Case Report: Case report: An unusual presentation of granulomatosis with polyangiitis

Introduction

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.

Patient and observation

Clinical findings

On physical examination, the patient had a ring-shaped squamous plaque on the face (Figure 1) and unilateral submandibular lymphadenopathy. A nasal endoscopy found congested nasal mucosa with bloody crusts while laryngoscopy showed increased thickness of the right vocal cord and paralysis of the left vocal cord. The ophthalmological examination concluded a low tear break-up time. The pulmonary auscultation revealed bibasilar crepitations and abdominal palpation hepatomegaly. A biopsy was performed in the cutaneous lesion showing a granulomatosis inflammation.

Figure 1. A ring-shaped squamous plaque on the face.

Diagnosis assessment

The laboratory findings showed an accelerated erythrocyte sedimentation rate (100 mm/h), an elevated C-reactive protein (66 mg/L), hyper gamma globulinemia (16 g/L), and an elevated alkaline phosphatase (twice the upper normal limit). The rest of the lab tests including cell blood count, creatinine, electrolytes, angiotensin-converting enzyme, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyltransferase, GGT were normal. Urinalysis was negative for glucosuria, proteinuria, and blood cells. Serological tests for bacterial and viral infections including hepatitis B, hepatitis C were also negative. QuantiFERON-TB Gold In-Tube (QFT-G) test for the diagnosis of tuberculosis disease was negative suggesting that there is not TB infection.

A nasal mucosa biopsy revealed a granulomatosis inflammation with necrosis.

The craniofacial and the thoracoabdominal computed tomography (CT) scans showed ethmoid and maxillary sinusitis, low facial bone density (Figure 2), multiple mediastinal and hilar lymphadenopathy, diffuse small pulmonary nodules, peripheral, linear reticulations with subpleural cystic lesions, compatible with fibrosis, and hepatomegaly. Plethysmography showed a restrictive pattern with normal forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio and severely diminished Total Lung Capacity (TLC of 64 per cent of the predicted level) and Forced Vital Capacity (FVC of 60 per cent of the predicted level). Autoimmune serology, including assays for auto-antibodies against nuclear antigen, SS-A/SS-B, anti-cyclic citrullinated peptide (anti-CCP), anti-ds-DNA was negative. Our patient had c-ANCA positivity with a titer of 1:40 (< 1:20). P-ANCA was negative. Proteinase 3 antibody (anti-PR3) was positive by an immunodot technique (Euroimmun, Germany). The serology was negative for autoimmune hepatitis and primary biliary cholangitis.

The clinical, biological, radiological, and histological findings substantiated the diagnosis of GPA.

Figure 2. Ethmoid and maxillary sinusitis and low facial bone density.

Since liver involvement was suspected, a liver biopsy was also performed and was positive on H&E staining for chronic inflammatory granulomatosis process without necrosis.

Follow-up and outcome

Two years later, he was readmitted for dyspnea on exertion, oedema of the lower limbs, and a painful ulcer of his leg that had appeared 3 months prior to admission. On examination, he had tachypnea with a respiratory rate of 34 breaths/min, a large ulcer with necrosis and pus in the right leg (Figure 3), and severe peripheral pitting oedema. The nasal endoscopic exam showed nasal septum cartilage perforation with resorption of the middle and inferior nasal concha. The lab tests revealed a biological inflammatory syndrome and elevated alkaline phosphatases. Pus culture was positive for Pseudomonas aeruginosa. A skin biopsy showed leukocytoclastic vasculitis. An electrocardiogram revealed a bifascicular block and a transthoracic echocardiography showed a dilated right ventricle, a pericardial effusion, a tricuspid valve regurgitation, and a pulmonary artery pressure of 80 mmHg. The patient received antibiotics to treat his skin infection and intravenous diuretics and oxygen via nasal cannula to manage his heart congestive failure. He was also started on three methylprednisolone pulses relayed by oral corticosteroids and cyclophosphamide. Two weeks later, he developed a diffuse alveolar hemorrhage. He was transferred to the intensive care unit, but died of respiratory failure 3 days later.

Figure 3. A large ulcer with necrosis and pus in the right leg.

Discussion

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 All that cases were revealed by a persistent elevation of liver biological parameters and confirmed by liver biopsies after excluding adverse drug affects, viral hepatitis, alcoholic or ischaemic hepatitis. The serology was also negative for autoimmune hepatitis and primary biliary cholangitis, and the liver biopsies did not show evidence for these diseases. All patients in the literature unlike the patient in this case, responded to aggressive immunosuppressive drugs.

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 this case, the patient had pulmonary fibrosis PF complicated with pulmonary hypertension. PF is an uncommon manifestation observed in patients with ANCA vasculitis.¹⁰ It is associated with worse prognosis.

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. He had an acute congestive heart with concomitant pericarditis, dilated cardiomyopathy, valvular dysfunction and conduction defect which is extremely exceptional in this pathology.⁹ 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.¹¹ 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.¹² 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).¹³ Valve disease and conduction disorder including intraventricular conduction defects and atrioventricular blockage are less common.¹⁴ As a result of aggressive treatment, cardiac involvement in patients with GPA was not associated with poorer outcome.¹⁴

In this case the patient died from a respiratory failure due to diffuse alveolar hemorrhage which can be, either another rare and mortal complication of GPA occurring in only 5% to 10% of the patients, or a complication of the acute heart failure.¹⁵ In another hand, necrotizing granulomatosis hepatitis could increase the risk of heart failure. The pathogenesis of death in this case might be multifactorial.

Conclusion

The goal of presentation of this case was to present some rare and unusual manifestations of granulomatosis with polyangiitis presenting with hepatic granuloma and pulmonary fibrosis pulmonary fibrosis. 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.

Declarations

Authors’ contributions

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.