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Autoimmune Hepatitis Type 1 Case Study

Abstract

Autoimmune hepatitis (AIH) is a rare autoimmune disorder causing chronic liver inflammation. The disorder, sometimes called lupoid hepatitis, is not well understood because its clinical presentation is highly variable. The liver becomes inflamed due to T-cell-mediated activation of B cells that produce autoantibodies directed against liver antigens. This article details the case of a 28-year-old female patient who was diagnosed with AIH type I almost a decade ago; her therapeutic regimen may serve as a useful model for the disorder. An extensive interview was conducted with the patient. Herein, a timeline of her diagnosis is discussed, and her laboratory results are presented. Currently, she is living a fairly healthy life despite her liver disease. Her most recent liver function test results were completely normal, which is unusual with AIH. The patient was prescribed the immunosuppressive drug azathioprine to treat her AIH shortly after diagnosis. She also began following a vegan diet with unrefined sugar along with regular sleep and exercise. Currently, the patient is taking no azathioprine due to consecutively normal liver function test results over the past few years. Her continued health improvement could be credited to her strict vegan diet.

autoimmune, hepatitis, liver inflammation

Case Study

In May 2001, a 21-year old woman was rushed to a local emergency room in Virginia, after coming home from college with severely jaundiced sclera. According to the patient, her eyes had been yellow for a few days, which she attributed to allergies. She reported feeling healthy except for slight pruritus (ie, intense itching) on the backs of her hands. Test results revealed extremely high serum liver enzyme levels and elevated serum total and direct bilirubin levels; small quantities of bilirubin were found in her urine (Table 1).

Laboratory Results From May 2001

Table 1.

Laboratory Results From May 2001

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Results of ultrasound imaging of her abdomen were unremarkable. The patient was questioned extensively about her lifestyle and her sexual history. She indicated that she was not sexually active, did not have a history of drug abuse, and consumed very little alcohol. She had not recently been out of the country and denied any deviations from her normal diet. Her medical history revealed that she was a young adult woman who had been extremely healthy and active before this admission to the hospital. The patient insisted that other than the pruritus on her hands, she felt well. She was discharged; in a few days, the jaundice disappeared. She was given a probable diagnosis of acute viral hepatitis.

In August 2001, the patient developed extreme joint pain. She was evaluated for rheumatoid arthritis; the results were negative. In December 2001, the pruritus on her hands returned. Blood work revealed that her liver enzymes remained extremely high but her bilirubin and albumin were within normal limits (Table 2). A liver biopsy was ordered; the results revealed lymphocytic infiltration, eosinophils, and plasma cells in the portal regions, with inflammatory cells (ie, neutrophils, macrophages, monocytes, eosinophils, and basophils) in the sinusoids. Scattered hepatic cell necrosis was also observed. There was evidence of scarring suggesting gradual progress of the disease. The scarred tissue was categorized at stage 2, with some parts categorized as stage 3 on a scale of 1 to 4. Test results for cytomegalovirus, Epstein-Barr virus, and hepatitis A, B, and C were negative. Antinuclear antibody (ANA) was detected in the liver tissue extracts, with a titer of 1:160 (>1:80 indicated abnormal levels); also, a speckled ANA pattern was observed. The biopsy and antibody screening results indicated chronic hepatitis of autoimmune origin (oral communication with the patient, March 2009).

Laboratory Results From December 2001

Table 2.

Laboratory Results From December 2001

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Overview of the Liver

The liver is the largest internal organ in the human body1; any substance that enters the bloodstream will pass through the liver. The functions performed by the liver are numerous and essential for survival. The vital functions of this organ include synthesis of proteins such as albumin, transferrin, and complement; the synthesis, storage, and lysis (ie, retrieval) of fats and carbohydrates for energy production; synthesis of bile acids and bilirubin; storage of vitamins and minerals; and metabolism and removal of toxins.

