CLINICAL PRACTICE
Autoimmune hepatitis: A noninfectious killer Laurie Anne Ferguson, DNP, APRN, FNP (Associate Professor) Loyola University School of Nursing, New Orleans, Louisiana
Keywords Autoimmune disorders; hepatitis; nurse practitioners; primary care. Correspondence Laurie Anne Ferguson, DNP, APRN, FNP, Loyola University, New Orleans, LA. E-mail: [email protected] Received: January 2012; accepted: July 2012 doi: 10.1002/2327-6924.12055
Abstract Purpose: This article reviews autoimmune hepatitis (AIH) to promote early recognition, diagnosis, and referral for nurse practitioners (NPs) encountering this rare condition. Data sources: Selected research and clinical articles from Medline, PubMed, and CINAHL. Conclusions: AIH is a rare condition of unknown etiology affecting women 3.6 times more than men and may result in liver failure, subsequent liver transplantation, and death. Untreated AH is associated with up to 80% mortality. Collaboration and referral to gastroenterologists, hepatologists, and other specialists are needed to improve outcomes for this potentially devastating disease. Implications for practice: Corticosteroid treatment has long been the mainstay of treatment of AIH, although newer therapies are promising. NPs can dramatically improve outcomes by early recognition, diagnosis, referral, and monitoring for common side effects of treatment working collaboratively with specialists.
Introduction Autoimmune hepatitis (AIH) is a rare immunemediated liver disease of unknown etiology, which may result in liver failure, subsequent liver transplantation, or death. Females are affected three times more commonly than males, and if left untreated are associated with up to 80% mortality (Lohse & Mieli-Vergani, 2011; Soloway & Hewlett, 2007). The diagnosis of AIH is frequently illusive and is often made as a diagnosis of exclusion. This article will discuss AIH and implications for nurse practitioners (NPs) to improve early diagnosis and treatment.
Epidemiology and pathophysiology The term hepatitis is defined as an inflammatory condition of the liver (Copstead & Banasik, 2010) and the causes of hepatitis include the more common viral etiologies, such as Hepatitis A, B, D, E as well as cytomegalovirus (CMV) and Epstein–Barr virus. However, hepatitis or liver inflammation may be secondary to drug effects, alcohol, nonalcoholic fatty liver disease (NAFLD), or because of autoimmune responses as seen in AIH (Copstead & Banasik, 2010). ¨ as a AIH was first described in 1950 by Waldenstrom chronic form of hepatitis in young women with jaundice,
elevated gammaglobulins, amenorrhea, and subsequent hepatic cirrhosis (McFarlane, 2002). Subsequent identification of antinuclear antibodies (ANAs) sometimes associated with the condition led to clinical trials establishing the effectiveness of immunosuppression (Lohse & Mieli-Vergani, 2011). AIH has been reported in all age groups, ethnicity, and geographical locations. AIH has a prevalence of at least 1:10,000 in Caucasians and Japanese and predominantly affects women 3:1 (Lohse & Mieli-Vergani, 2011). Previously considered a rare disease, many authorities are suggesting AIH is simply under diagnosed. Rates reported in Western Europe and North America suggest that the prevalence is similar to that of other autoimmune conditions, such as systemic lupus erythematosus (SLE), primary biliary cirrhosis, and myasthenia gravis (Strassburg, 2010). Up to 30% of adult patients with AIH have histological features of cirrhosis upon liver biopsy because of hepatic changes secondary to chronic inflammation (Strassburg, 2010). Diffuse hepatic fibrosis causes subsequent changes in hepatic blood flow and liver function and hepatic failure (Copstead & Banasik, 2010). Fortunately, cirrhosis because of AIH does not prognosticate poor long-term survival as in alcoholic cirrhosis (Strassburg, 2010). Several causative agents have been suggested in the development of AIH. Environmental agents, such as
C 2013 The Author(s) Journal of the American Association of Nurse Practitioners 26 (2014) 13–18
C 2013 American Association of Nurse Practitioners
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Autoimmune hepatitis
a virus, drug, and vaccines, have been studied; however, no firm link has been established. Human leukocyte antigen (HLA) subtypes have been found in over 50% of patients with AIH, suggesting a genetic predisposition (Lohse & Mieli-Vergani, 2011). AIH has been associated with other autoimmune diseases, including rheumatoid arthritis, thyroiditis, ulcerative colitis, and a family history of allergic disorders (Manns & Strassburg, 2011; Strassburg, 2010). Although a conclusive etiology has not been found, experts suspect some trigger is necessary to initiate the autoimmune hepatic response.
