Cellcept

Autoimmune hepatitis (AIH) is a rare, chronic, progressive disease of unknown etiology, causing hepatocellular inflammation and necrosis. Corticosteroids and azathioprine (Imuran), the standard therapy of AIH, induces remission in over 80% of patients.1,2 Untreated, prognosis of severe AIH is poor with 5-year survival rates of 50%.3 With successful immunosuppression, 90% of patients with AIH experience 10-year life expectancies.4 Effective treatment of AIH significantly improves survival.2,5

Preventive care can reduce the progression of chronic liver disease and minimize adverse effects of treatment. A multidisciplinary approach is essential to promote screening for adverse effects of pharmacologic treatment, early detection of disease progression, and general health maintenance. Recently, practice guidelines were published, providing a data-supported approach to the diagnosis and management of patients with AIH.5

* Description of Disease Process

AIH has been described in every race and ethnicity.5 Exact prevalence data are not available. Presently, it accounts for 20% of all patients with chronic hepatitis.3 Approximately 6% of all liver transplantations in the United States are performed in patients with AIH.5 The International Autoimmune Hepatitis Group (IAIHG) monitors developments that impact diagnosis, and fosters collaborative research.6 This group selected the term 'autoimmune hepatitis' to replace chronic active hepatitis.

Based on autoantibody markers, AIH is often subclassified into type I and type II. Recently, a type III was proposed. Much debate exists regarding the significance of subtyping. Fundamental aspects of these subclassifications do not differ clinically. Some differences do exist, however, in presenting features, age of onset, and disease progression.1,3

The pathogenesis of AIH appears to be a complex, multifaceted process involving triggering factors, autoantigen exposure, genetic predisposition, and defective immunoregulatory mechanisms. The etiology and the relationship between these factors remain unclear.5 The end result is a loss of self-tolerance, inflammation, and destruction of hepatic parenchyma. There is often an association with other autoimmune diseases in patients and/or first degree relatives, including thyroid disease, type I diabetes mellitus, Sjogren's syndrome, rheumatoid arthritis, renal tubular acidosis, fibrosing alveolitis, glomerulonephritis, or ulcerative colitis.4

AIH may present at any age or sex, although it occurs most frequently in women. The presentation may be acute or insidous, mimicking acute or chronic viral hepatitis, and may not be recognized until liver damage is advanced. Jaundice, anorexia, fatigue, and amenorrhea are common presenting complaints. Abdominal pain, hepatomegaly, splenomegaly, and fever may also be present. Many patients have evidence of decompensated cirrhosis with ascites, encephalopathy or esophageal varices at presentation. Extrahepatic manifestations may include arthropathy, periarticular swelling, maculopapular or acneform rashes, allergic capillaritis, and lichen planus.3,4

Diagnostic criteria of AIH have been codified by the IAIHG.6 Diagnosis requires the presence of characteristic features: histologie evidence of interface hepatitis (piecemeal necrosis), elevated aminotransferases (AST, ALT), an immunoglobulin G (IgG) predominant hypergammaglobulinemia, and the presence of autoantibodies. The diagnostic autoantibodies of AIH include: antinuclear antibody (ANA), smooth muscle antibodies (SMA), liver-kidney microsomal antibodies (anti-LKM), soluble liver antigen (anti-SLA), and liver-pancreas antigen (anti-LP). Additionally, the diagnosis requires the exclusion of viral hepatitis, genetic liver disease (Wilson's disease, alpha-1 antitrypsin deficiency, hemochromatosis), primary biliary cirrhosis, primary sclerosing cholangitis, alcohol or drug injury, and nonalcoholic steatohepatitis. Imaging studies are generally not helpful in making a diagnosis of AIH. Liver biopsy is important to determine inflammatory activity (grade) andfibrosis (staging) of chronic hepatitis. Always indicated for confirmation, liver biopsy may show evidence of plasma cell infiltration, bridging necrosis, and fibrosis in addition to the required interface hepatitis.3,5,6

* Pharmacologic Treatment

The treatment of choice for AIH is immunosuppression. Standard treatment is either corticosteroids (prednisone) alone, or a combination of corticosteroids and azathioprine (Imuran).4 Both regimes are effective in inducing remission. Although azathioprine alone does not induce remission, as monotherapy it may maintain remission.1-4

Prednisone (Deltasone) and prednisolone (Delta-Cortef) are intermediate acting corticosteroids that suppress immune reactivity and inflammation. Prominent adverse effects of corticosteroids include diabetes, hypertension, osteoporosis, glaucoma, cataracts, increased susceptibility to infections, depression, psychosis, weight gain, and edema.1,5,7

Azathioprine is an immunosuppressive agent that has a steroid-sparing effect when used in combination therapy. Adverse effects of azathioprine include bone marrow suppression (thrombocytopenia and leukopenia), pancreatitis, increased susceptibility to infections, increased risk of neoplasms, nausea and vomiting, and possibly teratogenicity.3,7

