AIH /Lupoid Hepatitis – Causes, Symptoms, Treatment

AIH /Lupoid Hepatitis /Autoimmune hepatitis refers to chronic and progressive inflammation of the liver from an unknown cause that is characterized by a loss of immune tolerance against liver antigens, resulting in progressive destruction of the hepatic parenchyma and histologically by interface hepatitis, serologically by the presence of non-organ specific autoantibodies, biochemically by elevated aminotransferases and serum IgG, and clinically by the response to immunosuppressive treatment in the absence of other known causes of liver disease. The proposed mechanism for the development of autoimmune hepatitis is thought to be the interplay of genetic predisposition, an environmental trigger, and failure of the native immune system resulting in chronic inflammation of hepatocytes and subsequent fibrosis of the liver. Chronic hepatitis occurring predominantly in young women with arthralgias, myalgia, hepatosplenomegaly, amenorrhea, skin rashes, fluctuating course, and invariably fatal outcome Autoimmune hepatitis may present concurrently with other autoimmune diseases like Graves disease, rheumatoid arthritis, celiac disease, type I diabetes, ulcerative colitis, hemolytic anemia, and immune thrombocytopenia.

Synonyms of Autoimmune Hepatitis

  • AIH
  • autoimmune chronic active hepatitis
  • lupoid hepatitis

Types of Autoimmune Hepatitis

There are two known types of autoimmune hepatitis.

  • Type 1¬† – is distinguished by the presence of anti-smooth muscle antibodies (ASMA) with or without anti-nuclear antibodies (ANA). This is the most common type in the United States, accounting for 96% of the AIH cases in North America, has a female to male ratio of 4 to 1, and a great response to corticosteroids. It is characterized by the presence of antinuclear antibody (ANA) and anti-smooth-muscle antibody (ASMA).
  • Type 2 – autoimmune hepatitis presents with positive anti-liver/anti-kidney microsome (anti-LMK) type 1 antibodies or anti-liver cytosol (anti-LC) type 1 antibodies. This type occurs most often in Europe and the patients tend to be younger (usually less than 14 years old), have more severe disease, worse response to corticosteroids, and relapse more often. Type 2 AIH accounts for only 4% of the AIH cases in North America. It is characterized by the presence of anti-liver kidney microsomal antibody type 1 (anti-LKM1) and/or anti-liver cytosol type 1 (anti-LC1) autoantibodies.

Four subtypes of autoimmune hepatitis are recognized, but the clinical utility of distinguishing subtypes is limited.

  • Type 1 AIH – Positive ANA and SMA,[rx]¬†elevated¬†immunoglobulin G¬†(classic form, responds well to low dose steroids);
  • Type 2 AIH – Positive LKM-1¬†(typically female children and teenagers; disease can be severe),¬†LKM-2¬†or¬†LKM-3;
  • Type 3 AIH – Positive antibodies against soluble liver antigen[14]¬†(this group behaves like group 1)[15]¬†(anti-SLA, anti-LP)
  • AIH -with no autoantibodies detected – (~20%)(of debatable validity/importance)