Clinical presentation and diagnosis Patients with AIH are often identified via routine laboratory evaluation especially if the diagnosis is made early in the disease process (Lohse & Mieli-Vergani, 2011). AIH may also present clinically with nonspecific complaints of fatigue, lethargy, and jaundice. Patients presenting with fatigue, nausea, vomiting, anorexia, icterus, darkcolored urine, and pale-colored stools should prompt the healthcare provider to order liver function tests (alanine transaminase [ALT] and aspirate transaminase [AST]). Mildly elevated (less than five time normal) ALT and AST are commonly encountered clinically. Damage at the hepatocellular level releases ALT and AST into the bloodstream. Because ALT is found primarily in the liver, abnormalities in ALT usually reflect liver injury. The ratio of AST/ALT is helpful in identifying disease causality (Oh & Hustead, 2011). Generally an AST/ALT ratio greater than 2 suggests possible alcohol abuse and a ratio of less than one suggests NAFLD (Bayard, Holt, & Boroughs, 2006; Oh & Hustead, 2011). NAFLD is the most common cause of mild elevation of liver enzymes and should be considered in patients with obesity, diabetes, elevated triglycerides, and metabolic syndrome (Oh & Hustead, 2011). A careful history and physical should follow the identification of elevated liver enzymes. The assessment should include occupation, prescription, and over the counter (OTC) medications or supplements and alcohol use to identify patients who have liver injury secondary to chemical or environmental exposure (see Table 1). A standard alcoholic drink is defined as 12 oz beer, 5 oz of wine, or 1.5 oz spirits; alcohol consumption should be no more than two alcoholic drinks per day for men and one for women (Poli et al., 2013). Many drugs are associated with liver injury with acetaminophen being one of the most common drugs. Four grams of acetaminophen per day for as little as 5–10 days has been associated with el14
L. A. Ferguson
Table 1 Common potentially hepatotoxic drugs Acetaminophen Allopurinol Amiodarone Amoxicillin/clavulanic acid Azithromycin Carbamazepine Ciprofloxin Cotrimoxazole Diclofenac Disulfram Enalapril Erythromycin Fluconazole Glyburide Halothane Heparin Isoniazid Kava Ketaconazole Levofloxacin Methotrexate Naproxen Nitrofurantoin Nonsteroidal anti-inflammatory drugs (NSAIDS) Oral contraceptives Phenytoin Protease inhibitors Ranitidine Rifampin Sulfonamides Tetracyclines Valproic acid Note: Adapted from Lucena, Garcia-Cortes, Cueto, Lopez-Duran, and Andrade (2008), Oh and Hustead (2011), Suzuki et al. (2010).
evated ALT and AST among nondrinkers (Watkins et al., 2006). Although statins are commonly associated with liver damage, the evidence supporting causality is not clear (Mills et al., 2010; National Cholesterol Education Program, 2002). Statin therapy is usually safe in patients with mild to moderately elevated transaminase levels and can reduce morbidity from cardiovascular events when elevated liver enzymes are because of NAFLD (Athyros et al., 2010). Patients with elevated ALT and AST should have seriologic testing for Hepatitis B and C. Millions of Americans have undiagnosed Hepatitis B and C. Testing for anti-HBc, HBsAg, and anti-HCV can identify individuals who would benefit by therapeutic interventions. Oh and Hustead (2011) recommend serologic testing for Hepatitis B and C even if repeat liver enzyme testing is normal as Hepatitis C can cause a transient rise in ALT and AST (see Figure 1).
Autoimmune hepatitis
L. A. Ferguson
↑ AST & ALT
History & Physical Assess ETOH* & Drug Use Viral Serology to exclude Hepa
AST/ALT ra o = > 2 – suspect ETOH < 1 – suspect NAFLD
s B and C (an -HBc IgM, HBsAg, an -HCV)
*2 standard alcoholic drinks for men, 1 for women
NO
Yes Remove offending agents and repeat labs 2-4 Weeks
Consider assessing for co-morbid diseases Metabolic Syndrome Hyperlipidemia Thyroid disease Consider liver ultrasonography PT/PTT, Albumin, CBC with platelets ANA, IgG, IgA, IgM
Consider serum iron, ferri n, TIBC and serum transferrin if Hemochromatosis is suspected
Persistent or unexplained ALT and AST eleva on
Chronic Liver Disease or Hepa c decompensa on
Abnormal
Nega ve Workup or consistent with NAFLD
Consulta on Further tes ng
Refer to Hepatology Expedited workup
Lifestyle modifica on Underlying disease treatment Persistent enzyme eleva on Re-evaluate 6 months
Labs normalized or improving then monitor
Refer to Hepatology Persistent enzyme eleva on
Figure 1 Evaluation of elevated liver enzymes. Note: Adapted from Bayard et al. (2006), Brandhagen, Fairbanks, and Baldus (2002), and Oh and Hustead (2011).
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Autoimmune hepatitis
Hemochromatosis is the most common single gene disorder in Caucasians in the U.S. population. Characterized by iron overload, hemochromatosis results in increase iron stores and elevated ALT and AST from liver damage (Brandhagen et al., 2002). Other less common causes of mildly elevated liver transaminase levels include alpha1 antitypsin deficiency and Wilson disease and are beyond the scope of this article.
Diagnosis of AIH Although patients may often be identified via routine laboratory screening, patients with advanced AIH may present with more severe symptoms of liver failure, including portal hypertension, ascites, and encephalopathy. AIH should always be considered a possible cause of liver failure (Manns & Strassburg, 2011). The presence of hypergammaglobulinemia, autoantibodies, histology, and the absence of viral hepatitis markers suggests a diagnosis of AIH (Lohse & Mieli-Vergani, 2011). Screening for hypergammaglobulinemia is cost effective and diagnostic, particularly if immunoglobulin G (IgG) is elevated and immunoglobulin A (IgA) and immunoglobulin M (IgM) are normal. Some patients with AIH may have elevations of IgG in the presence of AIH, but the IgG remains in the normal range because of lower baseline IgG levels (Lohse & Mieli-Vergani, 2011). No single autoantibody test is specific to AIH. ANAs, smooth-muscle antibodies (SMA), and liver–kidney microsomal (LKM) antibodies may be positive but are not disease specific in all cases of AIH (Lohse & Mieli-Vergani, 2011). Soluble liver antigen (SLA) and liver–pancreas antigen (LP) are disease specific and are diagnostic of AIH but may be present in only about 30% of patients with AIH (Lohse & Mieli-Vergani, 2011). Liver biopsy and histological evaluation is necessary to confirm an AIH diagnosis and needs to be evaluated in the presence of hypergammaglobulinemia and autoantibodies (Lohse & Mieli-Vergani, 2011). A revised, more simplified scoring tool was developed in 2008 (Hennes et al., 2008; see Table 2).
