MEDICAL STUDENT REPORT

Arthritis, Eosinophilia, and Autoimmune Liver DiseaseA Diagnostic Challenge

Júlia Boechat Farani,* Carolina Berzoini Albuquerque,* Juliano Machado de Oliveira, MD, MSc,†Emílio Augusto Campos Pereira de Assis, MD,‡ Eduardo de Oliveira Ayres Pinto, MD,*

and Herval de Lacerda Bonfante, MD, PhD*§

Abstract: Autoimmune hepatitis (AIH) is a chronic liver disease of un-known etiology. It is composed of immune-mediated liver injury and sig-nificant immunological aspects. Arthritis can be observed in patientswith AIH before recognition of the disease, which can lead to a diagnosticchallenge. Although there are few reported cases in literature, peripheralblood eosinophilia might also play a part in such diagnosis. We report anintriguing case of a 41-year-old man who presented to our service with ar-thritis and eosinophilia as initial manifestations and was eventually diag-nosed with overlap syndrome: AIH and primary sclerosing cholangitis.The present report aims to include eosinophilia among the clinical featuresof AIH, highlighting the possibility of its detection before the onset of ei-ther articular or hepatic disturbances.

Key Words: autoimmune hepatitis, arthritis, eosinophilia

(J Clin Rheumatol 2015;21: 95–98)

A rthritis is an inflammatory condition encountered in a widerange of diseases, whose etiologies include autoimmunity.1

In the presence of arthritis of uncertain etiology, a careful investi-gation for other clinical and laboratory abnormalities may contrib-ute to the diagnosis.2 In our case, eosinophilia was an intriguingassociated finding, which lead to extensive investigation.

Autoimmune hepatitis (AIH) is an idiopathic inflammatoryliver disorder characterized by seropositivity of autoantibodies,hypergammaglobulinemia, and elevated transaminase levels.3 Au-toimmune hepatitis is responsible for up to 20% of chronic hepa-titis in Western countries and has a point prevalence of 16.9 and amean annual incidence of 1.9 per 100,000 individuals in a north-ern European population.4

Based on autoantibody profiles, AIH has been categorizedinto 2 subtypes: type 1, which is associated with either antinuclearantibodies (ANAs) or anti–smooth muscle antibodies (SMAs) orboth, and less commonly type 2, which is associated with the pres-ence of either anti–liver-kidney microsomal antibody type 1 and/or anti–liver-cytosol type 1.3

As far as we are concerned, there are few reported cases ofAIH presenting with peripheral blood eosinophilia.5 Hereafter

From the *Division of Rheumatology, Hospital Santa Casa de Misericórdiade Juiz de Fora (SCMJF); †Department of Internal Medicine, School ofMedical Sciences and Health of Juiz de Fora (SUPREMA) and FederalUniversity of Juiz de Fora; ‡Department of Pathology, School of Med-ical Sciences and Health of Juiz de Fora (SUPREMA); §Department ofPharmacology, Federal University of Juiz de Fora, Juiz de Fora, MinasGerais, Brazil.

J.B.F. and C.B.A. are undergraduate students in the School ofMedicine, FederalUniversity of Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil.

The authors declared no potential conflicts of interest. This work did not receiveany financial, organizational, pharmaceutical or industry support.

Correspondence: Herval de Lacerda Bonfante, MD, PhD, Department ofPharmacology, Federal University of Juiz de Fora (UFJF), José LourençoKelmer, s/n, Campus Universitário, São Pedro, Juiz de Fora, Minas Gerais,Brazil. E-mail: herval.bonfante@ufjf.edu.br.

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we explore a case in which eosinophilia was the initial feature ofthe clinical presentation.

CASE REPORTA 41-year-old man from the Southeast region of Brazil pre-

sented to our clinic because of an acute episode of bilateral plantarpain, which was attributed to plantar fasciitis and treated withdiclofenac 150mg/d. Despite the ensuing pain relief, 2 weeks laterthe emergence of bilateral arthritis of interphalangeal joints of thehands was noticed, as well as episodes of evening fever rangingbetween 38°C and 39°C.

