1. Journal of The Association of Physicians of India ■ Vol. 63 ■ August 2015 71
history of similar disease. This is the
first such case report of FMF with
polyserositis and T1DM from India.
Case Report
Mr. S, 16 years, was admitted for the
first time on 19.05.2013 through triage
in CCU with the complaints of chest
pain off and on of 3 days duration. He
had T1DM since last 1 year and was
well controlled on basal bolus insulin
regime (insulin glargine and human
regular insulin). He was evaluated and
had acute pericarditis with moderate
pericardial effusion and mild ascites.
Pericardial effusion (PE) was tapped
and he was discharged on 25.05.2013
on tab. indomethacin and supportive
care as it was considered to be of viral/
idiopathic origin.
He was admitted 2nd
time on
28.07.2013 with abdominal distention
of 15 days duration and loose motions
Patient with Recurrent Polyserositis
(Familial Mediterranean Fever)
Arun Agarwal1
, Samiksha Sharma2
of 10 days duration. 2D echo done on
an OPD basis on 01.06.2013 was normal.
A repeat 2D echo was again done on
26.07.2013 and there was evidence
of minimal pericardial effusion.
USG abdomen showed moderate
ascites which was tapped and he was
discharged on 31.07.2013 on anti-
tuberculosis therapy empirically (4
drugs for 4 months and later 2 drugs
for 2 months protocol). The ascites fluid
SAAG (serum ascites albumin gradient)
was low.
A week later, he was again admitted,
3rd time, from 06.08.13 for 4 days
with tense ascites, breathlessness,
and mild right pleural effusion and
mild bilateral hydrocele. 5 liter ascitic
fluid was tapped and with evidence of
polyserositis in these three admissions
we started him empirically on 0.5 mg
colchicine twice a day along with ATT
and insulin.
Three weeks later, he was again
admitted, 4th time, on 30.09.2013
with breathlessness on exertion of 1
day duration and had moderate right
pleural effusion. 1500 ml fluid was
tapped and he was discharged on
01.10.2013 on same treatment.
After remaining asymptomatic
for about 3 months with he was re-
admitted for 5th
time on 04.01.14 with
one day history of vomiting, weakness
and had uncontrolled glycemia with
diabetic ketoacidosis (DKA). There was
no evidence of serositis at this time. He
was discharged on 08.01.14.
A week later, on 15.01.2014 he again
attended OPD with breathlessness
on exertion and had a large right
sided pleural effusion (Figure 1) and
was advised admission. He, however
got admitted,6th
time,on 20.01.2014
Thoracoscopy was done along with
1
Senior consultant and Head, Department of Internal Medicine, 2
Consultant, Department of Pathology, Narayana Multispecialty
Hospital, Jaipur, Rajasthan
Received: 22.12.2014; Revised: 06.05.2015; Accepted: 07.05.2015
C A S E O F T H E M O N T H
Introduction
We present a young type 1 diabetic
mellitus (T1DM) patient who
presented to us with recurrent
polyserositis and had 7 admissions
in a span of 16 months. Five of these
admissions were due to polyserositis
and two for diabetic keto-acidosis.
He was finally diagnosed as a case of
familial Mediterranean fever (FMF).
The most important aspect in this
case is that there was no fever, no
Mediterranean ancestry and no family
Abstract
Familial Mediterranean fever (FMF) is a hereditary autosomal recessive ,systemic,
auto-inflammatory disorder characterized by sporadic, unpredictable attacks of
fever and serosal inflammation. FMF is caused by mutations in MEFV, a gene
located on the short arm of chromosome 16 (16p13) which encodes a protein
‘Pyrin’. The disorder has been given various names including familial paroxysmal
polyserositis, periodic peritonitis, recurrent polyserositis, benign paroxysmal
peritonitis, and periodic disease or periodic fever, As the name indicates, FMF
occurs within families and is much more common in individuals of Mediterranean
descent than in persons of any other ethnicity. It has been described in several
ethnic groups including Sephardic Jews, Armenians, Turks, North Africans, Arabs,
Greeks, and Italians. However, the disease is not restricted to these groups and
sporadic cases have been reported. Diagnosis is usually clinical and it classically
presents with unprovoked, recurrent attacks of fever and painful polyserositis
mainly affecting the peritoneum (most common), synovium, and pleura that
usually (but not always) begin in childhood. We present a atypical case of FMF
with type 1 Diabetes Mellitus and FMF who had no fever, Mediterranean ancestory
or family history and discuss his clinical features,diagnosis and management.