Special situations Although a negative hepatitis serology suggests AIH in the presence of other indicators, a few patients may actually present with concomitant viral and AIH (Lohse & Mieli-Vergani, 2011). Patients who have positive viral hepatitis titers and concomitant AIH present both a diagnostic and treatment challenge. Although against conventional wisdom, patients with comorbid AIH and viral hepatitis diagnoses benefit from corticosteroid therapy. AIH should be suspected in patients who have 16
L. A. Ferguson
Table 2 Simplified diagnostic criteria for AIH Variable ANA or SMA ANA or SMA or LKM or SLA IgG
Liver histology (evidence of hepatitis is a necessary condition) Absence of viral hepatitis
Cutoff
Points
≥1:40 ≥1:80 ≥1:40 Positive >Upper normal limit >1.10 times upper normal limit Compatible with AIH Typical AIH Yes
1 2a 1 2 1 2 2 ≥6: Probable AIH ≥7: Definite AIH
Note: Hennes et al. (2008 used with permission). a Addition of point achieved for all autoantibodies (maximum, 2 points).
viral hepatitis and are deteriorating quickly with rapidly rising liver enzymes because the prognosis for untreated AIH is worse than for Hepatitis B and C infections. Therefore, AIH must be carefully histologically confirmed and treatment closely monitored (Lohse & Mieli-Vergani, 2011). Acquired liver disease in children is rare and usually presents more acutely than in adults. Severe druginduced hepatitis and AIH in children may present with more subtle laboratory values even in the presence of severe disease. According to Mieli-Vergani and Vergani (2008), children with symptoms of acute hepatitis often have evidence of chronic liver disease, such as spider nevi, palmar erythema, or striae on physical examination. In about 40% of children with AIH, there is a family history of autoimmune disorders, such as thyroiditis, inflammatory bowel disease, nephritic syndrome, and Type 1 diabetes and vitiligo (Mieli-Vergani & Vergani, 2008). IgG and autoantibodies may not always be elevated initially in acute AIH and hypocoagulopathy may make liver biopsy risky to confirm diagnosis (Lohse & Mieli-Vergani, 2011). However, whether it is drug-induced hepatitis or AIH, the treatment of choice are high-dosed steroids. When immunosuppressive therapy is completed, relapse will not occur in drug-induced hepatitis if the offending drug has been discontinued. However, relapse may occur after discontinuing immunotherapy in AIH, thus, confirming diagnosis. In AIH, IgG levels fluctuate to the corresponding transaminase levels before ultimately converting to autoantibody positive. Lower autoantibody titers thresholds are considered abnormal in the pediatric population. In children, titers of 1:10 LKM and 1:20 ANA and SMA are considered critically elevated (Lohse & Mieli-Vergani, 2011).
Autoimmune hepatitis
L. A. Ferguson
Treatment of AIH
Table 3 Treatment regimen
Patients who clinically are deteriorating may require institution of treatment before laboratory values reach panic levels. Treatment is absolutely indicated when aminotransferase levels exceed 10 times the upper limits of normal, or when both aminotransferase levels are greater than five or when gamma-globulin levels are greater than two times normal (Manns & Strassburg, 2011). Corticosteroids have been used to treat AIH for over 50 years (Jothimani, Cramp, Mitchell, & Cross, 2011). The American Association for the Study of Liver Disease (AASLD) recently published guidelines for the treatment of AIH (Jothimani et al., 2011; Manns & Strassburg, 2011). The current treatment of choice for AIH is prednisone either alone or in combination with azathioprine. Other drugs have shown promise including cyclosporine, tacrolimus, mycophenolic acid, cyclophosphamide, and budesonide, although the efficacy and safety of these drugs has not been proven in large randomized control trials (RCTs; Gluud, Dahl, Al-Rifai, & Prince, 2009; Strassburg, 2010). Glucocorticoids are naturally occurring hormones that decrease inflammation and immune responses when administered at pharmacological doses. Glucocorticoids inhibit leukocyte infiltration at the site of inflammation. They interfere with the mediators of inflammatory response, and the suppression of humoral immune responses (Edmunds, Mayhew, & Bridges, 2009). Prednisone is the most commonly prescribed corticosteroid for AIH. The mechanism of action for prednisone, which is metabolized in the liver, is reduction in leukocyte infiltration at the site of inflammation in addition to inhibiting the mechanism of the body’s inflammatory response. The broad influence of glucocorticoids on intracellular receptors found in most cells in the body in addition to the lymphocytes also contributes to a wide range of side effects, which include gastritis, appetite stimulation, palpitations, Cushing’s syndrome, anxiety, psychosis, diabetes, and osteoporosis. Steroids are categorized in terms of length of action. Prednisone has an intermediate duration of action and is used in many conditions, including allograft rejection, asthma, SLE, and other inflammatory states (Edmunds et al., 2009). The initial dose of prednisone for AIH is 40– 60 mg per day for the first 4 weeks and subsequent tapering dose for 6 months based on clinical response. Prednisone is often used in combination with azathioprine (see Table 3). After a clinical response has been achieved, the usual maintenance dose of prednisone is 5–15 mg per day. Azathioprine is chemically similar to the endogenous purines adenine, guanine, and hypoxanthine, and is an
Drug Therapy
Monotherapy
Combination
Prednis(ol)one
60 mg Reduction by 10 mg/week to Maintenance 20 mg Reduction by 5–10 mg Lowest dose in 2.5 mg N.A. (Maintenance with azathoprine: Monotherapy— 2 mg/kg
30–60 mg Reduction as in monotherapy
Azathioprine
50 mg
Strassburg (2010, p. 674; used with permission).