There was no history of recent travel; exposure to medica-tions, alcohol, or tobacco; blood transfusions; or weight loss. Healso denied any comorbidities or autoimmune disorders in thefamily, and there was no relevant information in the medical his-tory. Physical examination confirmed arthritis of the second, third,and fifth proximal interphalangeal joints of both hands; therewere no skin lesions, jaundice, abdominal pain, or any other sig-nificant changes. The nonsteroidal anti-inflammatory drug wassuspended, and he was administered prednisolone 20 mg/d, withremission of the joint condition and disappearance of fever.

Initial laboratory investigation revealed a global leukocytecount of 13,800/μL (reference range, 4000–10,000/μL), with anoteworthy absolute eosinophil count of 4968/μL (40–600/μL).There was elevated serum immunoglobulin G (IgG) 2480 mg/dL(751–1560 mg/dL) and inflammatory markers: erythrocyte sedi-mentation rate (ESR) 55 mm/h (0–15 mm/h) and C-reactive pro-tein (CRP) 2.58 mg/dL (<0.5 mg/dL). Immunological workupshowed positive ANA to a titer of 1:2560 (homogeneous pattern),but the following tests were negative: SMA, anti-DNA, anti-Smith, anti-SSA, anti-SSB, rheumatoid factor, and anti–cycliccitrullinated peptide. Serology for hepatitis B and C was negative,in addition to tests for syphilis, HIV, parvovirus B19, Epstein-Barrvirus, cytomegalovirus, and intestinal parasites. The remainingdata are shown in Table 1. Radiological evaluation of the handsshowed no abnormalities.

In the following weeks, there were alternate episodes of ar-thritis of the hands and migratory joint pain in shoulders, elbows,wrists, and knees, which improved with the use of prednisolonein the doses mentioned previously. Fever was sporadic and alsoyielded with medication. Follow-up examinations showed persis-tent eosinophilia.

Despite extensive clinical investigation, no conclusive diag-nosis was reached. The dosage of prednisolone was maintainedat 10 mg/d, combined with sulfasalazine 1 g/d and subsequently2 g/d. Afterward, an attempt of dose reduction and discontinua-tion of corticosteroid was followed by resurgence of the symp-toms, despite the use of sulfasalazine.

Four months later, new laboratory data surprisingly showedslightly increased liver enzymes: alanine aminotransferase (ALT)67 U/L (reference, <45 U/L), aspartate aminotransferase (AST)70 U/L (reference, <39 U/L), and γ-glutamyl transferase (GGT)157 U/L (reference, <55 U/L), as presented in Table 1. The patient

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TABLE 1. Laboratory Trend Before/After Immunosuppressive and UDCA Treatmenta

Laboratory Test Month 0 Month 4 Month 8 Month 12 Month 24 Reference Range

Hb, g/dL 15.1 15.6 15.2 14.9 14.6 13–18WBC, /μL 13,800 9300 13,700 12,200 9.800 4000–10,000Abs Eos, /μL 4968 1302 137 122 128 40–600ESR (after 1 h), mm/h 55 45 26 6 12 0–15CRP, mg/dL 2.58 1.51 0.76 0.58 0.62 <0.5IgG, mg/dL 2480 3180 1840 1622 1580 751–1560ANA (titer) 1:2560 (HP) 1:640 (HP) — 1:640 (HP) — NegativeP-ANCA (titer) Negative — — 1:160 — NegativeAST, U/L 42 70 34 33 30 11–39ALT, U/L 48 67 33 35 35 11–45GGT, U/L — 157 159 166 52 <55ALP, U/L — 140 86 83 85 27–100Total bilirubin — — 0.96 0.96 0,9 ≤1.2Direct bilirubin — — 0.4 0.4 0,3 ≤0.4

Institution of immunosuppressive treatment took place between months 4 and 8. Institution of ursodeoxycholic acid (UDCA) took place betweenmonths 12 and 24.

