|Year : 2020 | Volume
| Issue : 4 | Page : 581-585
Adult-onset still's disease, an unusual cause of severe acute liver injury: A case report
SC Adiyaman1, G Bengi2, M Civak1, M Birlik3, Z Kuruuzum4, C Altay5, M Soyturk2
1 Department of Internal Medicine, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
2 Department of Gastroenterology, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
3 Department of Rheumatology, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
4 Department of Infectious Diseases, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
5 Department of Radiology, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
|Date of Submission||01-Jan-2019|
|Date of Acceptance||26-Dec-2019|
|Date of Web Publication||4-Apr-2020|
Dr. S C Adiyaman
Department of Internal Medicine, Dokuz Eylul University Faculty of Medicine, Izmir
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Adult-onset Still's disease is a systemic inflammatory disease that often presents with spiking fever, typical rash, arthritis, and serositis. However, adult-onset-Still's-disease associated liver injury and acute liver failure are rare. Herein, we report a case of acute liver injury in a 23-year-old female patient with adult-onset Still's disease. She presented to the emergency department with a high fever and sore throat. She was then admitted to the department of infectious diseases with a preliminary diagnosis of an atypical respiratory infection. After being treated with antibiotics and antiviral agents, she was discharged. A few days later, she returned to the emergency department with jaundice and was rehospitalized. This time, she was admitted to the department of gastroenterology, where she was diagnosed with adult-onset Still's disease-associated acute liver injury. Eventually, the patient responded to immunosuppressive treatment with significant clinical improvement.
Keywords: Acute liver failure, acute liver injury, adult-onset Still's disease, fever of unknown origin, immunosuppressive treatment
|How to cite this article:|
Adiyaman S C, Bengi G, Civak M, Birlik M, Kuruuzum Z, Altay C, Soyturk M. Adult-onset still's disease, an unusual cause of severe acute liver injury: A case report. Niger J Clin Pract 2020;23:581-5
|How to cite this URL:|
Adiyaman S C, Bengi G, Civak M, Birlik M, Kuruuzum Z, Altay C, Soyturk M. Adult-onset still's disease, an unusual cause of severe acute liver injury: A case report. Niger J Clin Pract [serial online] 2020 [cited 2020 Sep 25];23:581-5. Available from: http://www.njcponline.com/text.asp?2020/23/4/581/281913
| Introduction|| |
Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder characterized by a typical salmon-colored non-pruritic rash, leukocytosis, fever, and arthralgia with or without arthritis. AOSD may present in a similar manner to other inflammatory diseases, and therefore, all other causes must be ruled out before making a diagnosis. Patients with AOSD usually test negative for rheumatoid factor and antinuclear antibodies, but their serum ferritin levels may be highly elevated. In most cases, AOSD has a favorable prognosis, but some manifestations of the disease can affect the lungs, heart, kidney, or liver, which can lead to severe life-threatening complications. Hepatic involvement is frequently observed in the clinical course of AOSD, typically manifesting as mildly elevated transaminases. However, this hepatic involvement rarely causes acute liver injury (ALI) or acute liver failure (ALF), which can require urgent liver transplantation. Herein, we aimed to present an unusual case of AOSD with ALI that was successfully treated with immunosuppressive treatment and did not further progress into ALF.
| Case Report|| |
A 23-year-old woman presented to the emergency department with a 7-day history of malaise, loss of appetite, sore throat, fever, pain in the extremities, and rash. The rash was accompanied by redness and a burning sensation which affected her entire body, especially the neck [
[Figure 1]. She also had myalgia, high spiking fever (39°C max), and oral herpes-like lesions.
