are proposed
as the triggering autoantigens.
Physiologically, TH 1 and TH 2 cells antagonize each other. Regulatory mechanisms strictlycontrol the autoantigen recognition process; their failure perpetuates an autoimmune attack.
Liver cell injury can be caused by the action of cytotoxic lymphocytes that are stimulated by IL-2, complement activation, engagement of natural killer lymphocytes by the autoantibody bound
to the hepatocyte surface, or reaction of autoantibodies with liver-specific antigens expressed onhepatocyte surfaces.
Autoantibody-coated hepatocytes from patients with autoimmune hepatitis are killed when
incubated with autologous allogenic lymphocytes. The effector cell was shown to be an Fc
receptor-positive mononuclear cell. Wen and others have shown that T-cell clones from liver
biopsy specimens in children with autoimmune hepatitis who express the / T-cell receptor are
preferentially cytotoxic to liver-derived cells.[11]
Evidence for an autoimmune pathogenesis includes the following:
Hepatic histopathologic lesions composed predominantly of cytotoxic T cells and plasmacells
Circulating autoantibodies (ie, nuclear, smooth muscle, thyroid, liver-kidney microsomal,soluble liver antigen, hepatic lectin)
Association with hypergammaglobulinemia and the presence of a rheumatoid factor Association with other autoimmune diseases Response to steroid and/or immunosuppressive therapy
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The autoantibodies described in these patients include the following:
Antinuclear antibody (ANA), primarily in a homogeneous pattern Antismooth muscle antibody (ASMA) directed at actin Antiliver-kidney microsomal antibody (antiLKM-1)
Antibodies against soluble liver antigen (anti-SLA) directed at cytokeratins types 8 and18
Antibodies to liver-specific asialoglycoprotein receptor or hepatic lectin Antimitochondrial antibody (AMA) - AMA is the sine qua non ofprimary biliary
cirrhosis(PBC) but may be observed in the so-called overlap syndrome with autoimmune
hepatitis.
Antiphospholipid antibodies[12]
Classification
Based on autoantibody markers, autoimmune hepatitis is recognized as a heterogeneous disorder
and has been subclassified into 3 types. The distinguishing features of these types are notedbelow in Table 1.
Table 1. Clinical Characteristics of Autoimmune Hepatitis[13] (Open Table in a new window)
Clinical Features Type 1 Type 2 Type 3
Diagnostic autoantibodies ASMA
ANA
Antiactin
Anti-LKM
P-450 IID6
Synthetic core motif peptides
254-271
Soluble liver-kidney
antigen
Cytokeratins 8 and 18
Age 10 y-elderly Pediatric (2-14 y)
Rare in adults
Adults (30-50 y)
Women (%) 78 89 90
Concurrent immune
disease (%)
41 34 58
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Gamma globulin elevation +++ + ++
Low IgA* No Occasional No
HLA association B8, DR3,
DR4
B14, Dr3, C4AQO Uncertain
Steroid response +++ ++ +++
Progression to cirrhosis
(%)
45 82 75
*Immunoglobulin A
Etiology
The etiology of autoimmune hepatitis is unknown. Several factors (eg, viral infection, drugs,environmental agents) may trigger an autoimmune response and autoimmune disease.
In a few patients with autoimmune hepatitis, illness onset follows acute hepatitis A, hepatitis B,
or Epstein-Barr virus infections. Autoantibodies are common in patients with chronic hepatitis Cvirus (HCV) infection. Some patients with chronic HCV infection exhibit liver-kidneymicrosomal type 1 (LKM-1) antibody.
Some cases of drug-induced liver disease have an immune-mediated basis. A number of drugs(eg, methyldopa, nitrofurantoin, minocycline,[14] adalimumab,[15] infliximab,[16] ) can produce an
illness with the clinical features of autoimmune hepatitis. Although most cases improve when the
drug is stopped, chronic cases of autoimmune hepatitis may be seen, even after drugwithdrawal.[17]
Casswall et al found Helicobacter species DNA in 50% of liver biopsies from patients with
autoimmune hepatitis and ulcerative colitis.
[18]
Epidemiology
United States statistics
Epidemiologic data are limited. Among white adults, the prevalence is estimated to be 0.1-1.2
cases per 100,000 individuals. The frequency of autoimmune hepatitis among patients with
chronic liver disease ranges from 11-23%. The disease accounts for about 6% of liver
transplantations in the United States. Autoimmune hepatitis type 2 (AIH-2) and AIH-3 areobserved infrequently in the United States, although AIH-2 is well characterized in Europe.
International statistics
The prevalence of autoimmune hepatitis is estimated to be 0.1-1.2 cases per 100,000 individuals
in Western Europe. The reported prevalence of autoimmune hepatitis in Europe ranges from
11.6-16.9 cases per 100,000 persons. The reported prevelance is higher than the estimatedprevalance. This is approximately the same prevalence as primary biliary cirrhosis and twice as
high as the prevalence of primary sclerosing cholangitis. Autoimmune hepatitis accounts for
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Greene and Whitington found that treatment fails in about 10% of patients, then requiring
alternative therapy and/or liver transplantation as liver disease progresses. Less than 10% ofpatients with autoimmune hepatitis die during 10 years of follow-up.[29]
In children with autoimmune hepatitis, 70% require treatment until adulthood. Many patients
already have cirrhosis at the time of diagnosis. Almost 20-25% of children with autoimmune
hepatitis die or require liver transplantation as a result of the disease. Guidelines published in2011 by the British Society of Gastroenterology (BSG) state that young patients with
autoimmune hepatitis should receive immunosuppressive treatment to prevent or delay cirrhosis,
even if they do not meet other treatment criteria.[30]
HLA status affects treatment outcome. As an example, HLA DR3-positive patients are more
likely to have active disease and are less responsive to therapy than patients with other HLA
types. These patients also are more likely to require liver transplantation at some point.