Subclassifications

1.Type 1 autoimmune hepatitis
  • ¬†Characterized by SMA and/or ANA
  • Ancillary markers (i.e., atypical pANCA [frequently present] and anti-SLA [16%])
  • Most common type in the United States and affecting all ages, including infants. Most (78%) patients women (female-to-male ratio, 3.6:1)
  • Concurrent ulcerative colitis cholangiography to exclude PSC
  • Acute onset in 40% and rarely, acute severe (fulminant) presentation. Implicated HLA: DRB1‚ąó0301¬†(northern European),¬†DRB1‚ąó0401 (northern¬† ¬†European), DRB1‚ąó0404¬†(Mexican),¬†DRB1‚ąó0405¬†(Japanese),¬†DRB‚ąó1301¬†(South American),¬†DRB1‚ąó1501 (protective)
  • Implicated polymorphic autoimmune promoters (all North American): TNFA-308‚ąóA,¬†CTLA4‚ąóG,¬†TNFRSF6‚ąóG,¬†MICA‚ąó008
  • Target autoantigen unknown
  • DRB1‚ąó0301¬†(principal susceptibility allele) and¬†DRB1‚ąó0401¬†(secondary but independent susceptibility allele) in white North American and northern European patients
  • Cirrhosis at presentation in 25% indicating subclinical aggressive stage
  • Concurrent extrahepatic immune diseases in 38%, including the following:
‚Ė™Autoimmune thyroiditis (12%)
‚Ė™Graves‚Äô disease (6%)
‚Ė™Ulcerative colitis (6%)
‚Ė™Rheumatoid arthritis (1%)
‚Ė™Pernicious anemia (1%)
‚Ė™Systemic sclerosis (1%)
‚Ė™Coombs-positive hemolytic anemia (1%)
‚Ė™Idiopathic thrombocytopenic purpura (1%)
‚Ė™Leukocytoclastic vasculitis (1%)
‚Ė™Nephritis (1%)
‚Ė™Erythema nodosum (1%)
‚Ė™Fibrosing alveolitis (1%)
2.Type 2 autoimmune hepatitis
  • Characterized by anti-LKM1
  • Ancillary marker (i.e., anti-LC1 [32%]); no atypical pANCA
  • Affects mainly children (age range, 2 to 14 years)
  • Of Europeans with type 2 autoimmune hepatitis, adults comprising 20%
  • Anti-LKM1 in only 4% of North American adult patients
  • Commonly associated with concurrent immune diseases, including vitiligo, insulin-dependent diabetes mellitus, and autoimmune thyroiditis
  • Frequent organ-specific autoantibodies (antibodies to parietal cells, thyroid, or islets of Langerhans)
  • Acute or acute severe (fulminant) presentation possible
  • DQB1‚ąó0201 principal genetic risk factor in strong linkage disequilibrium with¬†DRB1‚ąó07¬†and¬†DRB1‚ąó03
  • Cytochrome monooxygenase, CYP2D6, the target autoantigen
  • Five antigenic sites located within recombinant CYP2D6; amino acid sequence between positions 193 and 212 main epitope of anti-LKM1
  • Homologies between recombinant CYP2D6 and genome of hepatitis C virus,¬†cytomegalovirus, and herpes simplex virus type 1
  • Anti-LKM1 in 10% with chronic hepatitis C in Europe but rare in United States
  • Equally responsive to corticosteroid¬†therapy as type 1 autoimmune hepatitis