|Figure 1: Specific salmon-pink evanescent rash of adult-onset Still's disease|
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Her initial laboratory findings were as follows: White blood cells (WBC)—25500 × 103/μL, Neutrophil (Neu)—84%, C-reactive protein (CRP)—106 mg/dL (normal: 0.2–5), erythrocyte sedimentation rate (ESR)—22 mm/h (normal: 0–20), alanine aminotransferase (ALT)—27 U/L (normal: 0–35), and aspartate aminotransferase (AST)—28 U/L (normal: 0–35). In the emergency room, she was first diagnosed with an atypical respiratory infection and was hospitalized in the department of infectious diseases. There, she was treated with levofloxacin, and because there was an outbreak of H1N1 in Turkey at the time of her hospitalization, she was additionally treated with oseltamivir and acyclovir. During her hospitalization, the patient underwent repeated blood, urine, and stool cultures, as well as nasal PCR for influenza infection, all of which came back negative. Because of ongoing fever, the patient was thought to have a fever of unknown origin (FUO), and on the seventh day of her hospitalization, a series of additional laboratory diagnostic tests were performed (e.g. bone marrow sampling for atypical infectious causes). Serological tests for hepatitis-B virus (HBV), hepatitis-C virus (HCV), Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), herpes simplex virus (HSV), leishmaniosis, syphilis, and toxoplasma were negative, as were tests for ceruloplasmin, rheumatoid factor, antinuclear antibody (ANA), anti-mitochondrial antibody (AMA), and anti-Liver kidney microsome (anti-LKM). Levels of alpha-1 anti-trypsin (298 mg/dL (normal: 90–200)) and anti-cyclic citrullinated peptide (anti-CCp) (13.38 RU/mL (normal: 0–5)) were slightly high. The patient's additional lab results were as follows: ferritin—5950 ng/dL (normal: 11–306), total iron-binding capacity—146 μg/dL (normal: 250–450), serum iron—22 μg/dL (normal: 60–180), transferrin saturation—13% (normal: 12–45), TSH1.2 μIU/ml (normal: 0.3–5.6), and plasmodium parasite—negative (via peripheral blood smear).
Furthermore, her thoracoabdominal computerized tomography (CT) scan revealed hepatosplenomegaly as well as multiple cervical and axillary lymphadenopathies [Figure 2]. Based on those findings and the misinterpreted B symptoms (fever, malaise, and fatigue), she underwent axillary lymph node biopsy to exclude hematopoietic malignancy. Her condition improved while waiting for the pathology results, and she was discharged from the hospital with orders for weekly follow-up. A few days later, she returned to our hospital's emergency department with jaundice, fatigue, and unlocalized epigastric pain. Her initial liver function tests were as follows: ALT—803 U/L (normal: 0–35), AST—587 U/L (normal: 0–35), total bilirubin—11.41 mg/dL (normal: 0.3–1.2), direct bilirubin—7.03 mg/dL (normal: 0–0.2), and INR—2.2 (normal: 0.8–1.2). She was rehospitalized, this time by the department of gastroenterology, and she did not show any signs of hepatic encephalopathy. During this hospitalization, her axillary lymph node biopsy result revealed reactive hyperplasia, and she was re-evaluated by the departments of rheumatology and infectious diseases. Based on her skin findings, organomegaly, persistent fever, arthralgia, and elevated ferritin levels, it was initially thought that she was suffering from AOSD. While she received anti-viral and antibiotic treatment during her previous hospitalization, drug-induced hepatotoxicity was ruled out because of her laboratory results (e.g. negative anti-LKM), and because she had persistent liver enzyme elevation weeks after her latest antibiotic therapy.
|Figure 2: Contrast-enhanced thorax and abdomen CT reveal bilaterally axillar lymphadenopathy and hepatosplenomegaly|
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Because she was diagnosed with ALI, she was given IV methylprednisolone (1000 mg/day). About 12 h later, her condition improved, her ALT levels decreased from 602 U/L to 523 U/L, and her AST levels decreased from 572 U/L to 377 U/L. To mitigate the ongoing liver damage, the pulsed steroid treatment was continued for 5 days, and cyclosporine (2 × 50 mg/day) was added. On the 6th day, her oral methylprednisolone was decreased to 60 mg/day, and she continued the cyclosporine treatment (2 × 50 mg/day). Her condition continued to improve, and she was discharged on the 18th day of immunosuppressive therapy. Four months later she was continuing treatment with methylprednisolone (4 mg/day) and cyclosporine (2 × 100 mg/day), and her latest office visit revealed that her liver function tests had returned to normal: AST—17 U/L and ALT—12 U/L [Table 1].
|Table 1: Laboratory test results and body temperature before and after treatment|
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| Discussion|| |
AOSD is a rare systemic inflammatory disorder characterized by typical evanescent salmon-colored non-pruritic rash, leukocytosis, fever, and arthralgia with or without arthritis. Based on an epidemiological survey conducted in Japan, the estimated crude prevalence of AOSD was calculated as 0.73 and 1.47 per 100,000 for males and females, respectively, with a female to male ratio of 2:1. AOSD is typically a rare disease, but according to one study, its prevalence in Turkey (6.77/100,000) is higher than its worldwide prevalence.