Spontaneous resolution of disease is observed in 13-20% of patients, regardless of the
inflammatory activity. This is an unpredictable event.
In a series reported by Gregorio et al in 1997, 70% of children with AIH-1 and 40% of children
with AIH-2 developed cirrhosis.[31] Of the 52 children, 17% had multiacinar or panacinar collapse
with acute liver failure. The patients with the worst prognosis in this study, resulting either indeath or liver transplantation, were those who were young at presentation and who had AIH-2,
coagulopathy, high bilirubin counts, and severe initial histologic activity.
Hepatocellular carcinoma (HCC) is less common in patients with autoimmune hepatitisinduced
cirrhosis than in those with cirrhosis caused by other factors. Nevertheless, HCC is not a rareevent in autoimmune hepatitis.
In general, the following factors are associated with a worse prognosis:
Young age at presentation AIH-2 Coagulopathy Severe initial histologic activity
History
Clinical features of autoimmune hepatitis widely vary. Most cases have an insidious onset.Patients may be asymptomatic or have nonspecific symptoms (eg, fatigue, anorexia, weight loss,
behavioral changes, amenorrhea). Systemic or cutaneous abnormalities occur in 25% of patients.
Epistaxis, bleeding gums, and bruises with minimal trauma are frequent complaints.
Autoimmune hepatitis may present as acute hepatitis, chronic hepatitis, or well-established
cirrhosis. Autoimmune hepatitis rarely presents asfulminant hepatic failure.
Approximately one third of patients present with symptoms of acute hepatitis marked by fever,hepatic tenderness, and jaundice. In some patients, the acute illness may appear to resolve
spontaneously; however, patients invariably develop signs and symptoms of chronic liver
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disease. Other patients experience rapid progression of the disease to acute liver failure, as
marked by coagulopathy and jaundice.Ascitesandhepatic encephalopathyalso may ensue.
The chronic hepatitis associated with autoimmune hepatitis may range in severity from asubclinical illness without symptoms and with abnormal results on liver chemistries to a
disabling chronic liver disease. Symptoms and physical examination findings may stem from the
various extrahepatic diseases associated with autoimmune hepatitis. Common symptoms includethe following:
Fatigue Upper abdominal discomfort Mild pruritus Anorexia Myalgia Diarrhea Cushingoid features Arthralgias Skin rashes (including acne) Edema Hirsutism Amenorrhea Chest pain from pleuritis Weight loss and intense pruritus (unusual)
Many patients have histologic evidence of cirrhosis at the onset of symptoms. This is true both
for patients with an initial presentation of acute hepatitis and for patients with chronic hepatitis.
Thus, subclinical disease often precedes the onset of symptoms.
As many as 20% of patients present initially with signs of decompensated cirrhosis. In otherpatients, chronic hepatitis progresses to cirrhosis after years of unsuccessful immunosuppressant
therapy marked by multiple disease relapses. This is said to occur in 20-40% of patients. Patients
with cirrhosis may experience classic symptoms of portal hypertension, namely varicealbleeding, ascites, and hepatic encephalopathy. Patients with complications of cirrhosis should be
referred for consideration of liver transplantation.
Associated disease
Autoimmune hepatitis, especially type 2, is associated with a wide variety of other disorders.
Involvement of other systems may present at disease onset or may develop during the course of
active liver disease. Most of these conditions are immunologic in origin.
Patients may present with manifestations of the following hematologic disorders:
Hypersplenism Autoimmune hemolytic anemia Coombs-positive hemolytic anemia Pernicious anemia
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Idiopathic thrombocytopenic purpura Eosinophilia
Gastrointestinal disease associated with autoimmune hepatitis includes inflammatory bowel
disease, which is seen in 6% of cases. The presence ofulcerative colitisin patients with
autoimmune hepatitis should prompt performance of cholangiography to excludeprimarysclerosing cholangitis(PSC). A study of 140 pediatric patients with autoimmune hepatitis,
autoimmune cholangitis, and overlap syndrome identified 23 patients withceliac disease.[32]
Associated endocrinologic conditions include Graves disease (6%) and autoimmune thyroiditis(12%). Associated rheumatologic complications include the following:
Rheumatoid arthritis and Felty syndrome Sjgren syndrome Systemic sclerosis Mixed connective-tissue disease Erythema nodosum Leukocytoclastic vasculitis (patients may present with leg ulcers)
Other associated conditions are as follows:
Proliferative glomerulonephritis Fibrosing alveolitis Pericarditis and myocarditis Febrile panniculitis Lichen planus Uveitis
Pediatric presentation
In 1997, Gregorio et al published a series of 52 cases of autoimmune hepatitis in children (32
children with autoimmune hepatitis type 1 [AIH-1] and 20 children with autoimmune hepatitistype 2 [AIH-2]).[31] The following summary of clinical features of AIH was based on 20 years of
treating these children at King's College Hospital.
Median patient ages were 10 years for AIH-1 and 7.4 years for AIH-2. Other autoimmune
disorders occurred in 20% of patients and 40% of their relatives; these included autoimmune
thyroiditis, celiac disease, inflammatory bowel disease, diabetes mellitus, and other disorders.AIH-2 can be part of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
(APECED), an autosomal recessive genetic disorder in which liver disease is reportedly presentin about 20% of cases.[33]
In 50% of the children, acute presentation mimicked acute viral hepatitis (ie, abdominal
discomfort, vomiting, nausea, jaundice). Fulminant hepatic failure occurred in 11% of thechildren and was more common in patients with AIH-2. Insidious presentation was characterized
by intermittent jaundice or nonspecific symptoms. Routine blood analysis revealed incidental
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findings of abnormal liver enzymes. Patients with autoimmune hepatitis developed cirrhosis and
portal hypertension.
