A 20-year-old Turkish man with a fever of 101.9[degrees]F, stomach discomfort, and systemic tiredness presented to his family physician. After speaking with the patient, it was discovered that his symptoms began around six months prior. The patient had been having recurrent episodes of fever, with each episode resulting in a steady increase in abdominal pain. These episodes were self-limiting, usually lasting 24 to 72 hours, and were followed by long periods of non-symptomatic periods with no discernible patterns.
In addition, the patient indicated that two of his male cousins had experienced recurrent fevers with identical symptoms, but without abdominal pain or systemic tiredness. When pressure was applied to the right upper quadrant of the abdominopelvic area during a clinical examination, the patient showed considerable discomfort. The patient was hospitalized to a nearby hospital where blood and urine specimens were collected and a computed tomography (CT) scan of the abdomen was done due to the severity of his complaints and his relevant clinical history.
The CT imaging revealed that the right kidney was inflamed to a significant degree. Tables 1 and 2 show that his blood and urine values were abnormal, indicating a heightened immune response associated with acute renal failure. Chronic Familial Mediterranean Fever (FMF) was suspected based on the test results and the patient's clinical and family history. The presence of any known FMF gene mutations was then determined using a polymerase chain reaction (PCR) assay.
The patient was diagnosed with FMF and secondary amyloidosis of the kidney after the findings came back positive. The patient was started on a 0.6 mg colchicine three times a day regimen. Symptoms began to fade after the first 24 hours of medication. Additional laboratory testing revealed improved kidney function and a reduced immune response within three days. After three days in the hospital, the patient was released.
BACKGROUND
Familial Mediterranean Fever (FMF), also known as Armenian disease or paroxysmal polyserositis, is a genetic inflammatory condition that affects people of Mediterranean descent. (1) Recurrent fever bouts can be followed by self-limiting arthritis, pleuritis, peritonitis, and the development of secondary amyloidosis in FMF patients. In the Jewish, Armenian, Arab, and Turkish populations, about one out of every two hundred persons has inherited this autosomal recessive gene condition, with as low as one in five deemed carriers. (1)
The disease usually starts in childhood and lasts for the rest of a person's life. According to epidemiology research, the most prevalent ages for symptoms to appear are between the ages of 18 and 20. Males are more likely to be impacted than females (2,3). Furthermore, while the occurrence of symptoms is difficult to predict, and the secondary consequences connected with the disease can be severe, the sickness is easily controlled after patients are treated with prescription medicine. (2,3)
Frequent attacks of fever lasting 24 to 72 hours, polyserositis causing severe stomach or pleuritic discomfort, attacks of arthritis lasting up to 7 days, and sometimes a painful, swollen skin lesion on the lower legs are all common symptoms in FMF patients. (1) These symptoms can recur as frequently as twice a week or as infrequently as once a year, depending on the severity and frequency of the symptoms. The development of secondary amyloidosis, which generally affects the kidneys, is a common consequence of FMF.(4)
Renal amyloidosis is also characterized by weakness, tiredness, and enlargement of the kidneys. (4) The prognosis for FMF with secondary amyloidosis is usually good, although it relies on the severity of any amyloidosis-related damage and whether or not treatment was given effectively.
The Mediterranean Fever Gene is the hereditary gene that causes FMF (MEFV). This gene is found at position 13.3 on chromosome 16's short arm, between nucleotide base pairs 3,232,028 and 3,246,627. (5,6) This gene is made up of ten exons and spans roughly 14 kilobytes of genomic DNA (5). MEFV directs the creation of a protein called pyrin, also known as marenostrin, in the cell. (5,6) Pyrin is either mutated or not produced when the MEFV gene has nonsense or missense mutations.
Pyrin is a protein produced largely by white blood cells (neutrophils, eosinophils, and monocytes), and while its exact function is unknown, it is assumed to play a key part in the regulation of inflammation and infection.
The interaction of pyrin with the leukocyte cytoskeleton, the death domain included within the protein, and its capacity to deregulate chemotactic factors are all evidence that it is a regulator of inflammation. Pyrin has been found to attach to the cytoskeleton of leukocytes, and while little is known about this interaction, given the cytoskeleton is important for defining a cell's shape, size, and movement, this connection could have an impact on the cell's ability to manage inflammation or infection. (6) The protein also has a PYD domain, which is a death domain (Pyrin Domain). (5)
This domain has been linked to a number of different proteins that have a role in apoptosis. (7) Pyrin's inclusion of this domain suggests that it may have a function in cell apoptosis as well. Finally, dysregulation of chemotactic factor C5a and interleukin-8 has been linked to pyrin. Patients with normal pyrin have been reported to have the ability to deregulate inflammatory mediators such as C5a and interleukin-8, whereas patients with aberrant pyrin have a high accumulation of C5a and IL-8.