MedicineNet.com refers to the liver as the “biochemical factory of the body.”2 The structural organization of the liver includes the left, right, caudate, and quadrate lobes. The microscopic organizational unit of the liver is the acinus.1 The acini are further divided into zones I, II, or III, with each zone having different functions to regulate blood flow through the liver. Microscopic tubules called canaliculi are found throughout the liver and transport bile to the gallbladder for storage. Bile is prepared in the individual parenchymal cells of the liver, known as the hepatocytes. The hepatic blood supply is delivered via 2 routes, namely, the hepatic artery and the portal vein. The hepatic artery delivers oxygenated blood from the lungs, and the portal vein carries nutrients other substances absorbed from the intestine. Blood from the hepatic artery combines with blood from the portal vein in a network of tiny blood vessels called sinusoids.2

Liver disease results when these functions are not occurring normally. However, the liver has substantial functional reserve, and significant damage must occur before liver impairment is clinically evident. Abnormally elevated levels of liver enzymes and proteins are suggestive of liver disease. Autoantibodies such as ANAs or smooth muscle antibodies (SMAs) against liver antigens can reflect autoimmune liver disease.1 The type of antibodies against the liver are used to indicate the presence and type of autoimmune hepatitis (AIH). For proper, accurate diagnosis of AIH, a liver biopsy should be performed to assess the stage of hepatic tissue necrosis and/or cirrhosis. Early diagnosis and treatment of AIH improves the chance of the liver being able to regenerate healthy tissue.2

Overview of Autoimmune Disease

Autoimmune disease is a group of disorders in which the immune system produces antibodies against healthy organs and tissues. Currently, there are more than 80 different diseases known to be autoimmune.3 The liver was one of the first organs recognized to be targeted by autoantibodies.4 In 1950, Waldenström described an inflamed liver due to an unknown cause that produced hypergammaglobulinemia and cirrhosis; he called this inflammation chronic active or active chronic hepatitis and believed it to result from a previous liver infection. However, in the 1960s it was observed that there were no prerequisites for the contraction of chronic active hepatitis. Then, in 1972, shortly after the discovery of the encoding of the HLA genes that are part of the major histocompatibility complex, it was discovered that patients with the disease had an increased frequency of HLA-DRB1 (GenBank: JX667743.1), a particular locus allele gene set.5 This observation suggested that autoimmunity was a factor in these individuals. Some of the antigens against which the autoantibodies are produced have been identified.6 Today, Waldenström's chronic active hepatitis is known as AIH.

AIH affects approximately 0.1 to 1.2 of every 100 000 individuals.7 It occurs due to a CD4+ T-cell mediated series of events acting against a peptide expressed in the liver. This series of events begins when a naïve CD4+ T-helper cell detects a liver peptide it does not recognize as belonging to “self.” The T-helper cell becomes activated, differentiating and producing cytokines.4 The T-helper cell differentiates into several types of cells. The Th1 cells activate macrophages, enhance HLA class I expression, and induce HLA class II expression on the surface of liver cells. This increases the exposure of the liver cells to CD+8 cytotoxic attack. The Th2 cells handle autoantibody production.8 Regulation of self-recognition is controlled by CD+4CD+25 T cells; failure of this regulation allows for the autoimmune response.4 It is thought that environmental causes trigger the CD4+CD+25 T cells to fail. However, this only becomes a problem in individuals who are genetically predisposed toward this outcome.6 Most affected individuals are female, with HLA-DRB1 *0301 (GenBank Accession NM_022555) HLA-DRB1 *0401 (GenBank Accession AF 035803), and HLA-DRB3 *0101 (GenBank Accession AF 152844) haplotypes.7 Untreated, AIH can result in cirrhosis and liver failure.9 AIH is a chronic, often lifelong disease characterized by increased autoantibodies in circulation and inflammation around the portal vein. The disease has a variable presentation. Because of increasing and decreasing immunological activity, it makes AIH difficult to diagnose. The disease does not have unique histological characteristics; it is histologically similar to other chronic liver diseases.10 Common signs and symptoms of AIH include fatigue, malaise, arthralgia, abdominal pain, and pruritus of the hands. Laboratory findings include increased levels of the serum globulins, aminotransferases, and alkaline phosphatase, and prolonged partial thromboplastin time, typically without hyperbilirubinemia. AIH responds to corticosteroid and other immunosuppressive therapy, but is not currently curable. With proper management, remission of symptoms can be achieved, and further damage to the liver can be halted.11

Subtypes of AIH

AIH is grouped into types I, II, and III.12 Type I is the most common, followed by type II and type III; all 3 types mainly affect females. Type I and III are usually diagnosed in females in their teens to mid-thirties, whereas type II is often diagnosed in childhood. The clinical severities of AIH vary with each patient; however, the clinical presentations of the 3 types are similar.

The 3 types differ only by the autoantibodies that are present. Autoantibodies associated with type I AIH are ANAs and SMAs. In type II AIH autoantibodies are anti– liver/kidney microsome 1 (LKM1), and anti–liver cytosol 1 (LC1). The type III AIH autoantibodies react with the soluble liver antigen (SLA).13Table 3 compares the 3 types of AIH.