Variants

1.Overlap syndrome with PBC
  • Defined by features of autoimmune hepatitis,¬†antimitochondrial antibodies¬†(AMA), and histologic findings of¬†bile duct injury or loss
  • Most (88%) patients with AMA titers up to 1:160; seropositivity for antibodies to M2 autoantigens rare (8%) (see¬†Chapter 14)
  • AMA reactivity possibly false because of confusion with anti-LKM1 by IIF
  • Empiric treatment (3 to 6 months) with prednisone¬†alone (20 mg daily) or prednisone (10 mg daily) plus¬†azathioprine (50 mg daily) effective if autoimmune features predominant and alkaline phosphatase level less than twice the upper limit of normal (ULN)
  • Prednisone¬†(20 mg daily) combined with ursodeoxycholic acid (13 to 15 mg/kg daily) if PBC features predominant, alkaline phosphatase level more than twice the ULN, and/or florid duct lesions on histologic examination
2.Overlap syndrome with PSC
  • Defined by features of autoimmune hepatitis, cholestatic biochemical changes, histologic evidence of cholestasis including bile duct injury or loss, and abnormal bile ducts by endoscopic retrograde cholangiography (ERC) or magnetic resonance cholangiography (MRC)
  • Cholangiography required for diagnosis if inflammatory bowel disease present
  • Histologic features of bile duct injury, portal edema, and/or ductopenia and normal cholangiogram compatible with small duct PSC
  • Clues to diagnosis: inflammatory bowel disease, suboptimal response to corticosteroid therapy, and/or rising serum alkaline phosphatase level
  • Empirical therapy with prednisone (20 mg daily) and ursodeoxycholic acid (13 to 15 mg/kg daily) justified
  • Children with autoimmune hepatitis and abnormal cholangiograms in the absence of inflammatory bowel disease (‚Äúautoimmune sclerosing cholangitis‚ÄĚ) typically respond to corticosteroid therapy but have shorter transplant-free survival than patients with normal bile duct biliary changes by MRC in 8% of adults with classic autoimmune hepatitis, but similar frequency by MRC in non-autoimmune liver diseases and may incorrectly implicate PSC
3.Autoimmune hepatitis and chronic viral hepatitis
  • Concurrence of active viral hepatitis, high-titer autoantibodies, and histologic features of interface hepatitis with or without portal plasma cell infiltration
  • Definite¬†or¬†probable autoimmune hepatitis by diagnostic scoring systems defining autoimmune predominant disease with background coincidental viremia
  • Nondiagnostic autoimmune features by diagnostic scoring systems with active viremia defining viral predominant disease with coincidental autoimmune findings
  • Immune manifestations common in chronic viral hepatitis, including SMA in 11%, ANA in 28%, diverse autoantibodies in 62%, and concurrent immune disease in 23%
  • SMA and ANA titers typically low in chronic viral hepatitis (up to 1:80 in 89%, 1:160 or higher in 11%; 1:320 or higher rarely
  • Concurrent positivity for SMA and ANA in only 4% of patients with chronic viral hepatitis
  • Median serum titers of SMA and ANA in classical autoimmune hepatitis of 1:160 and 1:320, respectively; 60% with concurrent SMA and ANA; and only 6% with isolated titers up to 1:8
  • Liver tissue evaluation essential in discriminating predominantly autoimmune from predominantly viral hepatitis
  • Moderate to severe portal plasma cell infiltration (66% versus 21%), acinar (lobular) inflammation (47% versus 16%), and interface hepatitis (23% versus 0%) more common in autoimmune-predominant disease
  • Portal lymphoid aggregates (49% versus 10%), steatosis (72% versus 19%), and bile duct damage or loss (91% versus 20%) more frequent in viral-predominant (chronic hepatitis C) disease (Fig. 5.4)
  • The treatment administered according to the prevailing condition: corticosteroids for autoimmune-predominant disease and peginterferon and ribavirin for viral-predominant disease (chronic hepatitis C)
  • Treatment results assessed at 3 months, and therapy changed if response poor
4.Autoimmune hepatitis with the cholestatic syndrome
  • Heterogeneous syndrome with composite features of autoimmune hepatitis and AMA-negative PBC or small duct PSC
  • ANA and/or SMA typically present in women with cholestatic biochemical changes, normal cholangiogram, absent AMA, and/or histologic findings of bile duct injury or loss
  • Possible resemblance to mainly PBC or autoimmune hepatitis
  • Variable response to empirical therapy with corticosteroids, ursodeoxycholic acid, or both
  • Possible therapy-induced improvements in clinical and laboratory findings but not in histologic changes
5.Cryptogenic (autoantibody-negative) chronic hepatitis
  • Satisfies international criteria for diagnosis of autoimmune hepatitis but lacks conventional autoantibodies (SMA, ANA, anti-LKM1)
  • Similarities in age, female predominance, frequency of concurrent immune diseases, histologic features, the occurrence of HLA B8, DRB1‚ąó03 and A1-B8-DRB1‚ąó03, and laboratory findings to classic autoimmune hepatitis
  • As responsive to corticosteroid treatment as in autoantibody-positive patients
  • Possibly representing a form that has escaped detection by conventional serologic markers
  • Conventional autoantibodies possibly appearing late, or possible presence of nonstandard autoantibodies (atypical pANCA, anti-SLA)
    Must be distinguished from inactive cryptogenic cirrhosis¬†and liver disease associated with¬†celiac disease (i.e., negative for IgA antibodies to tissue transglutaminase or endomysium)Should be considered ‚Äúautoantibody-negative autoimmune hepatitis‚ÄĚ and treated with conventional corticosteroid regimens

Causes of Autoimmune Hepatitis

There is no specific evidence of the cause. Sixty percent of patients have chronic hepatitis but without serologic evidence of a viral infection. The disease is associated with anti-smooth muscle autoantibodies. 

AIH occurs when your immune system mistakes your liver cells for foreign aggressors and creates antibodies to attack them. Doctors don’t know precisely why this occurs. However, certain risk factors have been identified, including:

  • autoimmunity¬†‚Äď the process of your immune system making autoantibodies, which ‚Äėattack‚Äô and damage your body‚Äôs own cells and organs
  • environmental triggers¬†‚Äď causes starting outside of¬†the body; for example getting a virus, taking certain¬†medications, or coming into contact with other toxins
  • genetic predisposition ‚Äď inheriting genes that may make it easier for a trigger to set off the disease.
  • a family history of AIH
  • history of bacterial or viral infections
  • being female
  • the use of certain medications, such as minocycline

Other autoimmune conditions can cause symptoms of liver disease and are also associated with the development of AIH. These diseases include:

  • Grave‚Äôs disease
  • thyroiditis
  • ulcerative colitis
  • type I diabetes
  • rheumatoid arthritis
  • scleroderma
  • inflammatory bowel disease (IBD)
  • systemic lupus erythematosus
  • Sj√∂gren‚Äôs syndrome