Hb indicates hemoglobin level; WBC, white blood cell count; Abs Eos, absolute eosinophil count; HP, homogeneous pattern; ALP, alkaline phosphatase.

Farani et al JCR: Journal of Clinical Rheumatology • Volume 21, Number 2, March 2015

was then referred to the gastroenterology service, and after wideresearch, it was decided for a percutaneous liver biopsy.

The histopathologic report disclosed an unsuspected chronicactive liver disease, with the presence of moderate portal inflam-matory infiltrate of lymphocytes, plasma cells, and eosinophilsdamaging the parenchyma; lymphoid follicles with reactive ger-minal center and foci of lobular inflammatory activity; giant cellhepatocytes; mild intrahepatocyte cholestasis; ductular prolifera-tion with aggression to the epithelium; portal tract with concen-tric periductal “onion skin” fibrosis; and focal macrovesicularsteatosis (Figs. 1 and 2).

In association with our patient’s clinical, biochemical, andserological parameters, the typical histological pattern suggestiveof AIH despite biliary injury led to the definite diagnosis ofAIH by the revised criteria of the International Autoimmune Hep-atitis Group (Table 2).6 Hewas administered azathioprine 2 mg/kgper day, and prednisolone was increased to 40 mg/d. In 3 weeks,

FIGURE 1. Liver biopsy revealed typical findings of AIH(hematoxylin-eosin stain). A, Moderate lymphocyticinflammatory infiltrate and formation of lymphoid follicle (arrow),with reactive germinal center. B, Detail at higher magnificationshowing lymphocytes and plasma cells attacking the parenchyma.C, Giant cell hepatocyte with intrahepatocyte mild cholestasis.Color available online only at www.jclinrheum.com.

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he developed hepatotoxicity to azathioprine, defined by elevationof liver enzymes associated to nausea, vomiting, and pain onthe right upper quadrant of the abdomen. Such signs recoveredafter drug withdrawal. Rechallenge of azathioprine after 2 weekstriggered again the previous signs. Given the unavailability ofthiopurine methyltransferase measure, the patient was consideredclinically intolerant to azathioprine, which was replaced by myco-phenolate mofetil (MMF) 1 g/d and later 2 g/d.

On the eighth month of the clinical course, after about3 months of treatment, follow-up tests revealed normalization ofeosinophil count (137/μL), as well as ALT and AST, and signifi-cant reduction of IgG and inflammatory activity (CRP and ESR)(Table 1). These data reinforced the definite diagnosis of AIH ac-cording to the concept of response to therapy (Table 2).

After 12 months of evolution, our patient was still takingMMF 2 g/d and prednisolone with reduced dose to 10 mg/d,whichmaintained remission of joint symptoms. New radiographic

FIGURE 2. Liver biopsy also revealed involvement of the biliarybranch, which suggests AIH-PSC overlap syndrome. A.Inflammatory infiltrate and ductular proliferation (arrows)(hematoxylin-eosin stain). B, Portal tract with inflammatorydamage to the bile duct and concentric periductal “onion skin”fibrosis (hematoxylin-eosin stain). C, Gomori trichrome stainhighlighting the degree of concentric periductal fibrosis. Coloravailable online only at www.jclinrheum.com.

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TABLE 2. Revised Diagnostic Criteria for the Diagnosis of AIHand Patient’s Score

Parameter Score Patient’s Points

GenderFemale +2Male 0 0

ALP:AST (or ALT) ratio>3.0 −21.5–3.0 0<1.5 +2 +2

Serum globulins or IgG (times uppernormal limit)>2.0 +3 +31.5–2.0 +21.0–1.5 +1<1.0 0

ANA, SMA, or LKM-1>1:80 +3 +31:80 +21:40 +1<1:40 0

AMAPositive −4Negative 0

Seropositivity for other definedautoantibodiesP-ANCA, anti–LC-1, anti-SLA/LP,anti-ASGPR, antisulfatide