In 2005, Oettinger et al published a series of 142 children with autoimmune hepatitis.[34] Clinicalfindings included the following:
Jaundice (58%) Nonspecific weakness (57%) Anorexia (47%) Abdominal pain (38%) Paleness (26%)
AIH-1 was found in 73% of the children, AIH-2 was found in 25% of the children, and 4children could not be classified. Liver biopsy showed active hepatitis (52%), cirrhosis (38%),
and mild inflammatory activity (10%).
Additional autoimmune disorders often occur in children with autoimmune hepatitis. In children
with AIH-1, associated autoimmune disorders include the following:
Ulcerative colitis Sclerosing cholangitis Arthritis Vasculitis Glomerulonephritis Diabetes mellitus
In children with AIH-2, associated autoimmune disorders include the following:
Polyendocrinopathy Alopecia areata Diabetes mellitus Thyroiditis
Acute liver failure occurs primarily between the ages of 13 months and 4 years in children with
AIH-2. It typically occurs after puberty in patients with AIH-1.
Physical Examination
Common findings on physical examination are as follows:
Hepatomegaly (83%) Jaundice (69%) Splenomegaly (32%) Spider angiomata (58%) Ascites (20%) Encephalopathy (14%)
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All of these findings may be observed in patients with disease that has progressed to the point of
cirrhosis with ensuing portal hypertension. However, hepatomegaly, jaundice, splenomegaly, andspider angiomata also may be observed in patients who do not have cirrhosis.
Complications may include the following:
Cirrhosis and complications of cirrhosis (eg, ascites, coagulopathy, hepatic coma) Portal hypertension Esophageal varices Malnutrition (with poor growth in children)
GI tract bleeding as a complication of portal hypertension is usually rare.
Proceed toDifferential Diagnoses
Diagnostic Considerations
Because autoimmune hepatitis is a potentially treatable condition, a missed diagnosis can haveserious consequences. The diagnosis should be considered in all patients with hepatitis,
especially females. Untreated autoimmune hepatitis can result in death due to liver failure.
Similarly, a wrong diagnosis of autoimmune hepatitis can expose the patient to unnecessary
complications of immunosuppressant therapy, which can be serious and life threatening.
Regardless of the mode of presentation (ie, acute vs chronic), autoimmune hepatitis always
becomes chronic, making it unnecessary to wait 6 months to prove the chronic nature of thedisease.
Differential diagnoses for autoimmune hepatitis should include many causes of chronic liverdisease, including 1 -antitrypsin deficiency,Wilson disease, viral hepatitis, hepatotoxic drugs,
and excessive alcohol consumption.
Autoimmune hepatitis must also be differentiated from autoimmune polyendocrine syndrome
type I (APS-1), autoimmunity in hepatitis C virus (HCV) infection, immune-mediated drug-induced hepatitis, cryptogenic hepatitis, and overlap syndrome.
Autoimmune hepatitis and hepatitis C
HCV has several important associations with autoimmune hepatitis. The prevalence rate of HCV
infection in patients with autoimmune hepatitis is similar to that in the general population. This
implies that HCV is not an important factor in the etiology of autoimmune hepatitis.
However, patients who are seropositive for liver-kidney microsomal type 1 (LKM-1) antibodies
frequently are infected with HCV. These patients have predominant features of chronic viralhepatitis and frequently lack antibodies to cytochrome P-450 IID6. Such patients respond to
treatment with interferon. They should be distinguished from antiLKM-1-positive patients who
have a positive antiP-450 IID6, are seronegative for anti-HCV, and are responsive to steroidtherapy.[35]
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False-positive results on anti-HCV enzyme-linked immunoassay (ELISA) tests are described in
the setting of hypergammaglobulinemia, including that observed in patients with autoimmunehepatitis. In patients with antinuclear antibody (ANA) and/or antismooth muscle antibody
(ASMA) seropositivity and positive anti-HCV serology, a false-positive reaction to HCV should
be excluded by performing a test for HCV RNA using the polymerase chain reaction (PCR).
In general, patients with definite autoimmune hepatitis have median serum titers of ASMA andANA of 1:160 and 1:320, respectively. In contrast, these titers may be in the range of 1:80 or less
in patients with true chronic viral hepatitis.
Although autoimmune hepatitis and chronic HCV have similar histologic features, moderate-to-
severe plasma cell infiltration of the portal tracts is more common in patients with autoimmune
hepatitis. Portal lymphoid aggregates, steatosis, and bile duct damage are more common in
patients with chronic HCV.
Overlap syndromes
Patients with autoimmune hepatitis may present with features that overlap those classically
associated with patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis
(PSC).
About 7% of patients with autoimmune hepatitis have a disease that overlaps with PBC. They
may have detectable antimitochondrial antibody (usually in low titer), histologic findings of bileduct injury and/or destruction, and the presence of hepatic copper. The natural history of the
disease tends to echo type 1 autoimmune hepatitis. Patients with the autoimmune hepatitisPBC
overlap syndrome may improve with steroid therapy.
About 6% of patients with autoimmune hepatitis have a disease that overlaps with PSC. Patients
with the autoimmune hepatitisPSC overlap syndrome frequently have concurrent inflammatory
bowel disease. The liver biopsy findings reveal bile duct injury. Findings from cholangiogramsare abnormal. Such patients usually have mixed hepatocellular and cholestatic liver chemistries
and typically are resistant to steroid therapy. Treatment with ursodiol should be considered. Thenatural history of autoimmune hepatitisPSC is not well studied.