Presumed to suppress immunoglobulin production, ursodeoxycholic acid (ursodiol) is sometimes used as an adjunct to therapy. Other immunosuppressive agents that show promise as alternative therapies for standard treatment nonresponders, or those who develop drug intolerance include cyclosporin A (Sandimmune), FK 506 (Tacrolimus, Prograf), mycophenolate-mofetil (Cellcept), and cyclophosphamide (Cytoxan).3,4

Several major treatment centers have independently developed similar treatment strategies. Variations in treatment regimens exist. Treatment should be continued until remission, treatment failure, drug resistance, or intolerance develops.1-5 The average duration of treatment before remission is 22 months.3 Remission is defined as a lack of clinical symptoms and a reduction of ALT to

* Primary Care Concerns

Full remission may take years, and maintenance of remission may require lifelong immunosuppression. Objectives of primary care management include providing general health maintenance, anticipating and preventing potential side effects, and controlling and/or preventing further exacerbation of the disease process.

Patient education and emotional support serves to allay fears and prevent unrealistic expectations regarding the disease process. Despite quality care, poor outcomes may be a reality for some. Patient education of the pharmacotherapeutics is vital to enhance compliance. Following withdrawal of steroids, the need for corticosteroids in the event of physiological stress maybe necessary and should be conveyed to the patient.7

Aminotransferases must be evaluated every 1 to 3 months prior to remission and during tapering, and every 3 months during maintenance therapy. Worsening of aminotransferases under treatment, or during remission, may signal a resurgence of disease activity or noncompliance with medication regime.4 Serum IgG may also serve as a marker of disease responsiveness. Metabolic profiles including fasting glucose and electrolytes are necessary to monitor for hyperglycemic, hypokalemic, and hypocalcemic effects of steroid therapy. Patients taking azathioprine need monthly monitoring of complete blood counts to assess for thrombocytopenia and leukopenia.4,7

Dietary management should be implemented to prevent weight gain, edema and sodium retention from corticosteroid therapy, which may contribute to hypertension and glucose intolerance. Blood pressure monitoring at each visit is necessary. If indicated, antihypertensive therapy and potassium supplementation should be initiated.

Ophthalmologic risks of steroid therapy include glaucoma and increased risk for cataract formation. Slit lamp examination is necessary at baseline, 6 months, and then yearly for screening,5,7,8 or as recommended by the eye care provider.

Good hygiene, frequent hand washing, and exposure prevention should be promoted. Early presentation for assessment and diagnosis of infectious processes, which require aggressive treatment in the immunosupprcssed patient, is essential. The use of live viral vaccines is contraindicated due to the risk of disseminated infection and inadequate immune response.7 A single dose of pneumococcal vaccine and an annual influenza vaccine should be given if no contraindication exists.

Corticosteroid therapy and chronic liver disease have a negative impact on bone mineralization. Nearly one-half of individuals receiving chronic corticosteroids suffer a skeletal fracture, and vertebral fractures are the most common.9,10 Rapid bone loss can occur within the first few months of treatment.9 Baseline bone density measurement is recommended with periodic repeat evaluations, especially in postmenopausal women. Lifestyle, dietary, and preventive modifications are essential, including smoking cessation, weight bearing and resistance exercise, fall prevention, and caution in sports. Daily calcium (1000 mg to 1500 mg) and Vitamin D (400 IU) should be recommended for all patients. Alendronate (Fosomax) should be considered when indicated to prevent bone loss and reduce risk of vertebral fractures.9,10 Collaboration with a gastroenerologist or hepatologist regarding the role of HRT is prudent.

Long-term immunosuppression carries 1.5 times the normal risk of developing a malignancy.5,8 General health maintenance must include routine screening protocols for men and women. Particular attention is warranted for secondary prevention of gynecological, dermatological and hepatocellular carcinoma (HCC). Currently, no recommendation exists for HCC screening in AIH patients.5,11 Regular screening should be considered for patients with cirrhosis.

Secondary amenorrhea in females with AIH is not clearly understood. It is thought to be anovulatory, secondary to hypogonadism.3,9,11 Chronic anovulation increases the risk of endometrial cancer. Treatment with oral contraceptives, or combination HRT may be necessary to prevent endometrial hyperplasia.11 Safe contraceptive methods are available for AIH patients, including progesterone-only oral contraceptives, depot medroxyprogesterone acetate (Depo-Provera) injections, and the copper intrauterine device11; however, protection is often not taken.4 The pharmacokinetics, safety, and efficacy of recent contraceptive alternatives such as the etonogestrel/estradiol vaginal ring (NuvaRing), norelgestromin/ethinyl estradiol transdermal system (Ortho Evra), and the levonorgesterol intrauterine device (Mirena) have not been formally studied in women with liver impairment.12-14 A recent study of young female patients with AIH demonstrated that, despite menstrual irregularities, normal pregnancy with good fetal outcomes is possible, even with patients on azathioprine.15 This undertaking should only be considered during remission and requires close monitoring by specialists with expertise in management of AIH.4,15 The possible risk of teratogenicity of azathioprine use during pregnancy requires explicit instruction to childbearing age females.4,11,15 Corticosteroids and azathioprine should not be discontinued if pregnancy occurs.

