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Explore the diagnostic criteria, clinical manifestations, and treatment options for autoimmune hepatitis, a chronic liver disease. Learn about the pathogenesis, subclassifications based on autoantibodies, and prognosis indices.
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IMMUNE LIVER DISEASE Prof. Dr. AmrAlyAbd El Moety Hepatobiliary Unit
3- Autoimmune hepatitis • Autoimmune hepatitis (AIH) is a self-perpetuating hepatocellular inflammation of unknown cause. It is characterized by: • The presence of interface hepatitis on histologic examination. • Hypergammaglobulinemia, and autoantibodies in the serum. • Diagnosed after exclusion of other chronic liver diseases.
Interface hepatitis The limiting plate of the portal tract is disrupted by a lymphoplasmacytic infiltrate. This histologic pattern is the hallmark of autoimmune hepatitis
Diagnostic criteria • The propensity for an acute and rarely fulminant hepatitis. • Presence of lobular hepatitis. • Cholestatichistologic changes; • Including bile injury and dectopenia.
Diagnostic criteria Lobular hepatitis Mononuclear inflammatory cells line the sinusoidal spaces.Typically, lobular hepatitis coexists with interface hepatitis, but it may be pronounced during acute
Diagnostic criteria • Immunoserologic tests • Antinuclear antibodies (ANA). • Smooth muscle antibodies (SMA). • Liver/kidney microsome type 1 (anti-LKM1). • Perinuclearanti-neutrophil cytoplasmic antibodies (pANCAs) are common in type 1 AIH.
Clinical criteria A. The definite diagnosis of AIH requires: The exclusion of other similar diseases. Laboratory findings that indicate substantial immunore-activity. Histologic features of interface hepatitis.
Clinical criteria B. A probable diagnosis Is justified when findings are compatible with AIH but insufficient of a definite diagnosis. Patients who lack conventional autoantibodies but who are seropositive for investigational markers. Such as antibodies to the asialoglycoprotein receptor (anti-ASGPR), soluble liver antign/liver-pancreas (anti-SLA/LP), actin (antiactin), or liver cytosol type 1 (anti-LC1), are classified as having a probable disease.
Diagnostic algorithm for autoimmune hepatitis Abnormal AST and GG levels AST: Alkaline Phosphatase > AMA- ceruloplasmin normal α1 antitrypsin phenotype normal Normal or nonspecific iron level HBsAg, anti –HCV, IgM anti-HAV- Interface hepatitis ± lobular hepatitis Definite Probable GG ≥ 1.5 normal ANA, SMA or LKM 1 ≥ 1:80 No drugs or blood products Alcohol < 25 gm/d GG ≥ 1.5 normal ANA, SMA or LKM 1 ≥ 1:40 Previous drugs or blood products Alcohol use Other liver-related authoantibodies Type 2 Type 1 LKM1+ ANA and/or SMA+
Pathogenesis • The pathogenic mechanisms of AIH are unknown. The most popular hypotheses evoke a constellation of interactive factors that include; • A triggering agent (infectious agents, drugs, and toxins). • A genetic predisposition. • Autoantigendisplay, immunocyte activation, and effector cell expansion.
Pathogenesis The antigen binding groove of the class II molecule of the major histocompatibility complex (MHC) is encoded by alleles that determine its configuration and its ability to activate immunocytes. The susceptibility alleles of AIH reside on the DRB1 gene, and among white northern European and north American patients, they are DRB1*0301 and DRB1*0401.
Pathogenesis Different ethnic groups have different susceptibility alleles, and these findings support a shared motif hypothesis of pathogenesis. According to this hypothesis, risk of disease relates to amino acid sequences in the antigen binding groove of the class II MHC molecule, and multiple alleles encode the same or a similar sequence (shared motif).