Characteristics of Autoimmune Hepatitis, Types I to III6,7

Table 3.

Characteristics of Autoimmune Hepatitis, Types I to III6,7

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Diagnosis and Treatment of the Patient

The patient was diagnosed with AIH, type I, in January 2002. Her diagnosis was based on her increased levels of serum aminotransferases, biopsy results, and positive ANA titer of 1:160 with a speckled pattern. She was immediately started on corticosteroid treatment (prednisone, 50 mg per day). Corticosteroids block the synthesis of lymphokines and cytokines, inhibiting the T-cell response and decreasing the numbers of T and B cells in circulation. The immmunosuppressive drug azathioprine was added to the patient's regimen (100 mg/d); the drug inhibits purine synthesis, suppressing DNA, RNA and protein synthesis.1 After one month on this regimen, her liver function test results (Table 4) were close to normal. When an individual is taking azathioprine, the white-blood-cell count should be monitored on a regular basis to prevent possible bone marrow malfunction.1 After having taken azathioprine for 1 month, the patient's white blood cell count was 9.30 × 109 cells/mL (normal range, 4.00-11.00 × 109 cells/mL).

Laboratory Results From January 2002

Table 4.

Laboratory Results From January 2002

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Although the patient was advised that a change in diet was unnecessary, the patient began a vegetarian diet. The patient's health seemed to be improving until she began feeling adverse effects from the prednisone. The adverse effects of this drug include loss of appetite, menstrual period irregularities, gastrointestinal upset, sore throat, malaise, headache, fever, depression, dizziness, lethargy, exaggerated sense of well-being, mood swings, personality changes, thinning of bones, thinning of hair and skin, puffing of the face, swelling of feet and/or legs, weight gain, or weight loss.9 The patient experienced moderate-to-severe side effects ranging from loss of appetite to chronic sore throat and swelling of the extremities.

Following the cessation of prednisone therapy, the patient's immune system became hyperactive; small cuts and mosquito bites would swell to abnormal sizes and would not heal. In July 2003, the patient began relapsing into AIH symptoms. Her laboratory results indicated normal values except for a high eosinophil count and a low neutrophil count. These abnormal cell counts could be responsible for her exaggerated immune reactions to the small cuts and mosquito bites. Eosinophils are released during allergic reactions. What triggered the release of eosinophils in the patient is unknown. The low neutrophil count might have been due to immunosuppressive therapy. After the patient's relapse, she was diagnosed with depression. Bupropion hydrochloride (Wellbutrin, GlaxoSmithKline, London, England) was prescribed to treat her depression.

In August 2003, the patient suffered an anaphylactic-like reaction in which her throat and tongue swelled enough to hinder breathing; the reaction was attributed to the bupropion hydrochloride. The patient was switched to sertraline hydrochloride (Zoloft, Pfizer Inc, New York, NY) for treatment of her depression. Within the next year, she suffered 2 more episodes of this anaphylactic-like reaction; the cause of these episodes was never confirmed. Through the end of 2003 and the year 2004, the patient experienced poor health. She reported feeling very tired, experiencing lethargy, and becoming more depressed. She was still suffering adverse effects of prednisone and azathioprine. The adverse effects of azathiopurine, namely, occasional hoarseness and a sore throat were not as severe as those from prednisone. The patient converted to a vegan diet, which does not contain meat, poultry, eggs, fish, or dairy.14 this change was made without recommendation from a physician. Another dietary change she made was a switch to unrefined sugar. The patient stated that she wanted to give her liver the simplest nourishment to process so that it had a chance to recover (oral communication with the patient, March 2009).

At the beginning of 2005, the patient's health showed improvement. Her liver-function test results were within the normal range. She had a second biopsy performed in February 2006, the results of which showed inflammatory cell infiltrates composed of lymphocytes but few plasma cells or eosinophils. The sinusoids were slightly dilated, and no cellular necrosis was observed; mild fibrosis was observed. ANA results remained positive at a titer of 1:80, rather than 1:160, as had been the case 2 years earlier. Results of the patient's liver function test are shown in Table 5.

Laboratory Results from February 2006

Table 5.