Symptoms of Autoimmune Hepatitis

Signs and symptoms in people with autoimmune hepatitis range from mild to severe depending on the amount of liver damage present. Symptoms are generally due to scarring of liver tissue (cirrhosis). Some people have no symptoms at first and are diagnosed after being evaluated for another health problem.[rx] Some of the most common signs and symptoms in people with autoimmune hepatitis may be nonspecific and include:[rx][rx][rx][rx]

  • Most patients have nonspecific symptoms: fatigue, anorexia, nausea, weight loss, jaundice, pruritus, and amenorrhea
  • Clinical manifestations of¬†autoimmune hepatitis¬†depend on how acute liver disease is at presentation, the stage of inflammation, or the complication of liver cirrhosis.
  • The most common features of¬†autoimmune hepatitis¬†are fatigue, malaise, jaundice, abdominal pain, and sometimes, arthralgias.
  • Fatigue (the most common symptom reported).
  • Nausea.
  • Loss of appetite.
  • Diarrhea.
  • Jaundice (yellowing of the skin and whites of the eyes).
  • Loss of brain function (hepatic encephalopathy).
  • Fluid in the abdomen (ascitesb).
  • Swelling of the legs (edema).
  • Easy bruising and bleeding.
  • An enlarged spleen (splenomegaly).
  • Gallstones.
  • Itchy skin (pruritis) or skin rashes.
  • Joint pain.
  • Vomiting.
  • Dark urine.
  • Pale or gray-colored stools.
  • Absence of menstrual periods in women (amenorrhea).

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
100% of people have these symptoms
Increased circulating IgG level 0003237 
80%-99% of people have these symptoms
Anti-liver cytosolic antigen type 1 antibody positivity 0030909 
Antineutrophil antibody positivity 0003453 
Antinuclear antibody positivity 0003493 
Elevated hepatic transaminase
High liver enzymes
0002910 
Liver kidney microsome type 1 antibody positivity 0030908 
Smooth muscle antibody positivity 0003262 
30%-79% of people have these symptoms
Abdominal pain
Pain in stomach

[ more  ]

0002027 
Arthralgia
Joint pain
0002829 
Chronic fatigue
Chronic extreme exhaustion
0012432 
Depressivity
Depression
0000716 
Spider hemangioma 0012522 
5%-29% of people have these symptoms
Acute hepatitis
Acute liver inflammation
0200119 
Anxiety
Excessive, persistent worry and fear
0000739 
Arthritis
Joint inflammation
0001369 
Ascites
Accumulation of fluid in the abdomen
0001541 
Cirrhosis
Scar tissue replaces healthy tissue in the liver
0001394 
Diffuse hepatic steatosis 0006555 
Gastrointestinal hemorrhage
Gastrointestinal bleeding
0002239 
Glomerulonephritis 0000099 
Increased total bilirubin
High bili total
0003573 
Jaundice
Yellow skin

[ more  ]

0000952 
Sclerosing cholangitis 0030991 
Splenomegaly
Increased spleen size
0001744 
Thyroiditis
Thyroid gland inflammation
0100646 
Ulcerative colitis 0100279 
Vitiligo
Blotchy loss of skin color
0001045 
1%-4% of people have these symptoms
Fulminant hepatitis 0004787 
Hepatocellular carcinoma 0001402 
Viral hepatitis 0006562 

Diagnosis of Autoimmune Hepatitis

A multi-pronged approach is used to make a diagnosis. This approach includes determining symptoms, laboratory tests, and biopsies, as no single diagnostic test is pathognomonic for autoimmune hepatitis. Marked elevation of serum transaminases (AST, ALT) and gamma-globulin is common; elevation in alkaline phosphatase is less common.  The serum levels of AST, ALT, and gamma globulin reflect disease severity and immediate prognosis at presentation.

  • Diagnosis is based on combinations of clinical, laboratory, and histological features
  • Revised diagnostic International Autoimmune Hepatitis Group (IAHG) scoring system (rx):
    • Complex system evaluating 11 clinical, laboratory, and histological factors
    • For research purposes – not designed for clinical practice
  • Simplified diagnostic IAHG scoring system (rx):
    • Simple system evaluating 4 laboratory and histological factors: serum autoantibodies, IgG, liver histology and viral hepatitis serology
    • Cutoff values for probable and definite AIH are 6 points (88% sensitivity and 97% specificity) and 7 points (81% sensitivity and 99% specificity), respectively
  • AIH subtypes depend on autoantibody serology:
    • Type 1: positive for antinuclear antibody (ANA) or anti-smooth muscle antibody (SMA); 10% have other autoimmune disorders
    • Type 2: positive for anti-liver-kidney microsomal (LKM) antibody or anti liver cytosol type 1 (LC1) antibody-positive; often presents with acute or fulminant hepatitis; 17% have other autoimmune disorders
  • About 10% of AIH shows coexisting features of the immune-mediated biliary disease (overlap syndrome) or are associated with atypical features (variant syndrome)
    • Overlap syndrome: AIH primary biliary cirrhosis and AIH primary sclerosing cholangitis
    • Variant syndromes: seronegative AIH and antimitochondrial antibody (AMA) positive AIH