While the etiology of AOSD is still unknown, genetic factors and various infectious agents are thought to play a role. In AOSD, cytokines (e.g. IL-1, IL-6, IL-18, interferon-gamma, and tumor necrosis factor-alpha) play a leading role, and elevated levels of IL-1 and IL-18 are closely associated with AOSD's systemic symptoms, such as fever, rash, and hepatic dysfunction. Additionally, the overproduction of IL-18 is specifically related to high serum ferritin levels, which may be considered a major factor in hepatitis development.
The diagnosis of AOSDismostlybasedonclinicalfindings. AOSD can present in a similar fashion to other inflammatory diseases, and therefore, other causes must be ruled out before making a diagnosis. The most widely accepted and helpful set of criteria for the diagnosis of AOSD was formulated by Yamaguchi. Yamaguchi criteria consist of both major (e.g. fever, arthralgia, macular or maculopapular nonpruritic salmon-colored rash, and leukocytosis) and minor criteria (e.g. sore throat, lymphadenopathy and/or splenomegaly, elevated liver function tests, and absence of rheumatoid factor and antinuclear antibody). Yamaguchi criteria are based on five minor and four major criteria, of which the presence of two or more major criteria have a sensitivity and specificity of 96.2% and 92.1%, respectively. The patient described herein met al l of the Yamaguchi criteria for AOSD.
In general, AOSD typically follows a benign clinical course. It is rarely accompanied by serious complications such as macrophage activation syndrome/hemophagocytic syndrome, pericarditis, cardiac tamponade, disseminated intravascular coagulation, serous peritonitis, pleuritis, and respiratory failure. Hepatic involvement is frequently observed in the course of AOSD, usually as a mild elevation in transaminases. Although ALI and ALF are infrequent manifestations of AOSD, they are important to diagnose, as they may require urgent liver transplantation.
Hepatic involvement in AOSD typically occurs as an asymptomatic elevation in transaminases with or without hepatomegaly. The case described herein had highly elevated liver enzymes and jaundice, with no other manifestation of hepatic involvement. In general, disease activity in AOSD is positively correlated with liver damage. However, ALF is a rare complication of AOSD that can occur even during the tapering of immunosuppressive therapy or years after diagnosis.
In a review of 17 cases of AOSD with ALF, 12 of the patients were women, 7 of which were simultaneously diagnosed with AOSD and ALF, while the other 5 had been previously diagnosed with AOSD. Most of the patients were between 20 and 40 years old, and there were 4 patients older than 40 (the oldest was 74). In that review, 10 of the patients received iv steroids (i.e. methylprednisolone or prednisolone), with two of these also receiving cyclosporine and one anakinra. Seven of the reported AOSD cases required liver transplantation. Of the 17 patients, 2 died and 15 recovered following treatments. The 2 patients that died were only given steroid treatments. The age and gender of the case described herein were similar to those of previously reported cases, and she responded very well to treatment with steroids and cyclosporine.
Another review by Pouchot et al. included 62 cases of AOSD. That review revealed that the majority of AOSD cases had features of mild hepatitis; however, only rarely did patients present with life-threatening acute liver failure. Liver biopsy findings may be helpful for making the diagnosis of ALF in patients with AOSD. The case described herein did not undergo liver biopsy since these biopsy results can be somewhat nonspecific to AOSD-associated ALF. The histologic features of AOSD accompanied by liver dysfunction typically include periportal mononuclear infiltrates, Kupffer-cell hyperplasia, lobular inflammation, focal hepatocellular degeneration, periportal fibrosis, and massive or sub-massive hepatic necrosis. Ground glass-like cytoplasmic inclusions typically associated with venous outflow impairment are normally seen in chronic hepatitis B infection and in sinusoidal dilatation and have also been described in AOSD patients., In addition, a liver biopsy may reveal moderate portal mononuclear cell infiltration with occasional focal hepatocyte necrosis, which can be caused by nonsteroidal anti-inflammatory drugs. Even though liver biopsy is helpful in the diagnosis of AOSD, we believe that the lack of data on its use in AOSD indicates that it is not necessary to perform.