Laboratory Results from February 2006

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Vegan diets are typically higher in vitamins C and E, folic acid, fiber, magnesium, potassium, phytochemicals, and unsaturated fats than typical non-vegan diets. Vegan diets are low in vitamin D, protein, retinol, vitamin B12, calcium, and zinc. Many foods are fortified with these nutrients; however, supplements must often be taken to achieve a healthy, balanced diet.15

During the next year, the patient's overall health improved. Her laboratory results returned to normal. She continued to follow her vegan diet strictly. In June 2007, the patient experienced another anaphylactic-like reaction along with urticaria. A brief course of prednisone was prescribed, which cleared up the rash. The patient had taken naproxen sodium before the urticaria occurred; however, she had taken the anti-inflammatory drug on several previous occasions without adverse effects. Her case of hives was attributed to the unstable functioning of her immune system.

In May 2008, the patient was assessed as being in remission from her disease. Results of her liver function test for an 8-year period can be seen in Figure 1, Figure 2, and Figure 3).

Figure 1

Adverse effects of prednisone (50 mg/day) experienced by the patient between January 2002 and December 2004.

Figure 1

Adverse effects of prednisone (50 mg/day) experienced by the patient between January 2002 and December 2004.

Abstract

Background

Autoimmune hepatitis (AIH) is a chronic inflammatory disease of the liver with nonspecific clinical manifestations that causes greater liver damage in children than in adults.

Aims

To analyze the clinical progression, biochemical profiles, histopathologic changes, and treatment response in 20 children with AIH.

Material and methods

A retrospective study was carried out on the variables associated with clinical progression, diagnosis, and treatment response in children seen at the the Unidad Médica de Alta Especialidad (UMAE) No. 71 IMSS in Torreón, Coahuila, Mexico, from 1992 to 2012.

Results

Twenty patients were analyzed, 75% with type 1 AIH (AIH-1) and 25% with type 2 AIH (AIH-2). Girls predominated with a 3:1 ratio of girls to boys. The mean age was 10.07 ± 6.53 years for the AIH-1 cases and 6.75 ± 3.77 years for the AIH-2 cases. There was an association with immunologic diseases in 40% of the patients.

The patients in the AIH-2 group had greater biochemical profile alterations and IgA deficiency. Anti-nuclear antibody and anti-smooth muscle antibody were positive in 100% of the patients with AIH-1, and anti-liver kidney microsomal type 1 antibody was positive in 100% of the AIH-2 patients. Liver biopsy revealed interface hepatitis in both groups. The AIH-2 group responded more quickly to treatment, but had a higher recurrence rate.

Conclusions

Autoimmune hepatitis in the pediatric patient should be suspected in order to make an early diagnosis and thereby establish opportune treatment. Determining the type of AIH is necessary for making adequate diagnosis and for achieving a better outcome in relation to recurrence and complication rates.

Resumen

Antecedentes

La hepatitis autoinmune (HAI) es una enfermedad inflamatoria crónica del hígado con manifestaciones clínicas inespecíficas y mayor daño hepático en niños que en adultos.

Objetivo

Analizar la evolución clínica, los perfiles bioquímicos, los cambios histopatológicos y la respuesta al tratamiento de 20 niños con HAI.

Material y métodos

Estudio retrospectivo de las variables asociadas a evolución clínica, diagnóstico y respuesta al tratamiento en niños atendidos en la UMAE n.° 71 IMSS Torreón, Coahuila, México, en el período comprendido entre 1992 y 2012.

Resultados

Se analizó a 20 pacientes, el 75% con HAI-1 y el 25% con HA1-2. Se observó predominio del sexo femenino 3:1. La edad promedio ± desviación estándar fue de 10.07 ± 6.53 años para HAI-1 y de 6.75 ± 3.77 para HAI-2. La asociación a enfermedades inmunológicas fue del 40%.

Los pacientes del grupo HAI-2 mostraron mayores alteraciones en su perfil bioquímico y deficiencia de IgA. La positividad para anticuerpos antinucleares y anticuerpos antimúsculo liso fue del 100% en los pacientes con HAI-1, anticuerpos antimicrosomales para hígado y riñón tipo 1 en el 100% de HAI-2. Las biopsias hepáticas mostraron hepatitis de interfase en ambos grupos. Los pacientes del grupo HAI-2 respondieron más rápidamente al tratamiento y tuvieron mayor tasa de recaídas.

Conclusiones

Es necesario sospechar la HAI en pediatría para poder realizar un diagnóstico temprano y así establecer el tratamiento oportuno. Determinar el tipo de HAI nos permitirá establecer el diagnóstico adecuado y elaborar un mejor pronóstico respecto a tasas de recaídas y complicaciones.