Laboratory

  • Serum autoantibodies(rx):
    • ANA –¬†positive in 75% of type 1 AIH; not associated with disease course or outcome
    • Anti-SMA –¬†positive in 95% of type 1 AIH; not associated with disease course or outcome
    • Anti-LKM – diagnostic for type 2 AIH; associated with younger age at presentation, fulminant hepatic failure, and partial IgA deficiency
    • Anti-LC1 –¬†diagnostic for type 2 AIH; associated with more severe inflammation and rapid progression to cirrhosis
    • Anti soluble liver antigen (SLA) / live pancreas (LP) – positive in 20 – 50% of AIH; associated with more severe disease, treatment dependence, relapse after drug withdrawal, and need for transplantation
  • Serum immunoglobulin G (IgG) –¬† not only a diagnostic marker but also a marker for monitoring treatment response (rx)
  • Autoantibodies – A number of specific antibodies found in the blood (antinuclear antibody¬†(ANA),¬†anti-smooth muscle antibody¬†(SMA),¬†anti-liver kidney microsomal antibodies¬†(LKM-1, LKM-2, LKM-3),¬†anti soluble liver antigen¬†(SLA),¬†liver‚Äďpancreas antigen¬†(LP), and¬†anti-mitochondrial antibody¬†(AMA)) are of use, as is finding an increased¬†immunoglobulin G¬†level. The presence of¬†anti-mitochondrial antibody¬†is more suggestive of¬†primary biliary cholangitis. Hypergammaglobulinemia is also of diagnostic value.[rx]
  • Blood tests – Testing a sample of your blood for antibodies can distinguish autoimmune hepatitis from viral hepatitis and other conditions with similar symptoms. Antibody tests also help pinpoint the type of autoimmune hepatitis you have.
  • Liver function tests – These check for inflammation or damage to your liver.
  • Coagulation panel – This test looks at how well the clotting proteins are working.
  • Electrolyte panel – Checks to see if you have an electrolyte imbalance.
  • Other liver tests –¬†These are done to check for other possible types of liver disease.
  • CT scan – This is more detailed than a standard X-ray. It can show detailed images of any part of the body, including the bones, muscles, fat, and organs. It uses both X-rays and computer technology to make horizontal images (often called slices) of the body.
  • MRI – This test makes detailed pictures of organs and structures inside your body. It uses a magnetic field and pulses of radio wave energy. A dye may be shot or injected into your vein. The dye helps the liver and other organs in the belly to be seen more clearly on the scan.
  • Ultrasound –¬†This uses high-frequency sound waves to create a picture of the organs. It can also check blood flow in blood vessels.
  • Liver biopsy –¬†Doctors perform a liver biopsy to confirm the diagnosis and to determine the degree and type of liver damage. During the procedure, a small amount of liver tissue is removed, using a thin needle that’s passed into your liver through a small incision in your skin. The sample is then sent to a laboratory for analysis.
  • Anti-liver cytosol type I, anti-soluble liver antigen (SLA) antibodies, and perinuclear antineutrophil cytoplasmic antibodies (pANCA) can also be associated with autoimmune hepatitis. Conversely, anti-mitochondrial antibodies are more commonly seen with primary biliary cirrhosis and are usually absent in autoimmune hepatitis; however, they can be present in those with overlapping syndromes. Atypical perinuclear antineutrophil cytoplasmic antibodies are commonly associated with type-1 autoimmune hepatitis and primary sclerosing cholangitis. Anti-LKM1 is common in type-1 autoimmune hepatitis and mainly observed in children.
  • Anti-SLA antibodies – are more useful from a prognostic standpoint as these are associated with more severe disease, treatment failure, and higher relapse rates. A liver biopsy is required for both diagnosis and staging of autoimmune hepatitis.
  • Liver Enzyme Abnormalities Elevation of liver transaminases less than 500 UI/L with normal alkaline phosphatase is typical. Liver transaminase elevation to 1,000 UI/L resembling acute viral hepatitis and liver ischemia is less common but can occur. An elevation of alkaline phosphatase that is disproportional to transaminase ALT or AST elevation with alkaline phosphatase to ALT or AST ratio of ‚Č•3 is unusual and should prompt investigation of other causes of liver disease such as drug-induced disease, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Individuals with AIH may concomitantly have features of other autoimmune liver diseases such as PSC or PBC, termed overlap syndrome. The overlap syndrome of AIH with PBC or AIH with PSC will be discussed separately further in this chapter.
  • Gamma Globulin Elevation Gamma globulin elevation occurs in 80% of the cases. There is a polyclonal elevation in immunoglobulin (Ig), with a predominant IgG elevation. Along with liver transaminases, gamma globulin levels are important markers of disease activity.