One article assessed 41 consecutive patients with PSC, 34 patients with classical PSC and 7
patients with the autoimmune hepatitis-PSC overlap syndrome. [36] The mean follow-up period
was 14 years. Patients with autoimmune hepatitisPSC tended to present at a younger age andhad more elevated aminotransferases and serum immunoglobulin G (IgG) measurements than
patients with classical PSC. They also appeared to have a better chance for transplant-free
survival.
One case of cholangiocarcinoma, no deaths, and 1 transplant were reported among the 7 patientswith autoimmune hepatitisPSC, as compared to 5 cases of cholangiocarcinoma, 9 deaths, and 6transplants among the 34 patients with classical PSC.
Autoimmune cholangitis is characterized by mixed hepatic and cholestatic liver chemistries,
positive ANA and/or ASMA, negative AMA, antibodies to carbonic anhydrase, and histology
that resembles PBC. Some authors contend that this condition is AMA-negative PBC. Patients
may have an unpredictable response to therapy with steroids or ursodiol.
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AIH-1 - ASMA and ANA AIH-2 - AntiLKM-1 antibody AIH-3 - Antibodies to soluble liver antigen (anti-SLA)
SMAs are present in 90-100% of patients with autoimmune hepatitis type 1 (AIH-1). ANAs are
present in 10% of patients with AIH-1 and in association with SMAs in 40-60% of patients withAIH-1. Titers range from 1:100-500,000. SMAs occur in low titers in healthy children and
patients with viral hepatitis and other diseases that do not affect the liver.
LKM-1 antibodies are present in 40-45% of patients with AIH-2 and are associated with anti-LC1 antibodies in 50% of patients. Anti-LC1 antibodies occur alone in 30% of patients with
AIH-2; these antibodies recognize formiminotransferase cyclodeaminase, a liver-specific 58kD
metabolic enzyme. Anti-asialoglycoprotein receptor antibodies occur more often in patients with
AIH-1 and may serve as a marker of inflammatory activity.
Other autoantibodies may be evident. Atypical perinuclear antineutrophil cytoplasmic antibodies(pANCA) are frequently present. Czaja et al have shown that patients with autoimmune hepatitis
who have positive test results for actin antibody are younger, more commonly test positive forhuman leukocyte antigen (HLA)DR3, and required transplantation more frequently thanpatients with ANAs who test negative for actin antibody.[37]
Serum Proteins and Immunoglobulins
An IgG-predominant polyclonal hypergammaglobulinemia is a common finding in patients with
untreated autoimmune hepatitis. Gamma globulin values typically range from 3-4 g/dL and
frequently are as high as 5-6 g/dL. Cases of hyperviscosity syndrome secondary to high IgGlevels are reported. Autoimmune hepatitis is an unlikely diagnosis in patients who have acute
hepatitis without hypergammaglobulinemia.
The gamma globulin or the IgG level may be followed on a regular basis as a marker of disease
responsiveness to therapy.
Patients with AIH-2 commonly have partial immunoglobulin A (IgA) deficiency.[33]
Aminotransferases
Serum aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase
[ALT]) are elevated in 100% of patients at initial presentation, with average values of 200-300U/L. Aminotransferase values correlate poorly with the degree of hepatic necrosis; however,
values in the thousands may indicate acute hepatitis or a severe flare of preexisting disease.
Continued elevation of the aminotransferases in the face of ongoing therapy is a reliable marker
for ongoing inflammatory activity in the liver. Normalization of the aminotransferase levelsduring therapy is an encouraging sign, but active liver inflammation is present in more than 50%
of patients with normalized liver chemistries. Indeed, biochemical remission may precede true
histologic remission by 3-6 months.
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Typically, patients are treated for at least 1 year after documentation of normal liver chemistries.
Liver biopsy is recommended by some experts to confirm that the patient is in histologicremission. Drug withdrawal may be attempted at this time (see Treatment).
Worsening of aminotransferase levels in a patient undergoing treatment or in a patient who is in
remission may signal a resurgence of disease activity.
Other liver chemistries
Serum bilirubin and alkaline phosphatase values are mildly to moderately increased in 80-90%
of patients. A sharp increase in the alkaline phosphatase values during the course of autoimmunedisease might reflect the development of PSC or the onset of hepatocellular carcinoma as a
complication of cirrhosis.
Hypoalbuminemia and prolongation of prothrombin time are markers of severe hepatic synthetic
dysfunction, which may be observed in active disease or decompensated cirrhosis.
Complete Blood Count and Other Blood Studies
Other hematologic abnormalities may include the following:
Mild leukopenia Normochromic anemia Coombs-positive hemolytic anemia Thrombocytopenia Elevated erythrocyte sedimentation rate
Eosinophilia is uncommon, but counts ranging from 9% to 48% are described. Autoimmunehepatitis has even been described as the sole presenting feature of idiopathic hypereosinophilicsyndrome.
Hepatic Imaging Studies
Imaging studies, in general, are not helpful in reaching a definitive diagnosis of autoimmune
hepatitis; however, the presence of heterogeneous hepatic echotexture on abdominal ultrasoundor abnormal contrast enhancement on abdominal CT imaging may suggest the presence of active
inflammation or necrosis.
The appearance of an irregular nodular liver may confirm the presence of cirrhosis. Furthermore,these imaging studies may be used to rule out the presence of hepatocellular carcinoma, a
potential complication of autoimmune hepatitisinduced cirrhosis.
When alkaline phosphatase levels are 7-8 times reference values or gamma glutamyl transferase
levels are 2-3 times reference values, a patient with autoimmune hepatitis and ulcerative colitismay require endoscopic retrograde cholangiopancreatography (ERCP) to rule out coexisting
primary sclerosing cholangitis (PSC).