Pathogenesis The critical shared motif in AIH in white northern Europeans and North Americans is represented by the six-amino-acid code LLEQKR, where lysine (K) is in position 71 of the DRβ polypeptide chain of the class II MHC molecule. DRB1*0301 and DRB1*0401 encode identical sequences in this region. DRB1*0404 and DRB1*0405, which are the susceptibility alleles in Mexican, Japanese, and Argentine adults, encode a similar sequence except for an arginine (R) for lysine (K) at DRβ71 position.
Pathogenesis The critical six-amino-acid motif in AIH restricts the range of peptides that can be accommodated. Only the cytochrome monooxygenase p-450 iiD6 (CYP2D6) has been recognized as a target auto antigen in AIH.
Liver cell destruction is by Cell-mediated coytotoxicity, antibody-dependent cell-mediated cytotoxicity, or a combination of both mechanisms Subclassifications Three types of AIH have been proposed on the basis of immunoserologicmarkers.
Sub classifications of autoimmune Hepatitis based on Auto antibodies
Prevalence Among white northern Europeans is 1.9 cases par 100,000 persons per year. Prognostic indices of autoimmune hepatitis
Drug- related side effects 1. Prednisone Cosmetic changes, such as facial rounding, dorsal hump formation, obesity, acne, or hirsutism, occur in 80% of patients after 2 years of treatment regardless of regimen. Severe side effects, including osteopenia with vertebral compression, diabetes, cataracts, emotional lability, and hypertension, usually develop only after protracted therapy (more than 18 months) and on the higher dose prednisone schedule (20 mg/day).
Drug- related side effects 1. Prednisone Premature discontinuation of treatment is justified in 13% of patients, mainly because of intolerable obesity, cosmetic changes, or osteoporosis.
Drug- related side effects 2. Azathioprine Cholestatic hepatotoxicity, nausea, emesis, rash, and cytopenia. These side effects occur in fewer than 10% of patients treated with 50 mg/day and reverse with a reduction in dose or termination of therapy. Therefore, azthioprine with prednisone is preferred to prednisone alone because the combination produces fewer glucocorticoid related side effects during comparable periods of treatment (10% versus 44%).
B) Liver transplantation When decompensated patients with multilobular necrosis have at least at one laboratory parameter that fails to normalize or hyperbilitubinemia that does not improve during a 2-week treatment period, the immediate mortality rate is high and evaluation for liver transplantation is warranted.
Treatment End Points Prednisone + azathioprineOr Prednisone alone (higher dose) Remission Treatment failure Drug toxicity Incomplete response Nosymptoms AST ≤ 2x normal GG normal. Normal or minimalhistologicactivity Worsening AST and/or bilirubin level ≥ 67% Worsening histologic activity Improvement in all aspects Failure to satisfy remission criteria Intolerable symptoms Vertebral Compression Cytopenia No therapy High-dose therapy Continued therapy Dose reduction or withdrawal Sustained remission Relapse Stable liver function Decompensation Protracted therapy (≥3 years) Repeat therapy Chronic therapy Liver transplantation Indefinite low-dose Prednisone or azathioprine 2nd remission No therapy Indefinite low-dose Prednisone OR Sustained remission 2nd relapse Indefinite azathioprine
PRIMARY BILIARY CIRRHOSIS Epidemiology Primary biliary cirrhosis (PBC) is found in all races. Approximately 90 – 95% of patients are female. Age of onset typically ranges from 30 to 70.
Immunologic abnormalities • Antimitochondrial antibody (AMA) . • Detected in 95% of patients with PBC. • Increased levels of serum immunoglobulins. • Increased levels of a serum IgM that is immunoreactive and highly cryoprecipitable.
Association with other autoimmune diseases • Thyroiditis, hypothyroidism. • Rheumatoid arthritis. • CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectases). • Sjögren’s syndrome. • Scleroderma.
Pathogenesis Two related processes cause hepatic damage in PBC A-The first process • Is chronic destruction of small bile ducts, presumably mediated by activated cytotoxic T lymphocytes.