Treatment Of Autoimmune Hepatitis

Treatment (which is based on supportive care) is as follows

Medications

autoimmune hepatitis is a rare condition with no randomized controlled trials to guide treatment. Treatments that have been tried include intravenous immunoglobulin, plasmapheresis, corticosteroids, cyclophosphamide, and rituximab.[rx]

  • Corticosteroids ‚Äď are a class of drug that lowers inflammation in the body. They also reduce immune system activity. Because corticosteroids ease swelling, itching, redness, and allergic reactions, doctors often prescribe them to help treat diseases like autoimmune hepatitis. Because most patients respond to corticosteroids or¬†glucocorticoid¬†immunosuppressant treatment, this condition is now also referred to as steroid-responsive autoimmune hepatitis. Initial treatment is usually with oral prednisone (50‚Äď150 mg/day) or high-dose intravenous methylprednisolone (1 g/day) for 3‚Äď7 days or prednisone is usually administered orally at 2 mg/kg/day (up to a maximum of 60 mg/day), azathioprine is administered at the initial dose of 1 mg/kg/day, which can be further increased up to 2.5 mg/kg/day until sustained biochemical remission is achieved.[rx]
  • Budesonide – has been shown to be more effective in inducing remission than prednisone, and result in fewer adverse effects.[17]
  • Immunoglobulin infusion(IVIG)¬† ‚Äď Prompt treatment can be initiated before the final diagnosis in case of a reasonable degree of suspicion after collecting serum and CSF samples for confirmation of autoimmune hepatitis[rx] ¬†Expeditious immunomodulatory/immunosuppressive therapies with corticosteroids, immunoglobulin infusion(IVIG), and plasmapheresis (PLEX) are first-line therapies, as well as tumor removal if applicable, with robust supportive therapies.
  • Plasmapheresis ‚Äď can remove autoantibodies of the blood. Plasmapheresis is a method for removing unwanted substances (toxins, metabolic substances, autoantibodies) from the blood. During plasmapheresis, blood is removed from the affected individual and blood cells are separated from plasma. The plasma is then replaced with other human plasma and the blood is transfused back into the affected individual. [rx]
  • Biological Drugs ‚ÄstRituximab, cyclophosphamide, azathioprine, mycophenolate mofetil have been used as second-line therapies if clinical improvement does not occur after four weeks of treatment with first-line therapy. Some experts recommended the use of rituximab early in the disease process as first-line therapy. For refractory patients, bortezomib(proteasome inhibitor), alemtuzumab(humanized monoclonal antibody against CD52), intrathecal methotrexate, and tocilizumab(a monoclonal antibody against interleukin-6 receptor) can work in a small number of patients with success.[rx]
  • Anti Seizure Drugs ‚Äď management in the acute phase can be difficult and requires AEDs along with immunotherapy. However, these patients do not develop epilepsy as the seizure improves with the improvement of autoimmune hepatitis. A retrospective series reported that valproate, levetiracetam, and carbamazepine had been similarly effective, but carbamazepine was associated with fewer side effects. Gradual reduction of autoimmune hepatitis is possible during follow-up and most can be discontinued in 2 years without seizure recurrence. Antipsychotic agents are frequently used to treat behavioral symptoms, but the neuroleptic malignant syndrome can occur.[rx]
  • Benzodiazepines and electroconvulsive therapy ‚Äď have been utilized to treat catatonia. Abnormal movements associated with this autoimmune hepatitis are challenging to control and require a high dose of sedative medications, botulinum toxin, or tetrabenazine. ICU management is essential during the severe phase of the disease for several reasons: airway protection, altered cognition, dyskinesias, seizures, abnormal behavior, temperature instability, heart rate variability, and arrhythmia.[rx]
  • Antiviral Medication ‚Äď Herpes simplex encephalitis is the commonest autoimmune hepatitis. Any patient who presented with clinical features of autoimmune hepatitis should be treated empirically with IV acyclovir, pending the result of autoimmune hepatitis results. Acyclovir will be continued or stopped depending on the outcome of the PCR test. It is essential to recognize the fact that early recurrence of HSV encephalitis within 2 to 3 weeks of autoimmune hepatitis is often due to autoimmune hepatitis triggered by autoimmune hepatitis. The viral infection may lead to a higher likelihood of release of the receptor and subsequent antibody formation and secondary autoimmune hepatitis.[rx]
  • Liver transplant – When medications don’t halt the progress of the disease or you develop irreversible scarring (cirrhosis) or liver failure, the remaining option is a liver transplant. During a liver transplant, your diseased liver is removed and replaced with a healthy liver from a donor. Liver transplants most often use livers from deceased organ donors. In some cases, a living donor liver transplant can be used. During a living donor liver transplant, you receive only a portion of a healthy liver from a living donor. Both livers begin regenerating new cells almost immediately.