Generally, AOSD patients respond to treatment with glucocorticoids, immunosuppressive drugs, and disease-modifying anti-rheumatic drugs (DMARDs, e.g. methotrexate and intravenous immunoglobulins (IVIG)). Biologic agents should also be considered for corticosteroid and DMARD-refractory cases. IL-1 inhibition with Anakinra (IL-1 receptor antagonist), Canakinumab (anti-IL-1 monoclonal antibody), or Rilonacept (anti-IL-1 fusion protein) seems to be effective, well-tolerated, and steroid-sparing in some AOSD patients. In addition, TNF-α blockers may be useful in the treatment of chronic polyarticular AOSD. Inhibition of IL-6 with tocilizumab is also well-documented and may be effective in cases of AOSD with active arthritis. In the case described herein, we initiated therapy with pulse intravenous methyl-prednisolone treatment, and then we continued this treatment by adding cyclosporine and oral methylprednisolone. The patient had remarkable improvement after nearly two weeks of immunosuppressive treatment.
Although rare, patients diagnosed with AOSD can present with severe hepatitis. The case described herein is a reminder that early recognition of this unusual manifestation of AOSD is vital, and that prompt initiation of combined immunosuppressive therapy is associated with favorable outcomes.
Informed consent is taken from the patient.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwagi H, et al
. Preliminary criteria for classification of adult Still's disease. J Rheumatol 1992;19:424-30.
Efthimiou P, Kadavath S, Mehta B. Life-threatening complications of adult-onset Still's disease. Clin Rheumatol 2014;33:305-14.
Dino O, Provenzano G, Giannuoli G, Sciarrino E, Pouyet M, Pagliaro L. Fulminant hepatic failure in adult onset Still's disease. J Rheumatol 1996;23:784-5.
Wakai K, Ohta A, Tamakoshi A, Ohno Y, Kawamura T, Aoki R, et al
. Estimated prevalence and incidence of adult Still's disease: Findings by a nationwide epidemiological survey in Japan. J Epidemiol 1997;7:221-5.
Balci MA, Pamuk ON, Pamuk GE, Uzundere FK, Donmez S. Epidemiology and outcome of adult-onset Still's disease in Northwestern Thrace region in Turkey. Clin Exp Rheumatol 2015;33:818-23.
Efthimiou P, Flavell RA, Furlan A, Gasbarrini G, Gava A, Koné-Paut I et al
. Autoinflammatory syndromes and infections: Pathogenetic and clinical implications. Clin Exp Rheumatol 2008;26:53-61.
Fautrel B. Adult-onset Still disease. Best Pract Res Clin Rheumatol 2008;22:773-92.
Hogan T, Kao KT, Tung J. A rare case of severe acute hepatitis associated with adult-onset still disease dramatically improved by high-dose steroid therapy. Gastroenterol Hepatol (N
Valluru N, Tammana VS, Windham M, Mekonen E, Begum R, Sanderson A. Rare manifestation of a rare disease, acute liver failure in adult onset still's disease: Dramatic response to methylprednisolone pulse therapy-A case report and review. Case Rep Med 2014;2014:375035.
Pouchot J, Sampalis JS, Beaudet F, Carette S, Décary F, Salusinsky-Sternbach M et al
. Adult Still's disease: Manifestations, disease course, and outcome in 62 patients. Medicine (Baltimore) 1991;70:118-36.
Sari A, Tunakan M, Ozmen M, Turkkan E. Ground-glass-like hepatocellular inclusions in the course of adult-onset Still's disease. Mod Rheumatol 2010;20:90-2.
Kakar S, Kamath PS, Burgart LJ. Sinusoidal dilatation and congestion in liver biopsy: Is it always due to venous outflow impairment? Arch Pathol Lab Med 2004;128:901-4.
Zimmerman HJ. Effects of aspirin and acetaminophen on the liver. Arch Intern Med 1981;141:333-42.
Sfriso P, Priori R, Valesini G, Rossi S, Montecucco CM, D'Ascanio A, et al
. Adult-onset Still's disease: An Italian multicentre retrospective observational study of manifestations and treatments in 245 patients. Clin Rheumatol 2016;35:1683-9.
[Figure 1], [Figure 2]