+2 +2

Hepatitis viral markersPositive −3Negative +3 +3

Drug historyPositive −4Negative +1 +1

Average alcohol intake<25 g/d +2 +2>60 g/d −2

Genetic factors: HLADR3or HLADR4Positive +1

Other autoimmune diseasesPositive +2

Liver histologyInterface hepatitis +3 +3Predominantly lymphoplasmacyticinfiltrate

+1 +1

Rosetting of liver cells +1None of the above −5Biliary changes −3 −3Other changes −3

TABLE 2. (Continued)

Total = 17Response to therapyComplete +2 +2Remission with relapse +3

Total = 19

Interpretation of aggregate scores: pretreatment: definite AIH >15,probable AIH 10–15. Posttreatment: definite AIH >17; probable AIH12–17.

ALP indicates alkaline phosphatase; AMA: antimitochondrial anti-bodies; LKM-1, liver-kidney microsomal 1 antibody; SLA, soluble liverantigen; anti–LC-1, antibodies to liver-cytosol type 1; anti–SLA/LP, auto-antibodies to soluble liver antigen/liver pancreas antigen; anti-ASGPR,antibodies to the asialoglycoprotein receptor.

Adapted from Alvarez et al.6

JCR: Journal of Clinical Rheumatology • Volume 21, Number 2, March 2015 Arthritis, Eosinophilia, and Autoimmune Liver Disease

studies of the hands did not show abnormalities. However, persis-tence of increased serum GGT levels was noticed, which led tothe hypothesis of AIH and primary sclerosing cholangitis (PSC)overlap syndrome (AIH-PSC overlap). Besides the positiveANA and elevated IgG levels, the presence of perinuclearantineutrophil cytoplasmic antibody (P-ANCA) with titration of1:160 stood out (Table 1). A targeted review of the sample of liver

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tissue strengthened the findings of biliary lesions, despite thepredominance of inflammatory lesions characteristic of AIH. Thepatient underwent a colonoscopy to rule out association of ulcera-tive colitis with PSC, which is a common finding in male patients,but macroscopically and microscopically normal results were ob-served. Magnetic resonance cholangiography was performed, andit revealed minimal ectasia of left biliary tract with reduced caliberof left hepatic duct. In view of these findings, our patient was thenadministered ursodeoxycholic acid (UDCA) 15 mg/kg per day,with subsequent progressive decline of GGT levels.

DISCUSSIONAutoimmune hepatitis constitutes a disease with a wide

range of clinical manifestations, including the presence of arthri-tis. When compared with rheumatic diseases, there are similar-ities regarding serological markers, genetic predisposition, andpathogenic mechanisms.1,2

Although only a few studies describe rheumatic manifes-tations of AIH, it is nonetheless possible to link impaired liverfunction with the circulation of immune complexes and the con-sequent emergence of joint symptoms, which often precede theonset of signs of liver disorder and may therefore mask the under-lying etiology.1 Polyarthralgia and, less commonly, polyarthritisof large and small joints are observed in 25% to 50% of AIHpatients.7

The diagnostic challenge can be explained by the absenceof findings suggesting liver injury in the early presentation, be-sides the detection of eosinophilia and elevated IgG levels, whichdeviated the initial focus of our investigation.

At first, several hypotheses have been suggested, includingrheumatoid arthritis and systemic lupus erythematosus (SLE).Rheumatoid arthritis was suspected because of the bilateral in-volvement of small joints of the hands; nevertheless, arthritiswas episodic, and rheumatoid factor and anti–cyclic citrullinatedpeptide were negative. As for the SLE, it constitutes a major dif-ferential diagnosis of AIH, because 10% of patients with AIHmeet criteria for SLE.1,2 However, this was not the case in our pa-tient, because he met only 2 (arthritis and reagent ANA) of the 11criteria established by the American College of Rheumatology.8

In our case, the notable eosinophilia represented a challengefor early diagnosis. The spectrum of diseases involving arthritiswith a peripheral blood eosinophilia includes rheumatoid arthritis,vasculitis, parasitic infections, hematological malignancy, atopy,and drugs. Chowdry et al5 previously found only 4 cases thatdiscussed the association of AIH with eosinophilia, including that