immunosuppressive drug commonly used in transplant patients. The mechanism of action of azathioprine is believed to be the reduction in the metabolism of purines and possible retardation of DNA and RNA synthesis (Sahasranaman, Howard, & Roy 2008). Azathioprine 150 mg is given daily with prednisone or 2 mg/kg daily if used alone (Loza & Czaja, 2007). The choice of choosing combination or monotherapy to treat AIH is based on the fact that long-term steroid use is associated with many serious side effects. According to Strassburg (2010), 44% and 80% of patients experience serious side effects after 12 and 24 months, respectively, of steroid treatment. The side effects may ultimately negatively impact treatment adherence. When prednisone is used in combination with azathioprine, the total prednisone dose can be reduced. Azathioprine is also used for long administration after remission has been achieved. Remission is defined as the complete resolution of symptoms, histological inflammation, and laboratory indicators (Manns & Strassburg, 2011). Although a majority of patients will experience remission after 6–12 months of therapy with prednisone and azathioprine, about 20–40% of patients do not (Manns & Strassburg, 2011). Patients who do not achieve remission with conventional therapy may benefit from a combination of mycophenolate mofetil either alone or in combination with prednisone. Topically administered budesonide in combination with azathioprine has been shown to be effective in achieving remission in some patients without the side effects of systemic prednisone. However, budesonide has 90% first pass in the liver and so efficacy is questionable in patients who already have advanced liver cirrhosis and portal hypertension (Manns & Strassburg, 2011).
Primary care provider role Primary care providers (PCPs), including NPs, are often the first to diagnose hepatitis. Upon identification of
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Autoimmune hepatitis
elevated liver enzymes, the PCP should commence the initial work up (see Figure 1). If the hepatitis panel is negative, then the PCP should consider ordering an ANA, anti-liver–kidney antibodies (anti-LKM), and antismooth muscle (SMA), while initiating an immediate referral to a hepatologist (preferred) or gastroenterologist (Lohse & Mieli-Vergani, 2011; Strassburg, 2010). The PCP plays a key role in care coordination. Patients often have comorbid conditions, such as diabetes and hyperlipidemia, requiring consultation and closer monitoring. Long-term steroid treatment may negatively impact glucose control and accelerate osteoporosis, necessitating a change in the medication regimen. Additionally and perhaps most importantly, PCPs need to provide ongoing emotional patient support.
Conclusion AIH has historically been considered a rare disease but may have simply been under diagnosed. NPs and other healthcare providers can play pivotal roles in identifying patients who need referral and specialized work up as well as assist with monitoring and treating patient’s other chronic diseases that may be affected by AIH treatment. Access to care is often one of the most challenging issues for PCPs, whether it is financial, geographic, or lack of appropriate providers. Well-informed healthcare providers can reduce barriers by early identification of diseases and conditions that require specialty care and advocate for patients to be seen expeditiously as appropriate. The subtle clinical presentation of AIH can mask this noninfectious killer.
References Athyros, V. G., Tziomalos, K., Gossios, T. D., Griva, T., Anagnostis, P., Kargiotis, K., . . . Mikhailidis, D. P. (2010). Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: A post-hoc analysis. Lancet, 376, 1916–1922. Bayard, M., Holt, J., & Boroughs, E. (2006). Nonalcoholic fatty liver disease. American Family Physician, 73, 1961–1968. Brandhagen, D. J, Fairbanks, V. F., & Baldus, W. (2002). Recognition and management of hereditary hemochromatosis. American Family Physician, 65, 853–860. Copstead, L. C., & Banasik, J. L. (2010). Pathophysiology (4th ed.). Philadelphia: Saunders Elsevier.