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Liver Biopsy
Liver biopsy is the most important diagnostic procedure in patients with autoimmune hepatitis.This procedure can be performed percutaneously, with or without ultrasound guidance, or by the
transjugular route. The latter is preferred if the patient has coagulopathy or severe
thrombocytopenia. A transjugular liver biopsy also may be preferable if ascites is present or ifthe liver is small, shrunken, and difficult to reach percutaneously.
Liver biopsy routinely is performed in the outpatient setting to investigate abnormal liver
chemistries. Liver biopsy should be performed as early as possible in patients with acute
hepatitis who are thought to have autoimmune hepatitis. Confirmation of the diagnosis enablesinitiation of treatment at an early stage in the disease process.
The role of biopsy in patients presenting with well-established cirrhosis secondary toautoimmune hepatitis is less clear. As an example, the initiation of treatment in a patient with
cirrhosis, normal aminotransferase levels, and a minimally elevated gamma globulin level is not
expected to influence the disease outcome.
Histologic Findings
Histopathologic findings on liver biopsy specimens are crucial to determining the diagnosis ofautoimmune hepatitis and the disease's severity. Liver biopsy findings can help to differentiate
autoimmune hepatitis from chronic hepatitis C virus (HCV) infection, alcohol-induced hepatitis,
drug-induced liver disease, primary biliary cirrhosis, and PSC.[38]
Autoimmune hepatitis is characterized by a portal mononuclear cell infiltrate that invades thelimiting plate surrounding the portal triad and permeates the surrounding lobule (ie, periportal
infiltrate) and beyond. A plasma cell infiltrate sometimes occurs, which, in the past, led to use ofthe term plasma cell hepatitis.
Biopsies may show evidence for interface hepatitis (ie, piecemeal necrosis), bridging necrosis,and fibrosis. Interface hepatitis essentially spares the biliary tree but may involve most of the
lobule. Lobular collapse, best identified by reticulin staining, is a common finding.
Interface hepatitis does not predict a progressive disease course. By contrast, a strong likelihood
exists that cirrhosis will develop when bridging necrosis is present. The presence or absence of
cirrhosis on liver biopsy is an important determinant of the patient's prognosis.
Fibrosis is present in most patients with autoimmune hepatitis. Without effective therapy,
fibrosis starts to connect the portal and central areas, which ultimately leads to cirrhosis.
In 1999, the International Autoimmune Hepatitis Group established a scoring system that isparticularly helpful in establishing the diagnosis of autoimmune hepatitis in problematic cases.[39,40]
Histopathologic findings in patients with autoimmune hepatitis are characteristic but nonspecific;
autoimmune hepatitis has findings in common with chronic viral hepatitis, drug-associated
chronic hepatitis, and several other chronic liver disorders. Multinucleated giant hepatocytes are
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found in 10-20% of biopsy specimens; their occurrence after the neonatal period may suggest a
diagnosis of autoimmune hepatitis.
Proceed toTreatment & Management
Approach ConsiderationsFor more than 3 decades, corticosteroids, either alone or in combination with azathioprine, have
been the mainstays of drug therapy for patients with autoimmune hepatitis.[41] Considerable
variation in practice style exists when answering the following common clinical questions:
How high a dose of prednisone should be used when initiating therapy? When should azathioprine be added to the patient's treatment regimen? When should a reduction in steroid dosing be considered? How long should treatment continue beyond biochemical remission? Should liver biopsy be performed in order to document histologic remission, prior to
attempting withdrawal of immunosuppression? Should patients receive life-long low-dose maintenance therapy with azathioprine?
Azathioprine is metabolized to 6-mercaptopurine. One of the enzymes responsible for this isthiopurine methyltransferase (TPMT). About 0.3% of the population possesses mutations of the
genes coding for TPMT. These individuals, with low or no TPMT activity, may develop excess
levels of the metabolite 6-thioguanine. High 6-thioguanine levels, in turn, may predispose thepatient to bone marrow suppression. Some authors recommend that patients undergo TPMT
genotyping prior to the initiation of azathioprine therapy.[42]
Initial Therapy for Adults
Approximately 65% of patients respond to initial therapy and enter histological remission;
however, 80% of these patients relapse after drug withdrawal. The practice guideline of theAmerican Association for the Study of Liver Diseases (AASLD) provides recommendations for
therapy.[43] See Table 2, below.
Table 2. Indications for Treatment of Autoimmune Hepatitis in Adults (Open Table in a new
window)
Absolute Relative
Serum AST 10-fold or more greater than the upper limit of
normal
Symptoms (eg, fatigue,
arthralgia, jaundice)Serum AST 5-fold or more greater than the upper limit of
normal and gamma-globulin level 2-fold or more greater than
normal
Serum AST and/or gamma-
globulin less than absolute
criteria
Bridging necrosis or multiacinar necrosis on Interface hepatitis
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Pregnancy
Malignancy
Short course (6 mo or less)
Brittle diabetes
Obesity
Acne
Emotional lability
Hypertension
BSG guidelines strongly recommend the combination of prednisolone and azathioprine as initial
therapy, whereas the AASLD notes that combination therapy is preferred to prednisone alone.[43,30]
Patients whose liver chemistries normalize after initial therapy then require maintenance therapy.In the authors' opinions, prednisone dosing can be further reduced after achieving normalization
of liver chemistries. The authors commonly use azathioprine alone as a maintenance drug.
Azathioprine therapy is withdrawn approximately 1 year after the patient's liver chemistries havenormalized.
Initial Therapy for Children
The AASLD guidelines also propose an initial treatment regimen for children (see Table 4,
below).
