2. CASE PRESENTATION
A 7-year-old Turkish girl was admitted to our hospital with fever, gross hematuria, abdominal pain, and myalgia for four days before admission. She had been taking ceftriaxone for three days on suspicion of a urinary tract infection, and there was a history of throat infection three weeks before. There were no recurrent attacks of fever, abdominal pain, arthralgia, or chest pain. Past medical history was unremarkable with no consanguinity. On admission, there were bilateral lower extremity pitting edema, generalized muscle tenderness, and abdominal tenderness with guarding on physical examination. The patient was in the >95th percentile for blood pressure, and her body temperature was 38.7°C. Laboratory tests showed hemoglobin at 10 g/dL; white blood cells at 11700/mm³; platelets at 352000/mm³; C-reactive protein (CRP) at 185 mg/L; erythrocyte sedimentation rate (ESR) at 68 mm/hour creatinine at 0.4 mg/dL; and albumin at 2.4 g/dL. Liver function tests were normal. Urinalysis revealed 2210 red blood cells per high power field which were dysmorphic. The patient’s 24-hour urine protein excretion was at the nephrotic level (1045 mg, 55mg/m²/h). Chest X-ray and abdominopelvic and doppler ultrasounds were unremarkable. Viral serology, including hepatitis B, hepatitis C, HIV, EBV, and cytomegalovirus, was negative. Complement component 3 (C3) was 48.3 mg/dL while complement component 4, anti-nuclear antibodies, anti-double-stranded DNA antibodies, and antineutrophil cytoplasmic antibodies (ANCAs) were normal. There was a significant increase in antistreptolysin O level (3886 IU/ml), suggesting group A Streptococcus (GAS) infection.
Based on these findings, the patient was first diagnosed with APSGN. Hypervolemia regressed with furosemide in addition to salt and fluid restriction. Since acute phase reactants were still high, and she had a resistant fever, antibiotic treatment was replaced with clindamycin. Subsequently, we suspected a co-existing vasculitic disease as we did not observe clinical improvement, and we therefore performed abdominal computed tomography (CT) angiography. The maximum intensity projection images obtained from the CT data showed multiple microaneurysms in the peripheral branches of the left hepatic artery compatible with medium-sized vessel vasculitis (Figures 1a and 1b). The abdominal aorta and the iliac, celiac, superior mesenteric, and both renal arteries were normal. These angiographic findings confirmed a diagnosis of PAN. Steroid treatment was initiated and three doses of pulse methylprednisolone (20 mg/kg/dose) followed by 2mg/kg/day oral prednisolone were administered. Following the first pulse steroid dose, complaints dramatically reduced. CRP was 21mg/L by the third dose, and C3 had returned to normal levels by the fourth week. There was no progressive decline in renal function, and so no renal biopsy was performed.
Since glomerulonephritis is not expected in PAN but both clinical conditions can be seen in FMF, we performed analysis of the MEFV gene that revealed a homozygous M694V mutation, and colchicine was started. Following clinical and laboratory remission, steroid treatment was gradually tapered and ceased at the 18th month. At three years follow-up, the patient continues with colchicine treatment only, is now wholly symptom free, and has normal laboratory parameters with no proteinuria.
3. DISCUSSION
We have described a rare presentation of FMF with co-existing systemic PAN and APSGN preceded by GAS following a throat infection. In PAN, arterioles, venules, and capillaries (including the glomerular capillary) are characteristically not involved7,8,10. Unlike other systemic vasculitides which are idiopathic or autoimmune, PAN has several potential triggers including viruses, such as hepatitis B, hepatitis C, HIV, cytomegalovirus, EBV, and Parvovirus B19, as well as bacteria.8. Patients with PAN may have a defect in handling streptococcal infections which can lead to the development of circulating immune complexes with arterial or glomerular damage11.
The diagnosis of childhood PAN requires histopathologic confirmation of necrotizing vasculitis or angiographic abnormalities as mandatory criteria7, but, because of the potential development of microaneurysms and hemorrhage, kidney and liver biopsies should only be performed when other approaches have been unsuccessful8. Necrotizing vasculitis can result in luminal arterial changes, observable by arteriography, and a diagnosis of PAN can be established in this way 8,12,13. The classical arteriographic finding is aneurysmal dilatation, but other luminal changes such as beaded tortuosity, abrupt cut-offs, tapering stenosis of smaller vessels, and pruning of the peripheral renal arterial tree may also suggest vasculitis 7.
Liver involvement occurs in 16% to 56% of patients, and clinical findings related to liver disease are rare. Necrotizing vasculitis may be seen in liver biopsy whereas hepatic arteriograms may show caliber changes with corkscrew vessels and distal microaneurysms14. In the present case, the maximum intensity projection images obtained from CT angiography showing multiple microaneurysms in the peripheral branches of the left hepatic artery to confirm the PAN diagnosis. Treatment includes induction with high doses of corticosteroids and cyclophosphamide and maintenance therapy with low-dose prednisolone and azathioprine 7. In our patient, the abdominal aorta and iliac, celiac, superior mesenteric, and renal arteries were intact, and she responded dramatically to steroid treatment. We did not therefore administer cyclophosphamide or azathioprine.
As previously mentioned, capillaries are not involved in PAN, and so glomerulonephritis is not expected in its course. On the other hand, however, patients with FMF may have non-amyloid renal involvement characterized by transient or persistent hematuria, proteinuria, typical APSGN, and various other types of glomerulonephritis3. It has also been shown that vasculitic diseases such as PAN affect the kidney in FMF 6, and there is an association between childhood PAN and FMF 6,9,15. Mutations in the MEFV gene may provide a basis for PAN development by forming a proinflammatory state and prompting an exaggerated response to streptococcal infections 9, and homozygosity of the M694V mutation has been found to be associated with the most serious phenotype in the clinical spectrum of FMF 16.