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Farani et al JCR: Journal of Clinical Rheumatology • Volume 21, Number 2, March 2015

in their own report, in which eosinophilia was an isolated finding.In the other 3 cases, AIH was associated with other autoimmuneconditions. It is also remarkable that, even thoughAIH ismost fre-quently found in women (4:1 ratio), our report deals with a malepatient. Significantly, from the 4 patients described by Chowdryet al,5 3 were also men, which leads us to question whether eosin-ophilia in AIH is somehow a male-related characteristic. Regard-ing other autoimmune liver conditions, primary biliary cirrhosis isanother disease in which eosinophilia is a common and distinctivefeature and should be considered as differential diagnosis.9

Another aspect to be highlighted is the previous use ofdiclofenac, a potentially hepatotoxic drug, which is described amongthe possible triggers for the presentation of AIH.10 Notwithstand-ing, a review of previous routine tests detected both elevatedaminotransferases and eosinophilia prior to the use of the drug.

As for the formation of autoantibodies, this is usually associ-ated with hepatic disease, because the liver plays a major role inregulating immune response. Among the autoantibodies foundin our patient, ANA has been identified in type 1 AIH, althoughit is not specific; no pattern is dominant, but the homogeneousis the most typical. The absence of SMA does not exclude thediagnosis, as ANA is the only marker for AIH in 13% to 15%of patients.11 Another antibody found was P-ANCA, which is as-sociated to type 1 AIH, primary biliary cirrhosis, and PSC; it is amarker of severity and reflects a greater possibility of evolutionto cirrhosis.12

Our patient has type 1 AIH, marked by the presence of ANAand P-ANCA. A validated score confirmed definite diagnosis ofAIH, as shown in Table 2.6

Liver biopsy is essential for the diagnosis and severity as-sessment, which cannot be predicted by elevation of amino-transferases. It is, moreover, indispensable for the diagnosis ofoverlapping syndromes.13 In our case, inflammatory changes inthe bile ducts, corroborated by the presence of P-ANCA, initiallevels of canalicular enzymes, and male sex suggested the pres-ence of overlapping PSC (Fig. 2).14

The combination of histological evidence of hepatitis andelevated transaminases and serum IgG is an indication for treat-ment. Therefore, the patient was administered standard treatmentwith glucocorticoid and azathioprine. Treatment should be initi-ated when signs of inflammatory activity and elevation of γ-globulin are associated to histological changes.13

Complications of treatment with azathioprine affect 5% to10% of patients with AIH.13 In case of intolerance to azathioprine,which is our patient’s case, one of the preferred options is low-dose glucocorticoid in association with MMF, which selectivelyinhibits the proliferation of active lymphocytes.15 After approxi-mately 3 months of such therapy, the patient’s response was ade-quate. Besides the improvement of the joint disorder, there wasnormalization of AST and ALT, as well as decrease in IgG levels,indicating a reduction in hepatocellular inflammatory activity.

Nevertheless, persistence of increased serum GGT levelsand new magnetic resonance cholangiography findings compati-ble with AIH-PSC overlap syndrome led to adjustment of ther-apy and introduction of UDCA, which was followed by goodresponse, with progressive decline of GGT. Despite the favorableinitial evolution of our patient, PSC overlap to AIH worsens theprognosis of long-term liver autoimmune diseases, with greaterpossibility of cirrhosis despite adequate therapy. 14

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KEY POINTS

• Arthralgia and arthritis may be present in AIH and often precedethe onset of liver injury manifestations, which can justify thediagnostic challenge.

• Eosinophilia might constitute a relevant feature and seems toespecially occur in male patients with AIH.

• Autoimmune hepatitis has clinical and serological similaritieswith SLE, predominantly when ANA is detected.

• Inflammatory biliary lesions and the presence of P-ANCAsuggest AIH-PSC overlap syndrome.

• In case of intolerance to azathioprine, mycophenolate mofetilis the drug of choice in association with corticosteroid therapy.

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