Table 4. Treatment Regimens for Children (Open Table in a new window)
Initial Regimen Maintenance Regimen End Point
Prednisone, 1-2 mg/kg/d (up to60 mg/d),
for 2 weeks, either alone or in
combination with azathioprine,
a. Prednisone taper over 6-8 weeksto 0.1-0.2 mg/kg daily or 5 mg
daily
b. Azathioprine at constant dose if
a. Normal liver tests for 1-2 years during treatment
b. No flare during entire
interval
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1-2 mg/kg/d added initially
c. Continue daily prednisone dose
with or without azathioprine orswitch to
alternate day prednisone doseadjusted to response with or
without azathioprine
c. Liver biopsyexamination discloses no
inflammation
Prednisolone rather than prednisone may be used, at a dosage of 2 mg/kg/d (not to exceed 60mg/d). The BSG guidelines assume use of prednisolone.[30] Taper over 4-8 weeks, if testing of
transaminase levels demonstrates gradual improvement, then administer the minimum
maintenance dose required to sustain reference levels of liver enzymes.
Frequently check liver enzyme levels during the initial period of treatment (ie, first 6-8 wk).Liver enzyme levels are usually checked weekly to fine-tune the treatment and avoid adverse
effects from the steroids.
Liver enzymes levels may require several months to return to reference range values. In patients
with autoimmune hepatitis type 1 (AIH-1), transaminase levels took a median of 0.5 years(range, 0.2-7 y) to return to reference values; in patients with autoimmune hepatitis type 2 (AIH-
2), transaminase levels took a median of 0.8 years (range, 0.02-3.2 y) to return to referencevalues.
If liver enzyme levels do not return to reference values during the first 4-8 weeks of treatment or
if improvement requires high doses of steroids, initiate azathioprine administration at 0.5mg/kg/d and gradually increase to 2 mg/kg/d until transaminase levels return to reference values.
Some authors recommend starting azathioprine with prednisone at disease onset.
Alternative Agents
Budesonide may offer an alternative to prednisone. In a prospective, double-blind randomized
trial by Manns et al, 60% of budesonide-treated patients had normalized liver chemistries 6months after initiating treatment, compared with 39% of prednisone-treated patients.[44]
Furthermore, steroid-specific side effects were seen in only 28% of the budesonide-treated
patients but in 53% of the prednisone-treated patients.
Budesonide was given in a dosage of 3 mg three times daily or twice daily to prednisone. Theinitial prednisone dose was 40 mg daily, tapered to 10 mg daily. Patients also received
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azathioprine 1-2 mg/kg/d.[44] Longer-term follow-up is needed to better assess the efficacy and
safety of budesonide.
Based on moderate-quality evidence, the 2011 BSG guidelines strongly recommend use ofbudesonide for prednisolone-intolerant patients.[30]
Cyclosporine has been used successfully to avoid high steroid doses in both adult and pediatricpatients. In a study in children by Alvarez et al, cyclosporine induced biochemical remission of
the hepatic inflammatory process in children with autoimmune hepatitis while causing few and
well-tolerated adverse effects.[45] In this study, cyclosporine was administered for 6 months alone,followed by combined low doses of prednisone and azathioprine for 1 month, then cyclosporine
was discontinued.
A study in children and adolescents by Sciveres et al found that cyclosporine may be considered
as a safe treatment for all autoimmune liver diseases and as an effective alternative for front-linetherapy.[46] This study included patients with autoimmune hepatitis, autoimmune cholangitis, and
giant cell hepatitis.
Treatment Endpoints
Patients may achieve 1 of 4 treatment endpoints [43] :
Remission Treatment failure Incomplete response Drug toxicity
Remission
Remission is indicated by the absence of symptoms, normalization of aminotransferases, and
histologic improvement to normal or minimal inflammatory activity on liver biopsy. Patients
achieving remission may be able to taper off prednisone over a 6-week period. Azathioprine canbe discontinued after the withdrawal of prednisone.
Patients in acute liver failure whose liver chemistries improve rapidly after starting prednisone
have an excellent short-term prognosis. Many such patients ultimately achieve clinical remission
on immunosuppressant therapy.
There are no firm guidelines regarding the duration of therapy in either adults or children.
However, most patients need relatively long courses of immunosuppressant therapy. It iscommon for treatment to continue for 1.5-2 years or longer before an attempt is made to
withdraw medications. Indeed, adults infrequently achieve clinical, laboratory, and histologic
remission in less than 12 months. Immunosuppressant therapy can achieve remission in 65% ofpatients within 18 months and in 80% of patients by 3 years.
Histologic remission tends to lag behind clinical and laboratory remission by 3-6 months. Many
cliniciansand the currentpractice guidelines of the AASLD[43]recommend that a follow-up
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liver biopsy be performed. This is done in an effort to avoid medication withdrawal in a patient
who is not yet in histologic remission.
Treatment failure
Treatment failure is defined as deterioration in a patient's clinical condition, laboratory tests, orhistologic features during therapy. This is seen in approximately 9% of patients.[43] Some patients
will have a response to reinstitution of treatment with high-dose prednisone, with or withoutcombined azathioprine.
Patients with severe disease (eg, acute liver failure due to autoimmune hepatitis) have a highshort-term mortality rate if they fail to show normalization of at least 1 laboratory parameter
after starting prednisone-based therapy or if pretreatment hyperbilirubinemia fails to improve
during a 2-week treatment trial. Early liver transplantation should be considered in such
individuals.
High-dose prednisone (60 mg/d) alone or prednisone (30 mg/d) plus azathioprine (150 mg/d) are
alternative approaches when standard therapy fails. Patients whose condition is resistant tosteroids can be treated with cyclosporine or tacrolimus. The use of these medications is
supported by a number of small case series.[47, 48, 49] However, the potential toxicity of thesecalcineurin inhibitors must be assessed carefully before initiating treatment.