Fig. 1: X-ray chest PA view dated
15.01.2014

2. Journal of The Association of Physicians of India ■ Vol. 63 ■ August 201572
Fig. 2: Biopsy of pleural nodule
(45 x views), H and E stain.
Arrow show chronic non-specific
inflammation and fibroblasts
Fig. 3: X-ray chest PA view dated
05.03.2014
pleural biopsy from a suspicious
looking nodule on parietal pleura
along with a chest tube insertion.
On histopathology (Figure 2) it was
chronic non-specific inflammation with
negative AFB and PAS stain. By now he
had completed 6 months of ATT and
he was discharged on colchicine and
insulin on 24.01.2014.
He again presented on 5th
march
2014 with mild breathlessness of 2
days duration and was diagnosed
to have moderate right side pleural
effusion (Figure 3). By this time
we had a strong suspicion of him
having FMF in view of 5 episodes of
recurrent serositis (polyserositis on
three occasions), being asymptomatic
between these admissions (attacks),
not having any other underlying
condition that would explain the
symptoms (infective, inflammatory,
immunological or malignancy) and
probably partial response to colchicine.
He had no family history of similar
illness, had one younger brother who
was reportedly healthy, and there was
no history of consanguinity among
his parents. He is a resident of Jaipur
(a non-Mediterranean region). At this
time we did not admit him and instead
we increased colchicine dose to 1
mg thrice a day. Two weeks later on
20th
march 2014, on follow-up he was
asymptomatic and had no evidence of
pleural effusion (Figure 4). A complete
response with adequate recommended
dose of colchine further confirmed the
diagnosis to be FMF. Since then he
remained asymptomatic for almost 6
months.
He was again admitted on 18.09.2014
through triage with 1 day history of
vomiting and DKA and discharged
Fig. 4: X-ray chest PA view dated
20.03.2014
Table 1: Summary of admissions
Admission period Presenting diagnosis
19.05.2013 to
25.05.2013
Moderate PE, mild ascites
28.07.2013 to
31.07.2013
Moderate Ascites, minimal
PE
06.08.2013 to
10.08.2013
Large ascites, mild Right
pleural effusion and bilateral
Hydrocele
30.09.2013 to
01.10.2013
Moderate right pleural
effusion
04.01.2014 to
08.01.2014
DKA; No e/o serositis.
20.01.2014 to
24.01.2014
Large right pleural effusion
18.09.2014 to
22.09.2014
DKA; No e/o serositis
Table 2: Laboratory Investigations
Admission
1st
2nd
3rd
4th
5th
6th
Hb 13.9 14.7 13.3 15.2
TLC 15.33 8.66 7.05 33.88
APC 373 541 446 312
ESR 110 30 12 45
CRP 0.97 2.44
BGR 346.4 121 100 97 600 N
S. albumin 3.79 2.94 3.99 5.47
S. globulin 4.02 3.65
S. uric acid 11.3
S. creatinine 0.57 0.89
on 22.09.2014. He had no evidence of
serositis this time. He was last seen on
13th
Nov. 2014, and as regards serositis
he is asymptomatic now for almost 9
months since March 2014 on colchicine
1 mg thrice a day.
Summary of admissions is given
in Table 1. The investigations done
during these admissions are shown
in Tables 2 and 3. Fluid analysis was
done as mentioned in Table 4. Pleural
fluid was found to be exudates as per
traditional Light’s criteria rule. Ascitic
fluid SAAG analysis showed it to be
low gradient. Fluid ADA analysis did
not favor the diagnosis of tubercular
serositis. Fluid glucose analysis showed
glucose to be on higher side with fluid/
serum glucose ratio >0.5. Fluids were
moderately cellular with predominant
lymphocytosis.
Discussion
This is a case of recurrent serositis
with 5 episodes (and 7 admissions)
in 8 months time, with asymptomatic
periods in between these episodes, has
no underlying condition that would
explain the symptoms, and responded
to colchicine. This made us to suspect
FMF in the present case.