B-The second process • Is chemical damage to hepatocytes in areas of liver where bile drainage is impeded by the destruction of the small bile ducts. • The destruction of bile ducts eventually leads to portal inflammation and scarring, and ultimately to cirrhosis and liver failure.
Hepatic histology Four histological stages of PBC have been identified. Stage I • Damaged bile ducts are usually surrounded by a dense infiltrate of mononuclear cells, most of which are lymphocytes.
Stage I: Florid bile duct lesion. The epithelial cell lining of a small duct is infiltrated with lymphocytes
Stage II • The lesion is more widespread . • There may be reduced numbers of normal bile duct within portal triads and increased numbers of atypical, poorly formed bile ducts with irregularly shaped lumina. • There is diffuse portal fibrosis and mononuclear cell infiltrates within triads. • Inflammation may spill into the surrounding periportal areas.
Stage II : A typical bile duct hyperplasia is seen. There are tortuous bile ducts with inflammatory cell infiltrate consisting of primarily lymphocytes and few neutrophils.
Stage III • Similar to stage II except that fibrous septa extend beyond triads and form portal-to-portal bridges.
Stage III : Portal-to-portal fibrous septum is shown (massontrichrome).
Stage IV • Represents the end stage of the lesion, with frank cirrhosis and regenerative nodules. • The findings may be indistinguishable from other types of cirrhosis. However, a paucity of normal bile duct in areas of scarring suggests the possibility of PBC.
Stage IV: There is a noncaseatinggranuloma in the center of and portal triads are linked by bands of connective tissue and inflammatory cells. (Masson trichrome).
Clinical features Symptoms • About 48 – 60% of patients are asymptomatic at the time of diagnosis. • The symptoms and signs of PBC are due to long-standing cholestasis.
1- Fatigue • Most common symptom. 2- Pruritus • The earliest specific complaint of PBC is pruritus. 3- Malabsorption • Impaired secretion of bile leads malabsorption of the fat-soluble vitamins A, D, E and K, and calcium.
4- Osteoporosis • Osteopenic bone disease occurs in at least 25% of PBC patients. The pathogenesis is still unclear. • Osteomalacia is uncommon and occurs only in home-bound patients who have advanced PBC and little exposure to sunlight.
Physical examination • Hepatomegaly is found in approximately 43-70% of patients. • Splenomegaly is present in 16-35%. • Skin abnormalities: • Hyperpigmentation that resembles tanning is due to melanin, not bilirubin, in early-stage PBC. • Excoriations may be diffuse due to scratching caused by intractable pruritus. • Jaundice usually presents later in the course of the disease. • Xanthelasma and xanthomata correlate with hypercholesterolemia. • Less than 5% of patients will eventually develop xanthomata.
Xanthelasma Xanthomata are found on the palms of the hands and soles of the feet, over extensor surfaces of the elbows and knees, in tendons of the ankles and wrists, and on buttocks.
Bilateral plantar xanthomatas in the palms of a patient with PBC.
5- Eyes: • Kayser-Fleischer rings are rare and result from copper retention.
PRIMARY SCLEROSING CHOLANGITIS • Primary sclerosingcholangitis (PSC) is a chronic cholestatic liver disease characterized by fibrosing inflammation of both the intrahepatic and extrahepaticbiliary tree. • The histopathologic evolution of (PSC) results in irreversible damage to the bile ducts and ultimately leads to cholestatic, cirrhosis, liver failure, and premature death from liver failure unless liver transplantation is pe4rformed .
Long-term follow up of patients with (PSC) has revealed a high frequency of colon and bile duct cancers, both of which are probably related to chronic inflammation of the colon and bile ducts. • Although multiple medical and surgical therapies have been evaluated for the treatment of (PSC), there is currently no therapy that achieves complete clinical, biochemical and histologic remission. • Liver transplantation continues to be an important therapeutic intervention for the management of patients with end-stage PSC.