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Edmunds, M. W., Mayhew, M. S., & Bridges, C. (2009). Pharmacology for the primary care provider. St. Louis, MO: Mosby Elsevier. Gluud, L. L., Dahl, E. E., Al-Rifai, A., & Prince, M. (2009). Medical treatments for autoimmune hepatitis. Cochrane Database of Systematic Reviews. ´ A., Dalekos, G. N., . . . Lohse, A. Hennes, E. M, Zeniya, M., Czaja, A. J., Pares, W. (2008). Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology, 48, 169–176. Jothimani, D., Cramp, M. E., Mitchell, J. D., & Cross, T. J. S. (2011). Treatment of autoimmune hepatitis: A review of current and evolving therapies. Journal of Gastroenterology, 26, 619–627. Lohse, A. W., & Mieli-Vergani, G. (2011). Autoimmune hepatitis. Journal of Hepatology, 55, 171–82. Loza, A. J. M., & Czaja, A. J. (2007). Current therapy for autoimmune hepatitis. Nature Clinical Practice Gastroenterology & Hepatology, 4, 202–214. Lucena, M. I., Garcia-Cortes, M., Cueto, R., Lopez-Duran, J. L., & Andrade, R. J. (2008). Assessment of drug-induced liver injury in clinical practice. Fundamental & Clinical Pharmacology, 22, 141–158. Manns, M. P., & Strassburg, C. P. (2011). Therapeutic strategies for autoimmune hepatitis. Digestive Diseases, 29, 411–415. McFarlane, I. G. (2002). Definition and classification of autoimmune hepatitis. Seminars in Liver Disease, 22, 317–324. Mieli-Vergani, P., & Vergani, D. (2008). Autoimmune paediatric liver disease. World Journal of Gastroenterology & Hepatology, 14, 3360–3367. Mills, E. J., Wu, P., Chong, G., Ghement, I., Singh, S., Akl, E. A., . . . Briel, M. (2010). Efficacy and safety of statin treatment for cardiovascular disease: A network meta-analysis of 170,255 patients from 76 randomized trials. Quarterly Journal of Medicine, 104, 109–124. National Cholesterol Education Program. National Heart, Lung and Blood Institute. (2002). Third report of the expert panel on detection, evaluation and treatment of high blood cholesterol in adults. (NIH Publication No. 02–5215). Retrieved from http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf Oh, R. C., & Hustead, T. R. (2011). Causes and evaluation of mildly elevated liver transaminase levels. American Family Physician, 84, 1003–1008. Poli, A., Marangoni, F., Avogaro, A., Barba, G., Bellentani, S, Bucci, M., . . . Visioli, F. (2013). Moderate alcohol use and health: A consensus document. Nutrition Metabolic Cardiovascular Disease, 23, 487–504. Sahasranaman, S., Howard, D., & Roy, S. (2008). Clinical pharmacology and pharmacogenetics of thiopurines. European Journal of Clinical Pharmacology, 64, 753–767. Soloway, R. D., & Hewlett, A. T. (2007). The medical treatment for autoimmune hepatitis through corticosteroid to new immunosuppressive agents: A concise review. Annals of Hepatology, 6, 204–207. Strassburg, C. P. (2010). Autoimmune hepatitis. Best Practice & Research Clinical Gastroenterology, 24, 667–682. Suzuki, A., Andrade, R. J., Bjornsson, E., Lucena, M. I., Lee, W. M., Yuen, N. A., . . . Freston, J. W. (2010). Drugs associated with hepatotoxicity and their reporting frequency of liver adverse events in VigiBase. Drug Safety, 33, 503–522. Watkins, P. B., Kaplowitz, N., Slattery, J. T., Colonese, C. R., Colucci, S. V., Stewart, P. W., & Harris, S. C. (2006). Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: A randomized controlled trial. Journal of the American Medical Association, 296, 87–93.
Autoimmune hepatitis: A noninfectious killer Laurie Anne Ferguson, DNP, APRN, FNP (Associate Professor) Loyola University School of Nursing, New Orleans, Louisiana
Keywords Autoimmune disorders; hepatitis; nurse practitioners; primary care. Correspondence Laurie Anne Ferguson, DNP, APRN, FNP, Loyola University, New Orleans, LA. E-mail: [email protected] Received: January 2012; accepted: July 2012 doi: 10.1002/2327-6924.12055
Abstract Purpose: This article reviews autoimmune hepatitis (AIH) to promote early recognition, diagnosis, and referral for nurse practitioners (NPs) encountering this rare condition. Data sources: Selected research and clinical articles from Medline, PubMed, and CINAHL. Conclusions: AIH is a rare condition of unknown etiology affecting women 3.6 times more than men and may result in liver failure, subsequent liver transplantation, and death. Untreated AH is associated with up to 80% mortality. Collaboration and referral to gastroenterologists, hepatologists, and other specialists are needed to improve outcomes for this potentially devastating disease. Implications for practice: Corticosteroid treatment has long been the mainstay of treatment of AIH, although newer therapies are promising. NPs can dramatically improve outcomes by early recognition, diagnosis, referral, and monitoring for common side effects of treatment working collaboratively with specialists.
Introduction Autoimmune hepatitis (AIH) is a rare immunemediated liver disease of unknown etiology, which may result in liver failure, subsequent liver transplantation, or death. Females are affected three times more commonly than males, and if left untreated are associated with up to 80% mortality (Lohse & Mieli-Vergani, 2011; Soloway & Hewlett, 2007). The diagnosis of AIH is frequently illusive and is often made as a diagnosis of exclusion. This article will discuss AIH and implications for nurse practitioners (NPs) to improve early diagnosis and treatment.
Epidemiology and pathophysiology The term hepatitis is defined as an inflammatory condition of the liver (Copstead & Banasik, 2010) and the causes of hepatitis include the more common viral etiologies, such as Hepatitis A, B, D, E as well as cytomegalovirus (CMV) and Epstein–Barr virus. However, hepatitis or liver inflammation may be secondary to drug effects, alcohol, nonalcoholic fatty liver disease (NAFLD), or because of autoimmune responses as seen in AIH (Copstead & Banasik, 2010). ¨ as a AIH was first described in 1950 by Waldenstrom chronic form of hepatitis in young women with jaundice,
elevated gammaglobulins, amenorrhea, and subsequent hepatic cirrhosis (McFarlane, 2002). Subsequent identification of antinuclear antibodies (ANAs) sometimes associated with the condition led to clinical trials establishing the effectiveness of immunosuppression (Lohse & Mieli-Vergani, 2011). AIH has been reported in all age groups, ethnicity, and geographical locations. AIH has a prevalence of at least 1:10,000 in Caucasians and Japanese and predominantly affects women 3:1 (Lohse & Mieli-Vergani, 2011). Previously considered a rare disease, many authorities are suggesting AIH is simply under diagnosed. Rates reported in Western Europe and North America suggest that the prevalence is similar to that of other autoimmune conditions, such as systemic lupus erythematosus (SLE), primary biliary cirrhosis, and myasthenia gravis (Strassburg, 2010). Up to 30% of adult patients with AIH have histological features of cirrhosis upon liver biopsy because of hepatic changes secondary to chronic inflammation (Strassburg, 2010). Diffuse hepatic fibrosis causes subsequent changes in hepatic blood flow and liver function and hepatic failure (Copstead & Banasik, 2010). Fortunately, cirrhosis because of AIH does not prognosticate poor long-term survival as in alcoholic cirrhosis (Strassburg, 2010). Several causative agents have been suggested in the development of AIH. Environmental agents, such as
C 2013 The Author(s) Journal of the American Association of Nurse Practitioners 26 (2014) 13–18
C 2013 American Association of Nurse Practitioners
13
Autoimmune hepatitis
a virus, drug, and vaccines, have been studied; however, no firm link has been established. Human leukocyte antigen (HLA) subtypes have been found in over 50% of patients with AIH, suggesting a genetic predisposition (Lohse & Mieli-Vergani, 2011). AIH has been associated with other autoimmune diseases, including rheumatoid arthritis, thyroiditis, ulcerative colitis, and a family history of allergic disorders (Manns & Strassburg, 2011; Strassburg, 2010). Although a conclusive etiology has not been found, experts suspect some trigger is necessary to initiate the autoimmune hepatic response.
