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Clinical Features and Prognostic Significance of Liver Involvement in Sarcoidosis

European Respiratory & Pulmonary Diseases, 2016;2(1):26–9 DOI: //


Background: Sarcoidosis is a systemic disease, characterised by non-caseating granulomas in various organs. Liver involvement is not an uncommon feature of sarcoidosis. However, firm data establishing the clinical features and prognosis in these patients are lacking, although the incidence of liver sarcoidosis is high. In this study, we aimed to investigate the features of liver involvement in patients with sarcoidosis. Another aim was to evaluate the prognostic significance of liver disease by comparing the differences between patients with no liver involvement, limited and diffuse liver involvement. Methods: We conducted a retrospective study to evaluate the clinical and laboratory findings of 271 sarcoidosis patients seen at our institution. Patients with liver sarcoidosis identified by liver biopsy were compared to patients without liver involvement for clinical features and prognosis. The biopsy sample was considered positive if it demonstrated non-caseaiting granulomas with negative fungal and mycobacterial cultures. The patients were classified into three groups according to the radiological and histopathological biopsy results: no liver involvement; limited liver involvement: two sites positive; and diffuse liver involvement: three or more sites positive for granulomas. Results: Hepatic involvement was identified by biopsy in 81 (81/271, 29.8%) while 43 (43/271, 15.8%) patients had elevated liver function tests. Most of the patients (94.6%) had lung involvement. Other organs involved, in the order of frequency, were: lymph nodes, skin, eye, spleen and parotid gland. There was no significant difference between the three groups for forced expiratory volume in one second, forced vital capacity, total lung capacity, diffusing capacity of the lungs for carbon monoxide/alveolar volume, serum and 24-hour urinary calcium levels. Serum angiotensin-converting enzyme levels were significantly higher (p<0.01) in patients with diffuse liver involvement than patients with no or limited liver disease. Progressive disease was more frequent (p<0.01) in patients with diffuse liver disease. Extra-pulmonary organ involvement was significantly different between the three groups (p<0.01). Conclusions: Diffuse liver involvement in sarcoidosis is a significant risk factor for progressive disease. Patients with diffuse liver disease have a worse prognosis than patients without or with limited liver involvement. Diffuse hepatic involvement in sarcoidosis is also associated with an increased incidence of extra-pulmonary organ involvement. Presence of diffuse liver disease may reveal a severe prognosis for sarcoidosis patients.
Keywords: Sarcoidosis, liver, prognosis, diffuse, limited
Disclosure: Halil Yarnadag, Cuneyt Tetikkurt, Muammer Bilir and Sabriye Demirci have nothing to declare in relation to this article. No funding was received for the publication of this article.
Compliance with Ethics: The study has been approved by the institutional review board/ethics committee of Cerrahpasa Medical Faculty and each patient had provided informed, written consent. Patients fulfilled the American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria for sarcoidosis. All procedures were followed in accordance with the responsible committee on human experimentation and with the Helsinki Declaration of 1975 and subsequent revisions.
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit
Received: September 28, 2015 Accepted: March 29, 2015
Correspondence: Cuneyt Tetikkurt, Tanzimat Sok. Serkan Apt. No:8/16, 34728, Caddebostan, Istanbul, Turkey. E:

Sarcoidosis is a chronic systemic disease of unknown origin that is characterised by the formation of non-caseating granulomas in the affected organs, predominantly in the lungs and the intrathoracic lymph nodes.1–3 Non-caseating granulomas most often appear in the lungs and lymph nodes, but virtually any organ can be affected. Sarcoidosis of the gastrointestinal tract is extremely rare. In contrast to these organs, liver follows lung and lymph nodes in the frequency of involvement. About 50–79% of liver sarcoidosis is diagnosed by biopsy, while 67–70% is identified by autopsy.4–7 Although liver involvement is frequent in sarcoidosis patients, data relevant to the clinical characteristics and prognosis of such patients are scarce.

The aim of our study was to investigate the clinical features of liver sarcoidosis. Another objective of our study was to assess the significance of liver disease in regard to prognosis and extra-pulmonary organ involvement. Therefore, we undertook a retrospective study in patients with sarcoidosis to characterise the clinical aspects and outcome of limited and diffuse liver disease.

