Granulomatosis with polyangiitis (GPA) is an anti-neutrophilic cytoplasmic antibody (ANCA) associated systemic small vessel vasculitis with a necrotizing granulomatosis inflammation. It was described for the first time by Friedrich Wegener in 1936. ¹ GPA has as a wide spectrum of clinical manifestations making it a challenging diagnostic dilemma for clinicians. The diagnosis is based on the association of clinical features, laboratory tests, and histological findings. The condition It is mainly characterized by necrotizing granulomatosis of the upper and lower respiratory tract and by glomerulonephritis. However, the granulomatosis inflammation or the vasculitis can affect any organ. Liver involvement in patients with GPA was rarely reported. We are reporting a case of an unusual presentation of GPA involving the upper airways, lungs, skin, and the liver with lethal cardiac manifestations.

GPA is a severe life-threatening multi-systemic vasculitis usually involving the upper and lower respiratory tract and the kidneys. ¹ However, it may involve other organs with variable clinical presentations.

Our patient initially presented with upper airways signs, pulmonary symptoms, skin lesions and liver involvement. The diagnosis of GPA was based on the combination of clinical manifestations with serological and histological evidence. ¹

The liver involvement was confirmed by cholestasis and a chronic inflammatory granulomatosis process in the biopsy, which made this case worth reporting. In fact, although granuloma and/or the vasculitis may be found in any organ, the liver does not belong to the major target organs compared to the upper and lower airways. In fact, nasal and sinus involvement is the most common GPA manifestation. ¹ Up to 85% of patients present with necrotizing granulomatosis lesions in the nasal cavity and sinuses. ² The most frequent clinical features are nose crusting, blood stained rhinorrhea and nasal obstruction. ³ Pulmonary involvement is slightly less common and occurs in about 80% of patients with a wide spectrum of lesions. ⁴ Nodules are the most common radiological features. ⁴ Cavitation is a hallmark of the disease but it is only found in 22% of patients. ⁴ Liver involvement in patients with GPA is not quite clear. ⁵ It has been demonstrated that the liver is frequently affected in patients with active GPA when the affection is mirrored by liver test abnormalities. ⁴ The biochemical picture during active disease revealed both a cholestatic pattern ( i.e. increased g-GT and ALP) as well as a hepatocellular pattern (with increased ALT and AST) and was found in 2% to 25% patients with GPA at the time of diagnosis and was associated with a severe disease course and a poor prognosis. ⁶ However, necrotizing granulomatosis hepatitis in liver biopsy was rarely reported. ⁴ To the best of our knowledge, this might be the fifth case of hepatic involvement granulomatosis hepatitis reported in the literature. ⁷

Furthermore, it would be interesting to note that the patient presented with a squamous erythematosus plaque in the face as the initial presentation of the disease, which is particularly unusual since typical skin lesions in GPA consist of palpable purpura, papules, subcutaneous nodules and more rarely pyoderma-gangrenosum such as ulcers, digital ulcerations and gangrenes. ^{1 , 4} In fact, the cutaneous involvement in GPA is common and can be the revealing presentation in more than 30% of cases. ⁸ The spectrum of skin lesions is very large. ¹ They can be classified as specific or nonspecific depending on the presence of histopathological evidence of vasculitis with or without granuloma. ⁴ Despite the unusual clinical presentation, the histological findings consisted of specific skin lesions in an ANCA associated vasculitis.

Mortality rate associated with GPA is as high as 80% in untreated patients. The conventional treatment for severe GPA consists of combination of high doses of systemic glucocorticoid and immunosuppressant agents which have contributed to the improvement of the prognosis of patients with GPA. However, these patients are still at risk of various complications. Several clinical factors were identified to predict higher mortality rates. In fact, liver involvement was proven to be related to the disease activity and to predict poor clinical outcomes. ⁹

In the present case, the patient did not comply with the treatment. He presented after two years with acute heart failure with a rapidly progressive fatal outcome. Although cardiac involvement is considered to be uncommon in patients with GPA, the condition could be life threatening. ^{6 , 8} This manifestation is probably underestimated since it lacks specificity. ¹⁰ In fact, depending on the series and the methods applied such as electrocardiogram, echocardiography or cardiac magnetic resonance imaging (MRI), the prevalence of cardiac manifestations ranged between 40% and 60% of the patients. ¹¹ Pericarditis is the most common cardiac manifestation and was reported in up to 35% of patients, followed by cardiomyopathy [30%] and coronary artery disease (12% of the patients). ¹²

This case demonstrates that atypical clinical manifestations of GPA are very frequent, and the diagnostic of the disease should be guided by histological and laboratory findings. Clinicians should be aware of liver involvement because it can be life-threatening. Systemic corticosteroids and immunosuppressant drugs remain the mainstay in the treatment of this potentially fatal disease. However, the frequencies of these atypical manifestations are to be studied in patients with GPA.

Ichrak Bannour, Marwa Ben Brahim, OlfaBerriche, Sondes Arfa, Asma Ben Mabrouk and Sonia Hammemi all contributed equally to the conception, design, drafting and revising of the manuscript. All authors read and approved the final manuscript.