Clinical presentation and diagnosis Patients with AIH are often identified via routine laboratory evaluation especially if the diagnosis is made early in the disease process (Lohse & Mieli-Vergani, 2011). AIH may also present clinically with nonspecific complaints of fatigue, lethargy, and jaundice. Patients presenting with fatigue, nausea, vomiting, anorexia, icterus, darkcolored urine, and pale-colored stools should prompt the healthcare provider to order liver function tests (alanine transaminase [ALT] and aspirate transaminase [AST]). Mildly elevated (less than five time normal) ALT and AST are commonly encountered clinically. Damage at the hepatocellular level releases ALT and AST into the bloodstream. Because ALT is found primarily in the liver, abnormalities in ALT usually reflect liver injury. The ratio of AST/ALT is helpful in identifying disease causality (Oh & Hustead, 2011). Generally an AST/ALT ratio greater than 2 suggests possible alcohol abuse and a ratio of less than one suggests NAFLD (Bayard, Holt, & Boroughs, 2006; Oh & Hustead, 2011). NAFLD is the most common cause of mild elevation of liver enzymes and should be considered in patients with obesity, diabetes, elevated triglycerides, and metabolic syndrome (Oh & Hustead, 2011). A careful history and physical should follow the identification of elevated liver enzymes. The assessment should include occupation, prescription, and over the counter (OTC) medications or supplements and alcohol use to identify patients who have liver injury secondary to chemical or environmental exposure (see Table 1). A standard alcoholic drink is defined as 12 oz beer, 5 oz of wine, or 1.5 oz spirits; alcohol consumption should be no more than two alcoholic drinks per day for men and one for women (Poli et al., 2013). Many drugs are associated with liver injury with acetaminophen being one of the most common drugs. Four grams of acetaminophen per day for as little as 5–10 days has been associated with el14
L. A. Ferguson
Table 1 Common potentially hepatotoxic drugs Acetaminophen Allopurinol Amiodarone Amoxicillin/clavulanic acid Azithromycin Carbamazepine Ciprofloxin Cotrimoxazole Diclofenac Disulfram Enalapril Erythromycin Fluconazole Glyburide Halothane Heparin Isoniazid Kava Ketaconazole Levofloxacin Methotrexate Naproxen Nitrofurantoin Nonsteroidal anti-inflammatory drugs (NSAIDS) Oral contraceptives Phenytoin Protease inhibitors Ranitidine Rifampin Sulfonamides Tetracyclines Valproic acid Note: Adapted from Lucena, Garcia-Cortes, Cueto, Lopez-Duran, and Andrade (2008), Oh and Hustead (2011), Suzuki et al. (2010).
evated ALT and AST among nondrinkers (Watkins et al., 2006). Although statins are commonly associated with liver damage, the evidence supporting causality is not clear (Mills et al., 2010; National Cholesterol Education Program, 2002). Statin therapy is usually safe in patients with mild to moderately elevated transaminase levels and can reduce morbidity from cardiovascular events when elevated liver enzymes are because of NAFLD (Athyros et al., 2010). Patients with elevated ALT and AST should have seriologic testing for Hepatitis B and C. Millions of Americans have undiagnosed Hepatitis B and C. Testing for anti-HBc, HBsAg, and anti-HCV can identify individuals who would benefit by therapeutic interventions. Oh and Hustead (2011) recommend serologic testing for Hepatitis B and C even if repeat liver enzyme testing is normal as Hepatitis C can cause a transient rise in ALT and AST (see Figure 1).
Autoimmune hepatitis
L. A. Ferguson
↑ AST & ALT
History & Physical Assess ETOH* & Drug Use Viral Serology to exclude Hepa
AST/ALT ra o = > 2 – suspect ETOH < 1 – suspect NAFLD
s B and C (an -HBc IgM, HBsAg, an -HCV)
*2 standard alcoholic drinks for men, 1 for women
NO
Yes Remove offending agents and repeat labs 2-4 Weeks
Consider assessing for co-morbid diseases Metabolic Syndrome Hyperlipidemia Thyroid disease Consider liver ultrasonography PT/PTT, Albumin, CBC with platelets ANA, IgG, IgA, IgM
Consider serum iron, ferri n, TIBC and serum transferrin if Hemochromatosis is suspected
Persistent or unexplained ALT and AST eleva on
Chronic Liver Disease or Hepa c decompensa on
Abnormal
Nega ve Workup or consistent with NAFLD
Consulta on Further tes ng
Refer to Hepatology Expedited workup
Lifestyle modifica on Underlying disease treatment Persistent enzyme eleva on Re-evaluate 6 months
Labs normalized or improving then monitor
Refer to Hepatology Persistent enzyme eleva on
Figure 1 Evaluation of elevated liver enzymes. Note: Adapted from Bayard et al. (2006), Brandhagen, Fairbanks, and Baldus (2002), and Oh and Hustead (2011).