Materials and methods
A total of 271 patients with sarcoidosis attending our centre between January 1988 and March 2015 were evaluated retrospectively for liver involvement. The study has been approved by the institutional review board/ethics committee of Cerrahpasa Medical Faculty and each patient had provided informed, written consent. Patients fulfilled the American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria for sarcoidosis.1 All subjects underwent pulmonary function tests, diffusing capacity of the lungs for carbon monoxide/alveolar volume (DLCO/VA) tests, chest X-ray, thorax computed tomography (CT) and fiberoptic bronchoscopy (FOB).

Laboratory investigations included complete blood count, liver function, renal function tests, serum calcium, 24-hour urinary calcium, erythrocyte sedimentation rate, C-reactive protein and angiotensinconverting enzyme (ACE). Abnormal liver or renal function tests, high serum ACE, hypercalcaemia and hypercalciuria were considered to be present if they were above the normal range. Chest roentgenograms were staged according to the DeRemee as follows.

• Stage 0: normal.
• Stage I: bilateral hilar lymphadenopathy.
• Stage II: bilateral hilar lymphadenopathy and parenchymal involvement.
• Stage III: parenchymal involvement only.
• Stage IV: pulmonary fibrosis.8

Spirometry was performed according to the ATS/ERS recommendations. DLCO/VA was measured with the single-breath technique and was adjusted for alveolar ventilation. The pulmonary function tests and DLCO/VA were interpreted in accordance with the guidelines of ATS.9 Values for the pulmonary function tests and DLCO/VA were considered abnormal if they fell outside the 95% confidence interval for the predicted values. The evidence of restrictive (reduced total lung capacity [TLC] or forced vital capacity [FVC] and normal or high forced expiratory volume in one second [FEV1]), or decreased diffusion capacity (DLCO/VA<80%) were considered abnormal. For evidence of skin and ocular sarcoidosis, all patients were screened by a dermatologist and an opthalmologist. Central nervous system involvement was considered to exist if neurological findings were positive, a lesion was confirmed by CT or magnetic resonance imaging (MRI) and diagnosed by a consultant neurologist.

The medical records were used to obtain data about patient age, sex, radiological stage, laboratory, pulmonary function tests, FOB and histopathological findings. Sputum, bronchoalveolar lavage (BAL) culture was done to exclude infection. FOB was performed under local anaesthesia in all patients. Transbronchial and bronchial biopsies were taken. Liver biopsy was performed in case of radiological involvement demonstrated by ultrasound and/or CT. The biopsy was considered positive if it revealed non-caseating granulomas without mycobacterial or fungal organisms. Liver involvement was identified by the presence of a positive pathology and/or elevated liver function tests. The patients were classified into three groups:

• no liver involvement (NLI);
• limited liver involvement (LLI): positive liver biopsy; and
• diffuse liver involvement (DLI): positive liver biopsy.

Diffuse hepatic involvement was identified by the presence of three or more granulomas, whereas patients with limited disease had fewer than three granulomas detected by ultrasound (US) and/or CT. Extrapulmonary organ involvement was classified into two groups as: fewer than three, and three or more organs involved.

Ninety-four patients received corticosteroids, 16 patients received azathioprine and nine patients received methotrexate. Clinical, laboratory, pulmonary function test and radiology findings were first evaluated three months after diagnosis and every six months thereafter. Laboratory evaluation during follow-up included blood count, serum biochemistry, serum and 24-hour urinary calcium. Pulmonary function tests included FEV1, FVC, TLC, and DLCO/VA. Arterial blood gas (ABG) was done when necessary. The mean follow-up of patients was 106.4 ± 16.2 months.

Scale variables were represented by mean ± standard deviation. Clinical findings and prognosis of patients with limited and diffuse liver involvement were compared to patients without liver disease. The χ2 test was used for categorical variables as appropriate. Logistic regression was applied to determine the effect of age, gender and hepatic involvement on prognosis. Kruskal–Wallis and Bonferroni corrected two-way Mann–Whitney tests were used for comparison of the groups. After checking for normality, analysis of variance (ANOVA) was done to compare the difference between serum ACE, serum calcium, 24-hour urinary calcium, pulmonary function and DLCO/VA of the three groups. All tests were two-tailed and a p-value lower than 0.05 was accepted for statistical significance. Analyses were done using software (SPSS 22.0 version).


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Keywords: Sarcoidosis, liver, prognosis, diffuse, limited