At minimum, a yearly dermatological exam is necessary. Appropriate prevention includes skin inspection, avoidance of sun exposure, and daily sun block protection. Other adverse effects of long-term steroid therapy such as acne, impaired wound healing, hirsutism, skin atrophy or fragility may all warrant referral to a dermatological specialist.

Neuropsychiatric effects of corticosteroids require assessment at each visit, including screening for depression, mood changes, affect and sleep disorders, lethargy, or insomnia. Adverse cosmetic changes such as weight gain, acne, and hirsutism, in addition to fear, anxiety, and emotional lability require ongoing reassurance. There are several Internet support groups available specifically for AIH. Generally, patients with AIH may pursue any career, as tolerated by their individual limitations, however, a social service referral may be necessary if the patient is or becomes disabled due to AIH.

* Prevention of Disease Progression

Preventive care can reduce or slow the progression of hepatic fibrosis. Assessment for evidence of complications of chronic liver disease is essential. Portal hypertension may result in ascites, encephalopathy and gastroesophageal varices. As bleeding from gastroesophageal varices carries a high mortality, an endoscopic exam is recommended in patients with cirrhosis with the aim of preventing hemorrhage via prophylaxis with a nonselective beta-adrenergic blocker (propanolol hydrochloride, nadolol) or long-acting nitrates (isosorbide).3 If no immunity is evident, hepatitis A and B vaccination is recommended to prevent superinfection.3 Alcohol consumption, associated with accelerated progression of liver disease, should be avoided.

Vibrio vulnificus is a gram-negative bacterium found in coastal waters, particularly the Gulf of Mexico. Ingestion may cause a life-threatening bacteremia in which mortality, in compromised hosts, is greater than 50%.16 Thorough cooking of seafood remains the only effective means of prevention. All AIH patients, especially those with cirrhosis and on immunosuppressive medications, should be warned of the hazards of eating raw shellfish, particularly oysters. Exposure to open skin lesions, by swimming or handling seafood, can cause infection with progression to necrotizing fasciitis. Swimming in temperate waters with open lesions should be avoided. Gloves should be worn when handling uncooked seafood.

More than 600 medicinal agents, chemicals and herbal remedies are recognized to produce hepatic injury.17 Potentially hepatotoxic medications should be used with caution in patients with chronic liver disease. A full discussion of these agents is beyond the scope of this article. The nurse practitioner (NP) must consider the pharmacokinetics of all agents prior to prescribing. Medication inquiry, including over-the-counter and herbal supplements, is necessary at each office visit. Patients must be aware of the dangers of taking herbal supplements. Milk thistle (Silybum marianum) is a popular herbal agent frequently recommended in liver disease. Although evidence exists that milk thistle may be hepatoprotective, clinical efficacy has not been established.3,18 Further investigation is necessary.

Patients with complications of cirrhosis or progression to fulminant liver failure as a result of AIH should be referred for consideration of liver transplantation, a highly successful option with a post-transplant 5-year survival rate that exceeds 80%.5

AIH can be potentially life threatening if not detected and diagnosed early. With remission, the prognosis of AIH is generally favorable. NPs are adept at chronic disease management, and capable of spearheading a multidisciplinary team approach to support normal life expectancy. Dramatic advances have been made in understanding the pathogenesis, identification of autoantibodies, and treatment options, including liver transplantation. Further research is necessary to investigate the impact of AIH on individuals.

REFERENCES

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3. Schiff ER, Sorrell MF, Maddrey WC, eds: Schiff's diseases of the liver, 8th edition. Hagerstown, Md: Lippincott, Williams and Wilkins, 1999;919-935.

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9. Lane NE: An update on glucocortocoid-induced osteoporosis, Rheum Dis Clin North Am 2001;27(1):235-253.

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11. George ED, Schluger LK: Special women's health issues in hepatobiliary diseases. Clin Fam Prac 2000:2(1):155-169.

12. NuvaRing(r) Full prescribing information. West Orange, NJ: Organon, Inc. 2001. [20 Novenber 2002]

13. Ortho Evra Prescribing Information. Ortho-McNeil Pharmaceutical, Inc.:Rariton, NJ. 2001. [20 Novenber 2002]

14. Mirena Physician Package Insert. Berlex Laboratories, Inc.:Montville, NJ. 2000. [20 November 2002]

15. Heneghan MA, Norris SM, O'Grady JG, et al: Management and outcome of pregnancy in autoimmune hepatitis. Gut 2001;48, 97-102.

16. Neill MA, Carpenter CC: Other pathogenic vibrios. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett's principles and practice of infectious diseases, 5th edition. Philadelphia: Churchill Livingston. 2000. 2272-2275.

17. Lewis JH: Drug-induced liver disease. Med Clin North Am 2000;84(5):1275-1311.

18. Agency for Healthcare Research and Quality. Milk thistle: effects on liver disease and cirrhosis and clinical adverse effects. Summary, Evidence Report/Technology Assessment: Number 21, September 2000. [12 March 2002].

Maura Flynn, NP-C, MSN

ABOUT THE AUTHOR

Maura Flynn is a Nurse Practitioner in the Gastroenterology Section at the Providence VAMC, Providence, RI.

Copyright Springhouse Corporation Dec 2003
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