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Hemochromatosis is the most common single gene disorder in Caucasians in the U.S. population. Characterized by iron overload, hemochromatosis results in increase iron stores and elevated ALT and AST from liver damage (Brandhagen et al., 2002). Other less common causes of mildly elevated liver transaminase levels include alpha1 antitypsin deficiency and Wilson disease and are beyond the scope of this article.
Diagnosis of AIH Although patients may often be identified via routine laboratory screening, patients with advanced AIH may present with more severe symptoms of liver failure, including portal hypertension, ascites, and encephalopathy. AIH should always be considered a possible cause of liver failure (Manns & Strassburg, 2011). The presence of hypergammaglobulinemia, autoantibodies, histology, and the absence of viral hepatitis markers suggests a diagnosis of AIH (Lohse & Mieli-Vergani, 2011). Screening for hypergammaglobulinemia is cost effective and diagnostic, particularly if immunoglobulin G (IgG) is elevated and immunoglobulin A (IgA) and immunoglobulin M (IgM) are normal. Some patients with AIH may have elevations of IgG in the presence of AIH, but the IgG remains in the normal range because of lower baseline IgG levels (Lohse & Mieli-Vergani, 2011). No single autoantibody test is specific to AIH. ANAs, smooth-muscle antibodies (SMA), and liver–kidney microsomal (LKM) antibodies may be positive but are not disease specific in all cases of AIH (Lohse & Mieli-Vergani, 2011). Soluble liver antigen (SLA) and liver–pancreas antigen (LP) are disease specific and are diagnostic of AIH but may be present in only about 30% of patients with AIH (Lohse & Mieli-Vergani, 2011). Liver biopsy and histological evaluation is necessary to confirm an AIH diagnosis and needs to be evaluated in the presence of hypergammaglobulinemia and autoantibodies (Lohse & Mieli-Vergani, 2011). A revised, more simplified scoring tool was developed in 2008 (Hennes et al., 2008; see Table 2).
Special situations Although a negative hepatitis serology suggests AIH in the presence of other indicators, a few patients may actually present with concomitant viral and AIH (Lohse & Mieli-Vergani, 2011). Patients who have positive viral hepatitis titers and concomitant AIH present both a diagnostic and treatment challenge. Although against conventional wisdom, patients with comorbid AIH and viral hepatitis diagnoses benefit from corticosteroid therapy. AIH should be suspected in patients who have 16
L. A. Ferguson
Table 2 Simplified diagnostic criteria for AIH Variable ANA or SMA ANA or SMA or LKM or SLA IgG
Liver histology (evidence of hepatitis is a necessary condition) Absence of viral hepatitis
Cutoff
Points
≥1:40 ≥1:80 ≥1:40 Positive >Upper normal limit >1.10 times upper normal limit Compatible with AIH Typical AIH Yes
1 2a 1 2 1 2 2 ≥6: Probable AIH ≥7: Definite AIH
Note: Hennes et al. (2008 used with permission). a Addition of point achieved for all autoantibodies (maximum, 2 points).
viral hepatitis and are deteriorating quickly with rapidly rising liver enzymes because the prognosis for untreated AIH is worse than for Hepatitis B and C infections. Therefore, AIH must be carefully histologically confirmed and treatment closely monitored (Lohse & Mieli-Vergani, 2011). Acquired liver disease in children is rare and usually presents more acutely than in adults. Severe druginduced hepatitis and AIH in children may present with more subtle laboratory values even in the presence of severe disease. According to Mieli-Vergani and Vergani (2008), children with symptoms of acute hepatitis often have evidence of chronic liver disease, such as spider nevi, palmar erythema, or striae on physical examination. In about 40% of children with AIH, there is a family history of autoimmune disorders, such as thyroiditis, inflammatory bowel disease, nephritic syndrome, and Type 1 diabetes and vitiligo (Mieli-Vergani & Vergani, 2008). IgG and autoantibodies may not always be elevated initially in acute AIH and hypocoagulopathy may make liver biopsy risky to confirm diagnosis (Lohse & Mieli-Vergani, 2011). However, whether it is drug-induced hepatitis or AIH, the treatment of choice are high-dosed steroids. When immunosuppressive therapy is completed, relapse will not occur in drug-induced hepatitis if the offending drug has been discontinued. However, relapse may occur after discontinuing immunotherapy in AIH, thus, confirming diagnosis. In AIH, IgG levels fluctuate to the corresponding transaminase levels before ultimately converting to autoantibody positive. Lower autoantibody titers thresholds are considered abnormal in the pediatric population. In children, titers of 1:10 LKM and 1:20 ANA and SMA are considered critically elevated (Lohse & Mieli-Vergani, 2011).