Most Common Treatment Options for Autoimmune Hepatitis

Combination Treatment
Prednisone + Azathioprine
Combination Treatment
Budesonide + Azathioprine
Prednisone Monotherapy
Induction
Week 1 30 mg/d + 50 mg/d 9 mg/d + 50 mg/d Prednisone 60 mg/d
Week 2 25 mg/d + 50 mg/d 9 mg/d + 50 mg/d Prednisone 40 mg/d
Week 3 20 mg/d + 50 mg/d 6 mg/d + 50 mg/d Prednisone 30 mg/d
Week 4 15 mg/d + 50 mg/d 6 mg/d + 50 mg/d Prednisone 20 mg/d
Maintenance
First 12 months Prednisone 10 mg/d + Azathioprine 50 mg/d Budesonide 6 mg/d + Azathioprine 50 mg/d Prednisone 20 mg/d or less for at least 24 months
12-24 months Prednisone taper 2.5 mg/week until withdrawal. Thereafter azathioprine monotherapy 50-100 mg/day Consider budesonide taper until withdrawal. Thereafter azathioprine monotherapy 50-100 mg/day
Treatment Withdrawal
After 24 months of complete remission
OR
Liver biopsy showing absence of inflammation
Same Same
Indication
Preferred over prednisone monotherapy as fewer side effects Potential frontline therapy
Patients with obesity, acne, diabetes, and hypertension may benefit
Reserved for patients who cannot take azathioprine
Disadvantages
Side effects of prednisone, although less often and less severe than high-dose prednisone Expensive
Fewer studies showing efficacy
Severe corticosteroid-induced side effects

 

Induction Phase

In the induction phase, prednisone 30 mg per day plus azathioprine 50 mg per day is started for 1 week. This is followed by a prednisone taper over the course of 4 weeks with a fixed azathioprine dose of 50 mg per day to achieve a dose of prednisone 10 mg per day plus azathioprine 50 mg per day as shown in Table 5.

Should budesonide plus azathioprine be selected, induction is achieved with a combination of budesonide 3 mg three times daily plus azathioprine 50 mg per day for 2 weeks, followed by a budesonide 3 mg twice daily thereafter.

Maintenance Phase

For those receiving prednisone plus azathioprine, the maintenance phase begins typically after 4 weeks, when the dose of prednisone 10 mg per day plus azathioprine 50 mg per day is started. This dose is continued for at least 1 full year. The daily maintenance dose of prednisone should remain fixed, as dose titration according to liver transaminases or alternate day schedules of prednisone are associated with incomplete histological improvement despite laboratory improvement.

After 1 year of controlled disease, consideration can be given to withdrawal of prednisone while continuing azathioprine. Thereafter azathioprine monotherapy is continued for long-term maintenance. Patients can often be maintained on doses of azathioprine monotherapy of 50 mg per day to 100 mg per day with normal liver enzymes. Azathioprine doses of less than 100 mg per day have the advantage of less toxicity, particularly less leukopenia. Table 5 shows the medical regimen for AIH.

If budesonide is used, the maintenance dose is 6 mg twice daily in combination with azathioprine 50 mg per day. One may consider tapering budesonide while maintaining azathioprine 50 mg per day to 100 mg per day (azathioprine monotherapy) after 12 months, but there are currently no studies on the long term effect of azathioprine monotherapy after budesonide plus azathioprine combination.

Current Alternative Treatments

Although conventional treatment with steroids ¬Ī azathioprine allows achieving remission in most patients, in cases of initial treatment failure or multiple relapses during tapering or discontinuation attempts, alternative therapies are often proposed.