Familial Mediterranean fever (FMF)
is an autosomal recessive systemic
auto-inflammatory disorder. It is
characterized by recurrent episodes
of fever accompanied by peritonitis,
pleuritis, pericarditis, and/or arthritis,
s o m e t i m e s a c c o m p a n i e d b y a n
erysipelas-like skin rash. The condition
was first described in 1945 under the
name ‘benign paroxysmal peritonitis.1
The disorder may also be referred to
as recurrent polyserositis, recurrent
hereditary polyserositis, periodic
disease, and periodic peritonitis.1
MEFV gene, as it is called, is located
on the short (p) arm of chromosome 16 at

3. Journal of The Association of Physicians of India ■ Vol. 63 ■ August 2015 73
position 13.3. More than 80 MEFV gene
mutations that cause FMF have been
identified. The most common mutation
replaces the amino acid methionine
with the amino acid valine at protein
position 694 (written as Met694Val or
M694V) leading to an abnormally small,
nonfunctional protein, known as prying
or sometimes called marenostrin. This
transcript is thought to be expressed in
mature neutrophils and in fibroblasts
derived from skin, peritoneum, and
synovium, suggesting that it functions
as an inflammatory regulator at the
level of cytoskeletal organization.1-3
These inflammatory episodes lead
to excess production of amyloid A
protein from the acute phase reactant
serum. Widespread amyloid deposition
occurs in the kidneys primarily by the
age of 40 years but can also affect the
gastrointestinal tract, liver, spleen,
thyroid, and in much later stages, the
heart and testes as well.4
However, only
patients with specific MEFV haplotypes
develop amyloidosis.
FMF classically presents with
unprovoked, recurrent attacks of
fever and painful polyserositis mainly
affecting the peritoneum (most
common), synovium, and pleura that
usually (but not always) begin in
childhood.1
The majority of affected
individuals (80%) present before 10
years of age and 90% before reaching
the age of 20 years. Disease onset after
the age of 40 years may represent a
Table 3: Summary of investigations
Date Test(s) Result
19.05.13 Serology Negative
Mantoux test Negative
22.05.13 USG
abdomen
Mild hepatomegaly,
Mild free fluid in
abdomen
01.06.13 2D echo NAD
26.07.13 2D echo Minimal PE
30.07.13 ANA (IFA) Negative
TSH Normal
PCR-TB
(ascitis)
Not detected
06.08.13 2D echo NAD
07.08.13 S. fibrinogen 399 (200-400 mg/dl)
08.08.13 CECT
abdomen
Marked free fluid, b/l
mild hydrocele, sub-
centimeter lymph node
in omentum, right iliac
fossa and mesentery
04.01.14 Serology Negative
23.01.14 CECT chest Right side
hydropneumothorax,
Ground glass opacity
with multiple nodular
opacities in RLL
? Consolidation
? Pulmonary edema
Table 4: Fluid analysis
Date Total proteins/albumin Glucose Total cells Differential cells ADA
Ascitic fluid*
30.07.13 6.33/- 317 1470 P10 L90 22.9
Ascitic fluid 07.08.13 4.65/2.03 150 680 P00 L100 21.0
Pleural Fluid 30.09.13 6.03/- 163 890 P10 L90 21.40
Pleural Fluid 20.01.14 14.0
*
PCR TB: not detected; AFB stain: negative; Cytology: no malignant cells
separate and milder disease entity.2
Other acute manifestations include
erysipelas like skin lesion, pericarditis,5
self-limiting orchitis and recurrent
aseptic meningitis, febrile myalgia,6
and
increased incidence of IgA vasculitis.7
Acute episodes may last from 24 to 72
hours and have variable frequency,
often without a recognized triggering
event. Some commonly reported
precipitating causes include viral
illness, emotional stress, excessive/
intense physical activity, high-fat
diet, extremes of temperature, and
menstruation in women. The frequency
of attacks may vary from once per
week to once every 5–10 years, with the
median frequency being approximately
once a month.1,3
A c u t e a t t a c k s o f F M F a r e
accompanied by elevation of many
of the serum markers of systemic
i n f l a m m a t i o n w h i c h i n c l u d e s
leukocytosis with neutrophilia, raised
erythrocyte sedimentation rate (ESR)
and other acute phase reactants,
including beta-2 microglobulin,
C-reactive protein (CRP), SAA (serum
amyloid protein), and fibrinogen.
Genetic testing i.e., testing for many
of the known mutations is currently
available at commercial laboratories
outside India. Genetic testing was not
done in our patient due to resource
limitations.
FMF is still primarily a clinical
diagnosis. Several diagnostic criteria
have been proposed by now - Livneh
A et al 8
(Table 5) and Tel Hashomer19
(Table 6).There is a set of validated
diagnostic criteria by Livneh A et
al8
with a reported sensitivity and
specificity of 96% to 99% (Table 5).
Amyloidosis, Positive family history
and Mediterranean ancestry may or
may not be present. Our patient fits into
the diagnosis of FMF by these criteria.
Differential diagnosis include
surgical emergencies (appendicitis,
intussusceptions, perforated peptic
ulcer, etc), hereditary angioedema,
a c u t e i n t e r m i t t e n t p o r p h y r i a ,
relapsing pancreatitis, systemic
lupus erythematosus and vasculitis,
hypertriglyceridemia, abdominal
epilepsy and abdominal migraine.