Autoimmune hepatitis
L. A. Ferguson
Treatment of AIH
Table 3 Treatment regimen
Patients who clinically are deteriorating may require institution of treatment before laboratory values reach panic levels. Treatment is absolutely indicated when aminotransferase levels exceed 10 times the upper limits of normal, or when both aminotransferase levels are greater than five or when gamma-globulin levels are greater than two times normal (Manns & Strassburg, 2011). Corticosteroids have been used to treat AIH for over 50 years (Jothimani, Cramp, Mitchell, & Cross, 2011). The American Association for the Study of Liver Disease (AASLD) recently published guidelines for the treatment of AIH (Jothimani et al., 2011; Manns & Strassburg, 2011). The current treatment of choice for AIH is prednisone either alone or in combination with azathioprine. Other drugs have shown promise including cyclosporine, tacrolimus, mycophenolic acid, cyclophosphamide, and budesonide, although the efficacy and safety of these drugs has not been proven in large randomized control trials (RCTs; Gluud, Dahl, Al-Rifai, & Prince, 2009; Strassburg, 2010). Glucocorticoids are naturally occurring hormones that decrease inflammation and immune responses when administered at pharmacological doses. Glucocorticoids inhibit leukocyte infiltration at the site of inflammation. They interfere with the mediators of inflammatory response, and the suppression of humoral immune responses (Edmunds, Mayhew, & Bridges, 2009). Prednisone is the most commonly prescribed corticosteroid for AIH. The mechanism of action for prednisone, which is metabolized in the liver, is reduction in leukocyte infiltration at the site of inflammation in addition to inhibiting the mechanism of the body’s inflammatory response. The broad influence of glucocorticoids on intracellular receptors found in most cells in the body in addition to the lymphocytes also contributes to a wide range of side effects, which include gastritis, appetite stimulation, palpitations, Cushing’s syndrome, anxiety, psychosis, diabetes, and osteoporosis. Steroids are categorized in terms of length of action. Prednisone has an intermediate duration of action and is used in many conditions, including allograft rejection, asthma, SLE, and other inflammatory states (Edmunds et al., 2009). The initial dose of prednisone for AIH is 40– 60 mg per day for the first 4 weeks and subsequent tapering dose for 6 months based on clinical response. Prednisone is often used in combination with azathioprine (see Table 3). After a clinical response has been achieved, the usual maintenance dose of prednisone is 5–15 mg per day. Azathioprine is chemically similar to the endogenous purines adenine, guanine, and hypoxanthine, and is an
Drug Therapy
Monotherapy
Combination
Prednis(ol)one
60 mg Reduction by 10 mg/week to Maintenance 20 mg Reduction by 5–10 mg Lowest dose in 2.5 mg N.A. (Maintenance with azathoprine: Monotherapy— 2 mg/kg
30–60 mg Reduction as in monotherapy
Azathioprine
50 mg
Strassburg (2010, p. 674; used with permission).
immunosuppressive drug commonly used in transplant patients. The mechanism of action of azathioprine is believed to be the reduction in the metabolism of purines and possible retardation of DNA and RNA synthesis (Sahasranaman, Howard, & Roy 2008). Azathioprine 150 mg is given daily with prednisone or 2 mg/kg daily if used alone (Loza & Czaja, 2007). The choice of choosing combination or monotherapy to treat AIH is based on the fact that long-term steroid use is associated with many serious side effects. According to Strassburg (2010), 44% and 80% of patients experience serious side effects after 12 and 24 months, respectively, of steroid treatment. The side effects may ultimately negatively impact treatment adherence. When prednisone is used in combination with azathioprine, the total prednisone dose can be reduced. Azathioprine is also used for long administration after remission has been achieved. Remission is defined as the complete resolution of symptoms, histological inflammation, and laboratory indicators (Manns & Strassburg, 2011). Although a majority of patients will experience remission after 6–12 months of therapy with prednisone and azathioprine, about 20–40% of patients do not (Manns & Strassburg, 2011). Patients who do not achieve remission with conventional therapy may benefit from a combination of mycophenolate mofetil either alone or in combination with prednisone. Topically administered budesonide in combination with azathioprine has been shown to be effective in achieving remission in some patients without the side effects of systemic prednisone. However, budesonide has 90% first pass in the liver and so efficacy is questionable in patients who already have advanced liver cirrhosis and portal hypertension (Manns & Strassburg, 2011).
Primary care provider role Primary care providers (PCPs), including NPs, are often the first to diagnose hepatitis. Upon identification of
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Autoimmune hepatitis
elevated liver enzymes, the PCP should commence the initial work up (see Figure 1). If the hepatitis panel is negative, then the PCP should consider ordering an ANA, anti-liver–kidney antibodies (anti-LKM), and antismooth muscle (SMA), while initiating an immediate referral to a hepatologist (preferred) or gastroenterologist (Lohse & Mieli-Vergani, 2011; Strassburg, 2010). The PCP plays a key role in care coordination. Patients often have comorbid conditions, such as diabetes and hyperlipidemia, requiring consultation and closer monitoring. Long-term steroid treatment may negatively impact glucose control and accelerate osteoporosis, necessitating a change in the medication regimen. Additionally and perhaps most importantly, PCPs need to provide ongoing emotional patient support.
Conclusion AIH has historically been considered a rare disease but may have simply been under diagnosed. NPs and other healthcare providers can play pivotal roles in identifying patients who need referral and specialized work up as well as assist with monitoring and treating patient’s other chronic diseases that may be affected by AIH treatment. Access to care is often one of the most challenging issues for PCPs, whether it is financial, geographic, or lack of appropriate providers. Well-informed healthcare providers can reduce barriers by early identification of diseases and conditions that require specialty care and advocate for patients to be seen expeditiously as appropriate. The subtle clinical presentation of AIH can mask this noninfectious killer.
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