Similarly, a few studies have supported the use of mycophenolate mofetil in patients whose
disease was refractory to standard therapy.[50, 51, 52, 53] In these studies, a dose of 1 g orally twice per
day was employed initially.
The authors have seen a number of patients who experienced treatment failure with prednisoneplus azathioprine but achieved treatment success with low-dose prednisone plus mycophenolate
mofetil. However, mycophenolate mofetil has not been subjected to a randomized trial inpatients with autoimmune hepatitis.
Aw et al concluded that mycophenolate mofetil is an effective rescue therapy for children with
autoimmune hepatitis, but not for those with autoimmune sclerosing cholangitis (ASC).[54]
Inclusion criteria this study included failure to achieve/maintain remission with
prednisolone/azathioprine or significant treatment side effects. Of the 26 children recruited, 16
had AIH type 1, 2 had AIH type 2, and 8 had ASC. Of the 26 children, 18 responded tomycophenolate mofetil and 8 (6 with ASC) did not respond.
There are no clear guidelines as to how mycophenolate mofetil should be tapered if a therapeutic
response has been achieved. The authors have used doses as low as 500 mg twice per day to
maintain patients in a drug-induced remission.
Budesonide has been has been used with variable success in patients who had treatment
failures.[55, 56] Limited data are available regarding the use of tacrolimus, methotrexate, and otheragents.
Incomplete response
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Incomplete response is defined as an improvement that is insufficient to satisfy remission
criteria. It is estimated to occur in 13% of patients.[43] Many such patients will require indefinitetreatment with as low an immunosuppressant dose as is needed to prevent clinical deterioration.
A prednisone schedule similar to that used after relapse (10 mg/d) is reasonable. The goal of
therapy is to control disease activity on the lowest dose of medication possible. Azathioprine
may help to serve as a steroid-sparing agent.
Patients should be referred for consideration of liver transplantation if they manifest signs of
hepatic decompensation (eg, new onset of hypoalbuminemia, coagulopathy, variceal bleeding,ascites, hepatic encephalopathy).
Drug toxicity
Drug toxicity may occur. Patients must be tapered off from the culprit medication. Some patients
successfully achieve treatment goals on alternative medications.
Cushingoid features, acne, and hirsutism develop in 80% of patients after 2 years of prednisone-based therapy. Osteoporosis with vertebral compression, diabetes, cataracts, severe emotional
lability, and hypertension may develop in patients who are treated with prolonged courses of
high-dose prednisone. Premature treatment withdrawal is justified in patients who develop
intolerable obesity, cosmetic changes, or osteoporosis.
Azathioprine can function as a steroid-sparing agent. The authors have had great success andminimal drug-related adverse effects using a regimen of prednisone 10 mg/d plus azathioprine 50
mg/d.
Patients should be co-treated with calcium and vitamin D in order to prevent the development of
steroid-induced osteoporosis. Regular exercise should be encouraged. Bone densitometry
performed every 1-2 years should be used to monitor patients. Signs of early osteoporosis maywarrant the institution of treatment with alendronate.
Azathioprine therapy can be complicated by cholestatic hepatotoxicity, nausea, vomiting, rash,
cytopenia, and pancreatitis. These complications occur in fewer than 10% of patients treated with
azathioprine at 50 mg/d.
To date, most studies of azathioprine efficacy in autoimmune hepatitis have used a dose of 50mg/d. In contrast, many authors in the field of inflammatory bowel disease (IBD) suggest
individualizing the dose so that patients achieve a 6-thioguanine level of 230-400 pmol/8x108
erythrocytes.[57] This level has been associated with optimal clinical outcomes for patients with
IBD. It remains to be determined whether such an approach should be applied to azathioprinedosing in patients with autoimmune hepatitis.
Cytopenias, particularly leukopenia, may occur at any time after the initiation of azathioprine
therapy. All patients undergoing treatment with azathioprine should undergo routine interval
testing of the complete blood count.
Teratogenicity has been ascribed to treatment with azathioprine; however, the gastroenterologyliterature is replete with references that describe the safe use of azathioprine and 6-
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mercaptopurine in pregnant women with inflammatory bowel disease. Whether this observation
can be extended to pregnant women with autoimmune hepatitis and whether azathioprine can beemployed safely in these patients is unclear.
The 2011 BSG guidelines include a weak recommendation to maintain combination treatment
with as little change as possible during pregnancy, whereas the AASLD guideline suggests
discontinuing azathioprine in pregnant patients. Both guidelines warn of postpartumexacerbation and recommend a prompt return to standard therapy; the BSG recommends this
return immediately after delivery, whereas the AASLD recommends a return 2 weeks prior to the
expected delivery date.[43, 30]
Hematologic malignancy has been reported in patients undergoing treatment with azathioprine;
however, the risk of malignancy is thought to be low in patients with autoimmune hepatitis who
are treated with low doses of the drug.
Relapse
Relapse occurs in 50% of patients within 6 months of treatment withdrawal and in 80% of
patients within 3 years of treatment. Reinstitution of the original treatment regimen usually
induces another remission; however, relapse commonly recurs after a second attempt atterminating therapy. The major consequence of relapse and re-treatment is the development of
drug-related complications, which occurs in 70% of patients.
Patients who relapse twice require indefinite therapy with either prednisone or azathioprine. The
dose is titrated as low as possible in order to prevent symptoms and to maintain an AST level 5-
fold below the reference range. The median dose of prednisone required to achieve this is 7.5mg/d.