The goals of overall management
for FMF are twofold: 1. Prevention
of acute attacks and 2. Prevention of
the development and progression of
amyloidosis, as the major cause of
mortality is the insidious development
of secondary (AA) amyloidosis with
eventual renal failure. Colchicine is
the gold standard and indeed the
only recommended drug for treating
FMF. It is thought to primarily
concentrate in neutrophils and inhibit
their increased chemotactic activity
Table 5: Criteria for the diagnosis of familial
Mediterranean fever8,19
Major criteria
1. Typical attacks*
with peritonitis (Generalized)
2. Typical attacks with pleuritis (unilateral) or
pericarditis
3. Typical attacks with monoarthritis (hip, knee,
ankle)
4. Typical attacks with fever alone
5. Incomplete#
abdominal attack
Minor criteria
1. Incomplete attacks involving chest pain
2. Incomplete attacks involving monoarthritis
3. Exertional leg pain
5. Favorable response to colchicine
Requirements for diagnosis of FMF are ≥1 Major
criteria or ≥2 minor criteria.
*
Typical attacks are defined as recurrent (>3 of
the same type), febrile (>38°C), and short (lasting
between 12 hours and 3 days); #
Incomplete attacks
are defined as painful and recurrent attacks not
fulfilling the criteria for a typical attack.
Table 6: Tel Hashomer criteria for
the diagnosis of familial
Mediterranean fever19
Major Criteria Minor Criteria
1. Recurrent febrile
episodes with
serositis
1. Recurrent febrile
episodes
2. Amyloidosis
(AA) without
predisposing
diseases
2. Erysipelas–like
erythema
3. Favorable response
to colchicine
treatment
3. FMF in first degree
relative
The clinical diagnosis of FMF is considered
definitive in the presence of atleast two major
criteria, or one major plus two minor criteria. The
diagnosis of FMF is probable in the presence of one
major criterion plus one minor criteria (Table 6).

4. Journal of The Association of Physicians of India ■ Vol. 63 ■ August 201574
Mediterranean fever. MolGenetMetab 2000; 71:256–260.
3. Zadeh N, Getzug T, Grody WN, et al. Diagnosis and
mamagementoffamilialMediterraneanfever:Integrating
medical genetics in a dedicated interdisciplinary clinic.
Review Genetics Med 2011; 13:263-269.
4. Ben-Chetrit E, Levy M. Familial Mediterranean
fever. Lancet 1998; 351:659–664.
5. Kees S, Langevitz P, Zemer D, et al. Attacks of pericarditis
as a manifestation of familial Mediterranean fever (FMF).
QJM 1997; 90:643.
6. Ertekin V, Selimoğlu MA, Alp H, Yilmaz N. Familial
Mediterranean fever protracted febrile myalgia in
children: report of two cases. RheumatolInt 2005; 25:398.
7. Ozen S, Ben-Chetrit E, Bakkaloglu A, et al. Polyarteritis
nodosa in patients with Familial Mediterranean Fever
(FMF): a concomitant disease or a feature of FMF? Semin
Arthritis Rheum 2001; 30:281.
8. Livneh A, Langevitz P, Zemer D, etal. Criteria for the
diagnosis of familial Mediterranean fever. ArthritisRheum
1997; 40:1879.
9. Ozkaya N, Yalçinkaya F. Colchicine treatment in children
with familial Mediterranean fever. Clin Rheumatol 2003;
22:314–317.
10. Tunca M,Tankurt E, Akbaylar Akpinar H, et al.The efficacy
of interferon alpha on colchicine-resistant familial
Mediterranean fever attacks: a pilot study. BrJRheumatol
1997; 36:1005.
11. Calguneri M, Apras S, Ozbalkan Z, et al. The efficacy
of continuous interferon alpha administration as
an adjunctive agent to colchicine-resistant familial
Mediterranean fever patients. Clin Exp Rheumatol 2004;
22:S41.
12. Seyahi E, Ozdogan H, Celik S, et al. Treatment options in
colchicineresistantfamilialMediterraneanfeverpatients:
thalidomideandetanerceptasadjunctiveagents.ClinExp
Rheumatol 2006; 24:S99.
13. Metyas S, Arkfeld DG, Forrester DM, Ehresmann GR.
Infliximab treatment of Familial Mediterranean fever and
its effect on secondary AA amyloidosis. J Clin Rheumatol
2004; 10:134.
14. Ehrenfeld M, Brzezinski A, Levy M, etal. Fertility and
obstetric history in patients with familial Mediterranean
feveronlong-termcolchicinetherapy. BrObstetGynaecol
1987; 94:1186-91.
