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.