Dr Alexander Mullin ( left ) Respiratory advanced trainee , Liverpool Hospital ; conjoint lecturer , University of Notre Dame , Sydney , NSW .

Associate Professor Jonathan Williamson ( right ) Consultant respiratory physician , Liverpool Hospital and Macquarie University Hospital , Sydney , NSW .

First published online on 23 February 2024

BACKGROUND

SARCOIDOSIS is a multisystem

inflammatory disorder characterised by non-necrotising granulomatous inflammation . Its discovery is ascribed to Sir Jonathan Hutchinson in 1878 ; he described the condition in a coal-wharf worker with purplish skin lesions and arthropathy who eventually died from kidney failure . 1 While more than 90 % of presentations of sarcoidosis are pulmonary , a myriad of organ systems may be involved in a patient ’ s sarcoidosis phenotype . Sarcoidosis may present a significant diagnostic challenge for both GPs and specialist physicians alike as it is a great mimic of many conditions . Fortunately , sarcoidosis in the Australian context is usually mild and can be managed without steroids or other immunomodulatory agents .

This How to Treat suggests an approach to the diagnosis and current management of sarcoidosis .

EPIDEMIOLOGY

SINCE 2005 , the reported incidence of sarcoidosis in Australia has been estimated to be 4.4 – 6.3 per 100,000 population . However , this does not

account for the increase in endobronchial ultrasound biopsy ( EBUS )– facilitated diagnosis and may be a significant underestimate . 2 Sarcoidosis is primarily a sporadic disease with a 2:1 ( male : female ) predominance . Rarely , familial clusters have been reported . Its peak incidence appears between the ages of 20 and 39 , but it may arise at any age . 3

PATHOGENESIS AND IMMUNO- PATHOLOGY

THE pathogenesis of sarcoidosis is

unclear and appears to reflect an aberrant

immune response in genetically susceptible individuals to an external antigenic stimulus — for example , infection ( see figure 1 ). There is speculation that Propionibacterium acnes and non-tuberculous Mycobacterium sp . may be implicated as the exogenous trigger for inflammation and sarcoidosis granuloma formation . 4 , 5

T-cell activation is mediated through the process of antigen presentation via HLA molecules found on sarcoidosis antigen-specific T-cells . The subsequent release of cytokines stimulates granulomatous inflammation ( see figure 2 ). Similarly , T helper

2 cells and macrophage-derived cytokines promote development of fibrosis and chronic disease . 6 The role of autoimmunity has not been completely elucidated and is reported to be present at local sites of inflammation , driven by T helper 17 cells .

CLINICAL PRESENTATION

THE clinical presentation of sarcoidosis

in Australia appears to be different from overseas counterparts in America and Europe , where the condition is symptomatic in 50-70 % of cases . 7 Australian sarcoidosis data are scarce in comparison , and from local experience , individuals predominantly present with either asymptomatic mediastinal lymphadenopathy that is incidentally noted during investigations for other conditions , or as a chronic dry cough . The authors suspect this is because of the lower populations of individuals from Afro-Caribbean descent living in Australia , who experience a more severe disease phenotype . 8

Sarcoidosis presents predominantly in the lungs . However , as an infiltrative inflammatory disease , multiple organ systems may be

affected ( see table 1 ). The presentations range from generalised and vague , such as prolonged fatigue , to pathognomonic — that is , lupus perino ( see cover image ). There are two specific systemic presentations that reflect acute multisystem involvement of sarcoidosis granulomatous inflammation : Löfgren syndrome and Heerfordt syndrome ( see box 1 ).

Hypercalcaemia in sarcoidosis

Hypercalcaemia is a common coexisting

presentation with a new diagnosis of sarcoidosis , requiring careful evaluation and appropriate management . It occurs in about 7-18 % of patients with sarcoidosis and is caused by the overproduction of calcitriol ( 1,25 hydroxyvitamin D3 ) from activated macrophages of sarcoidosis granulomas . 9 Hypercalcaemia can cause a wide range of symptoms , including fatigue , weakness , muscle and bone pain , constipation and kidney stones . It can also lead to more serious complications , such as kidney failure , pancreatitis and an altered mental state .

The management of hypercalcaemia in sarcoidosis typically involves