Some authors advocate indefinite treatment with azathioprine only. In one study, 60 of 72patients (83%) receiving long-term therapy with azathioprine at a dose of 2 mg/kg/d remained in
remission, with a median follow-up period of 67 months (range, 12-128 mo).[58]
Patients should be cautioned against premature withdrawal of drug therapy. Abruptdiscontinuation of medical therapy is not infrequently complicated by an acute flare of disease
activity. Such flares may be severe and potentially life-threatening.
Liver Transplantation
This procedure is an effective form of therapy for patients in whom medical therapy has failed,
or those with decompensated cirrhosis caused by autoimmune hepatitis. Liver transplantationalso may be used to rescue patients who present with fulminant hepatic failure secondary to
autoimmune hepatitis. A low threshold should exist for transferring patients with acute liver
failure to tertiary care hospitals that are capable of performing emergent liver transplantation.
Approximately 10-20% of patients require liver transplantation.
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The long-term outlook after liver transplantation is excellent, with 10-year survival rates reported
as greater than 70%.[59] Positive autoantibodies and hypergammaglobulinemia tend to disappearwithin 2 years of transplantation.[60]
Recurrence of autoimmune hepatitis is described after liver transplantation. It has been reported
primarily in inadequately immunosuppressed patients. It may occur more often in HLA DR3
positive recipients of livers from HLA-DR3negative donors.
Recurrent disease is seen in 10-35% of patients undergoing transplantation for autoimmune
hepatitis. Although such recurrences are often mild events, one paper described a need forretransplantation in one half of patients experiencing recurrent disease.[59, 61, 62]
Montano-Loza et al concluded that recurrence risk factors include concomitant autoimmune
disease and high levels of aspartate aminotransferase, alanine aminotransferase, and IgG prior to
the transplant.[62] The presence of moderate to severe inflammatory activity or plasma cellinfiltration in the liver explant also was said to increase the recurrence risk. According to the
authors, their findings suggest that incomplete suppression of disease activity before liver
transplantation promotes autoimmune hepatitis recurrence.
Treatment of Overlap Syndrome
Treatment combining ursodiol and immunosuppressants may be advisable in patients with theautoimmune hepatitisprimary biliary cirrhosis (PBC) overlap syndrome. In one study, of
noncirrhotic patients, fibrosis progression was seen in 4 of 8 patients treated with ursodiol
monotherapy, versus 0 of 6 patients treated with combination therapy.[63] The mean duration of
follow-up was 7.5 years.
Diet and ActivityPatients with acute autoimmune hepatitis and symptoms of nausea and vomiting may require
intravenous fluids and even total parenteral nutrition; however, most patients can tolerate a
regular diet. A high caloric intake is desirable.
Patients with cirrhosis secondary to autoimmune hepatitis may develop ascites. A low-salt diet(generally < 2000 mg of sodium daily) is mandatory in these individuals. Patients should
continue to consume protein (ie, >1.3 g protein per kg body weight), given the catabolic nature
of the disease and the high risk for developing muscle wasting.
Most patients do not need hospitalization, although this may be required for clinically severe
illness. Forced and prolonged bed rest is unnecessary, but patients may feel better with restrictedphysical activity.
Long-Term Monitoring
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Perform liver function tests in patients with autoimmune hepatitis (AIH) weekly during the first
6-8 weeks of treatment and then every 2-3 months, based on results. Schedule regular follow-upvisits to assess disease activity and to search for signs and symptoms of chronic liver disease.
Surveillance abdominal imaging studies (eg, ultrasound, CT, MRI) and alpha-fetoprotein testing
are typically performed every 6 months in patients with most types of cirrhosis. The optimal
interval for surveillance and the best type of abdominal imaging study have not yet beendetermined for patients with autoimmune hepatitisinduced cirrhosis. Detection of a small
hepatocellular carcinoma on imaging studies should prompt immediate referral for consideration
of liver transplantation.
Proceed toMedication
Medication Summary
The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Treatment
with corticosteroids and azathioprine is the cornerstone for achieving remission. Initiatingazathioprine with prednisone at the beginning of treatment enables a faster decrease of the
prednisone dose. Cyclosporine has steroid-sparing effects when administered for several months
before corticosteroids and azathioprine.
Corticosteroids
Class Summary
Rapid institution of treatment with high-dose corticosteroids may rescue patients whose disease
ultimately would have progressed to either fulminant hepatic failure or cirrhosis. Treatment with
corticosteroids has been shown to improve the chances for survival significantly.
These agents have anti-inflammatory properties and cause profound and varied metabolic effects.
They modify the body's immune response to diverse stimuli.
View full drug information
Prednisone
Prednisone is an immunosuppressant for treatment of autoimmune disorders. It may decrease
inflammation by reversing increased capillary permeability and suppressing polymorphonuclear
neutrophil (PMN) activity. It stabilizes lysosomal membranes and also suppresses lymphocytesand antibody production.
View full drug information
Prednisolone
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Prednisolone decreases autoimmune reactions, possibly by suppressing key components of
immune system. It may decrease inflammation by reversing increased capillary permeability andsuppressing PMN activity.
Immunosuppressant agents
Class Summary
These agents inhibit immune reactions resulting from diverse stimuli. Initiating azathioprine withprednisone at the beginning of treatment enables a faster decrease of the prednisone dose.
Cyclosporine has steroid-sparing effects when administered for several months before
corticosteroids and azathioprine.
View full drug information
Azathioprine (Imuran, Azasan)
Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins.It may decrease proliferation of immune cells, which results in lower autoimmune activity.
View full drug information
Cyclosporine (Gengraf, Sandimmune, Neoral)
Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater
extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection,
experimental allergic encephalomyelitis, graft versus host disease) for a variety of organs. The
dose is based on ideal body weight.
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