Cyclosporine (CSA) is a powerful immunosuppressant that has been successfully used in patients with JAIH as a short-term initial treatment alternative to steroid-azathioprine or as a salvage treatment (rx, rx). The main side effects of CSA include nephrotoxicity, arterial hypertension, and gastrointestinal and neurological toxicity. Minor but frequent side effects are Hypertrichosis and gum hypertrophy; although transient they occasionally can influence adherence to treatment. Since 1985, the use of CSA has been documented in 133 adults with autoimmune hepatitis. CSA was used as salvage therapy and showed an overall positive response of any degree in about 93% of patients and a negative response, defined as no response, non-compliance, or drug intolerance in 7% (rx, rx).

Regarding pediatric patients, there are only five major publications in which CSA is mostly administered for short periods, mainly to induce remission, as a bridge to conventional treatment (rx, rx).

Furthermore, the effectiveness of CSA was similar to steroids as salvage therapy in children with JAIH and liver failure (rx). Prolonged CSA treatment for autoimmune pediatric liver disorders was first reported in 2004 with an excellent safety profile (rx), confirmed also in a recent follow-up study (rx).

A recent meta-analysis by Zizzo et al. confirmed that CSA has the highest short-term response rate (86%) in conventional treatment-refractory children with autoimmune hepatitis (rx).

Besides CSA, a wide range of immunosuppressive drugs has been used in small series of children (rx).

Mycophenolate Mofetil (MFM) is the second most effective drug for conventional treatment-refractory children with JAIH after cyclosporine (36% remission rate at 6 months) (rx). The main concern is the use of MMF is the lack of knowledge regarding its therapeutic range and toxic threshold; moreover, MFM is more expensive than azathioprine and is absolutely contraindicated during pregnancy.

Recently, Budesonide, a corticosteroid with potentially fewer side effects than other glucocorticoids, emerged as an alternative first-line treatment in association with azathioprine. When comparing the effects of budesonide vs. prednisone, both in combination with azathioprine, budesonide did cause fewer side effects than prednisone; however, after 12 months, only 46% of the patients treated with budesonide achieved complete remission (rx). The low proportion of remission observed in this study does not support its use as a first-line treatment of AIH (rx, rx).

mTOR inhibitors as sirolimus or everolimus have been used as salvage therapy with good results in few published adult patients (rx, rx).

Liver transplantation represents a therapeutic option for a small proportion of patients under two main circumstances: patients presenting with acute liver failure that does not respond to salvage therapy with rescue immunosuppression, and patients with cirrhosis with end-stage liver disease.

Monitoring

We suggest the following tests to monitor patients with AIH.

Prior to treatment

  • Pregnancy test
  • Vaccination for hepatitis A and hepatitis B viruses
  • Bone density in postmenopausal women
  • Bone maintenance regimen of calcium and vitamin D supplementation and exercise for all patients
  • Complete blood count to rule out severe cytopenia that would preclude azathioprine

During induction phase

  • AST or ALT, total bilirubin concentration, and alkaline phosphatase every 1-2 weeks

During maintenance phase

  • AST or ALT, total bilirubin concentration, alkaline phosphatase, and gamma globulin or IgG levels every 3-6 months
  • Complete blood count every 6 months while on azathioprine
  • Bone mineral density once a year while on prednisone
  • Routine eye examination in patients on prednisone at least once a year

During treatment withdrawal

  • AST or ALT, total bilirubin concentration, alkaline phosphatase, and gamma globulin or IgG levels every month for 3 months, then every 6 months for 1 year, and then yearly lifelong

When end-stage liver disease ensues

  • Hepatic ultrasonography every 6 months or computed tomography of the abdomen with contrast once a year to screen for hepatocellular carcinoma
  • Esophagogastroduodenoscopy screening for esophageal varices every 2-3 years for primary prophylaxis of variceal bleeding
  • Bone mineral density every 3 years

Next steps

Tips to help you get the most from a visit to your healthcare provider:

  • Know the reason for your visit and what you want to happen.
  • Before your visit, write down questions you want to be answered.
  • Bring someone with you to help you ask questions and remember what your provider tells you.
  • At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also write down any new instructions your provider gives you.
  • Know why a new medicine or treatment is prescribed, and how it will help you. Also, know what the side effects are.
  • Ask if your condition can be treated in other ways.
  • Know why a test or procedure is recommended and what the results could mean.
  • Know what to expect if you do not take the medicine or have the test or procedure.
  • If you have a follow-up appointment, write down the date, time, and purpose for that visit.
  • Know how you can contact your provider if you have questions.

References

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