Case Report: An unusual presentation of granulomatosis with polyangiitis [version 1; peer review: 1 approved with reservations]

Aim: We are reporting a case of an unusual presentation of granulomatosis with polyangiitis (GPA) with liver involvement. Case presentation: A 45-year-old male patient presented with erythematous

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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 Patient
A 45-year-old Tunisian male patient working as a professor, who had no relevant family history presented with erythematous plaques on the face and bilateral nasal obstruction. He reported fatigue, loss of appetite, and unintentional weight loss with mouth and eye dryness for several months.

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.

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 and alanine aminotransferase were normal. Urinalysis was negative for glucosuria, proteinuria, and blood cells. Serological tests for bacterial and viral infections including hepatitis B, hepatitis C, and tuberculosis were also negative. Serum ANCA against PR3 was positive.
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, and hepatomegaly. The clinical, biological, radiological, and histological findings substantiated the diagnosis of GPA.
Since liver involvement was suspected, a liver biopsy was also performed and was positive for chronic inflammatory granulomatosis process without necrosis ( Figure 3).

Therapeutic intervention
The patient received systemic steroids initiated by a 3-day regimen of methylprednisolone at a dose of 1 g a day, then oral prednisone at a dose of 1 mg/kg/day combined with cyclophosphamide pulses at a dose of 0.6 mg/m 2 on days 1, 14 and 28. Then he was lost to follow-up.

Follow-up and outcome
Two years later, he was readmitted for dyspnea on exertion, edema 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 4), and severe peripheral pitting edema. 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.

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 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

Conclusion
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.

Declarations
Ethics approval Not applicable.

Consent for publication
Written informed consent was obtained from the patient's next of kin for publication of this case report and any accompanying images.

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.

Data availability
Underlying data All data underlying the results are available as part of the article and no additional source data are required.

Gloria Vasquez
Rheumatology Section, Facultad de Medicina, Universidad de Antioquia, Medellín, Antioquia, Colombia I consider that the case is very interesting, but there is data in the clinical history that are missing.
In the initial evaluation of liver function, neither the levels of g-GT nor LA appear, in the presence of a granulomatous infiltration of the liver, these data are critical.
In the image of the liver biopsy, it would be worth pointing out the findings and specifying the site of the taking, the staining and the resolution of the image in the figure caption.
In the second part of the story, the patient arrives with right heart failure and pulmonary hypertension, its origin is not clear.
The discussion refers to seven cases of liver involvement in the literature but does not describe whether the findings were similar to the case described or different.
It is reported that liver involvement can be a cause of mortality but here the patient died of alveolar hemorrhage, so this aspect is not clear.
It would be useful to describe the title of the anti PR3.
The authors describe that tuberculosis was ruled out serologically, what type of test was used.
I think that all these details should be clarified, the discussion should be improved, in order to take advantage of a case that is very interesting.

Is the background of the case's history and progression described in sufficient detail? Partly
Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly Is the case presented with sufficient detail to be useful for other practitioners? Partly Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Rheumatologist and immunology
I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Reviewer comments
In the initial evaluation of liver function, neither the levels of g-GT nor LA appear, in the presence of a granulomatous infiltration of the liver, these data are critical.
We thank the reviewer for underscoring this point which allows us to add the initial evaluation of liver function in lines 31 and 33 "and an elevated alkaline phosphatase (twice the upper normal limit)." and "gamma-glutamyl transferase, GGT were normal".
In the image of the liver biopsy, it would be worth pointing out the findings and specifying the site of the taking, the staining and the resolution of the image in the figure caption.
We are grateful to the reviewer for this comment. We pointed out in the liver biopsy Liver biopsy hepatic sinusoids with neutrophilic infiltration and microabscess formation. And we added in line 48, 49 and 50 "Liver biopsy showing hepatic sinusoids with neutrophilic infiltration and microabscess formation (arrows), H&E staining, 200× magnification." In the second part of the story, the patient arrives with right heart failure and pulmonary hypertension, its origin is not clear.
We thank the reviewer for this remark. In this case the patient did not adhere to the immunosuppressive treatment and presented after two years with a rapidly lethal right heart failure. What made our patient different was the fact that he presented with an acute congestive heart with concomitant pericarditis, dilated cardiomyopathy, valvar dysfunction and conduction defect which is extremely exceptional. We precise in line 133-136 that ". 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".
The discussion refers to four cases of liver involvement in the literature but does not describe whether the findings were similar to the case described or different.
As underlined by the reviewer, this was the fifth case of liver involvement described in the literature all revealed by a persistent elevation of liver biological parameters and confirmed by liver biopsies after excluding adverse drug affect, viral hepatitis, alcoholic or ischaemic hepatitis in all patients. 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 the literature unlike the patient in this case, responded to aggressive immunosuppressive drugs. This was added in line 109-114: "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." It is reported that liver involvement can be a cause of mortality but here the patient died of alveolar hemorrhage, so this aspect is not clear.