15. Ben-Chetrit E, Ben-Chetrit A, Berkun Y, Ben-Chetrit
E. Pregnancy outcomes in women with familial
Mediterraneanfeverreceivingcolchicine:isamniocentesis
justified?. Arthritis Care Res 2010;62:143–148.
16. Ben-Chetrit E, Ben-Chetrit A, Berkun Y, Ben-Chetrit
E. Pregnancy outcomes in women with familial
Mediterraneanfeverreceivingcolchicine:isamniocentesis
justified?. Arthritis Care Res 2010; 62:143–148.
17. Atabek ME. Case Report:Familial Mediterraen Fever
Association with Type 1 Diabetes Mellitus. Association
or coincidence? The Endocrinologist 2006; 16:133.
18. Bas F, Kabatar-Eryilamazs, Gunoz H, et al.Type 1 diabetes
mellitus associated with autoimmune thyroid disease,
celiac disease and familial Mediterranean fever: case
report. Turk J Pdiatr 2009; 51:183-6.
19. Wang, et al. Familial Mediterranean Fever: From
Pathogenesis toTreatment.JGenetSyndrGeneTher 2014.
serositis; i.e., he either had serositis
or DKA during the seven admissions
but never had both of them. We could
not find any explanation for this.
The association between FMF and
T1DM also need to be looked into.
Is it really an association or just a
coincidence? First such case report of
FMF association with T1DM in a 9 year
old girl was reported by Atabek et al
from Turkey17
in 2006. Another case of
FMF, T1DM with ATD (autoimmune
thyroid disorder ) and CD (celiac
disease) was reported by Bas etal18
from Turkey in 2009. To the best of our
knowledge this is the first such case
report of FMF associated with T1DM
from India.
To the best of our knowledge
this is the first such case report of
a patient who is diagnosed to have
FMF but did not had any fever,
Mediterranean ancestory,or familial
history. Nevertheless suspect FMF in
any patient who 1) has had at least four
episodes of abdominal pain or chest
pain or both, lasting from 24-72 hours,
2) without symptoms between attacks,
3) does not have any other condition
that would explain the symptoms, 4)
has positive family history of FMF,
and 5) responds to colchicine. Positive
family history and Mediterranean
ancestory may or may not be present.
Given its genetic nature, there is no cure
for FMF. Colchicine therapy should be
continued for life.
Acknowledgement
A special mention of thanks to
our colleagues Dr. Devendra Shrimal
(Department of Cardiology) and
Dr. Shubhranshu (Department of
Pulmonary Medicine) for their help
in management of this patient and
therapeutic invasive procedure.
References
1. El Shanti H, Majeed HA, El-Khateeb M. Familial
Mediterranean fever in Arabs. Lancet 2006; 367:1016–
1024.
2. TelatarM,GrodyWW.Moleculargenetictestingforfamilial
during FMF attacks.4
Colchicine
should be administered orally once
the diagnosis of FMF is confirmed (or
as a therapeutic trial in establishing
the diagnosis). Adult dosing is 1.2–2.4
mg/day. It may take some months of
adjustment before the optimal dosage
(evidenced by essentially complete
prevention of attacks) is reached.
Our patient responded to 3 mg/day
of colchicines and it took 8 months
to adjust the dosage. It is crucial to
drive home to patients that daily
lifelong administration of colchicine
is required to prevent both the fever/
pain attacks and the silent amyloid
deposition.3
Also, despite the common
misconception, taking colchicine at the
start of an attack is of no use; the drug
will prevent attacks if taken continually
but will not block an acute attack in
progress.3
Colchicine unresponsiveness
is known and several other treatment
modalities including Interferon-alfa,10,11
thalidomide, etanercept, infliximab,
anakinra, and rilonacept have been
reported.12,13
About one-third of female patients
with FMF are infertile, and 20-30%
of pregnancies result in fetal loss.14
Colchicine has antimitotic effects and
could be terratogenic but there is no
firm evidence to support that concern.15
A recent study by Ben-Chetrit et al16
in
Israel found no difference in fetal
outcome or incidence of birth defects
between affected women who either
continued taking or abstained from
colchicine during pregnancy. They also
pointed out that the common practice in
Turkey (where FMF is quite prevalent)
is not to recommend amniocentesis for
prenatal colchicine exposure.16
Our patient was diagnosed to have
T1DM almost one year before his
initial presentation and later had two
admissions with diabetic ketoacidosis.
Surprisingly, he did not have any
evidence of serositis during these
admissions. Similarly he did not have
any DKA during five admissions for