Overall, the persistent inflammation found in FMF patients, which is most likely caused by defective pyrin, causes an accumulation of acute phase proteins and the deposit of acute phase protein amyloid A in many tissues. (10) If the accumulation continues, the result will be an interference with normal tissue structure and function, which is referred to as amyloidosis. (10)
Amyloidosis is an uncommon, potentially lethal condition that can be localized or systemic in nature. (4) Amyloidosis is divided into four categories. Immunoglobulin (primary) amyloidosis, reactive (secondary) amyloidosis, beta-2 microglobulin amyloidosis, and hereditary amyloidosis are the four major kinds. Each kind of amyloidosis has a unique prognosis and is caused by a variety of underlying diseases. Amyloid deposits include pathologic traits such as beta-pleated sheet formations made up of amyloid fibrils with widths ranging from 8 to 10 nm. (10)After being dyed with Congo Red stain, beta-pleated sheets can be examined under polarized light; these stained fibrils have an apple green birefringence. (10)
Chronic inflammatory illnesses like FMF are linked to secondary amyloidosis. (4,10) Serum amyloid A, an acute-phase reactant, is the precursor protein that builds the amyloid fibrils associated with secondary amyloidosis. The spleen, liver, lymph nodes, adrenal glands, and kidneys are all common places where amyloid builds up. (4) Nonspecific symptoms include complaints of weakness and weariness. Organ involvement is linked to specific complaints, which frequently include edema and discomfort.While secondary amyloidosis can cause organ malfunction and failure, it can be treated with prescription colchicine, and the organ damage can be reversed if caught early enough. (8)
Fever episodes have also been connected to pyrin deficiency. Pyogens, which can be endogenous (cytokines) or exogenous (toxins), cause fever (bacteria). Pyrogens stimulate the production of prostaglandin E2 (PGE2), which operates on the hypothalamus to raise body temperature. Overproduction of cytokines linked to generating fever (interleukin-1, interleukin-6, interleukin-8, and tumor necrosis factor alpha) increases in concentration when pyrin fails to regulate inflammation or infection. (11)Increased concentrations of these fever-inducing cytokines are the result of both increased white blood cell concentrations and increased white blood cell activity in response to inflammation or infection.
LABORATORY RESULTS CORRELATION
The majority of routine laboratory tests are useless, but higher erythrocyte sedimentation rate and white blood cell and polymorphonuclear leukocyte concentrations have been linked to FMF during non-symptomatic periods. (5) Laboratory results will demonstrate decreased albumin concentrations, defective complement C5aINH (an inhibitor of the innate immune system's complement cascade), higher levels of fibrinogen, C-reactive protein, amyloid A protein, and haptoglobin during or shortly after an attack. (5)IgA climbed 23 percent, IgM increased 13 percent, IgG increased 17 percent, and IgD increased 13 percent in studies evaluating immunoglobulin (Ig) levels in the blood. Because FMF is caused by the presence of the MEFV gene, PCR can be used to identify some of the most common mutations (see Table 3). (5,6) Although there are many other variants that can cause FMF, the mutations M6994V and V726A have the strongest link to renal amyloidosis. (5,6) When FMF was detected, the patient's M6994V and V726A mutations were evaluated. The presence of the mutation V726A was discovered.
The patient's hematology and chemistry results, as shown in Table 1, clearly indicate a heightened immunological response. This immunological response can be shown in the increased white blood cell count, erythrocyte sedimentation rate, increased presence of band neutrophils, increased neutrophil concentrations, and increased acute phase protein concentrations. Because of the patient's prolonged fever, acute phase proteins and a progressive shift in white blood cell type have increased at the outset of an inflammatory response. (11) The generation of white blood cells is boosted when a person has a chronic fever. Neutrophils are the most prevalent white blood cell type in the body, and their primary role is to combat infection and inflammation. They are an important part of the innate immune system. (11) In FMF, a mutation in the neutrophil pyrin gene causes a constitutively active acute phase response, which is followed by enhanced neutrophil production and an increased acute phase protein response. (6,12)
When inflammation occurs, acute phase proteins are present in the blood and their concentration rises. Acute phase proteins are divided into various categories, each of which has a different physiological purpose for the immune system. C-reactive protein and serum amyloid A are two of the most prominent proteins. Serum amyloid A, in particular, attracts immune cells to the site of inflammation and activates enzymes that breakdown extracellular matrixes. (11) As a result of the lack of pyrin, significant levels of amyloid protein are formed, which has collected in the kidney and induced inflammation. Acute kidney failure is caused by this accumulation, as seen by increased creatinine levels and a low eGFR. (13)
Table 2 shows that urobilinogen levels are enhanced, ketones, microalbumin, and proteins are abnormally present, and the urine has a higher specific gravity. Urobilinogen in the urine indicates hemolytic anemia; the patient's chronic inflammation is likely to be the cause of this excessive red blood cell disintegration. (13) The presence of ketones in the urine is a result of the patient's elevated fever. High fever speeds up the body's metabolism, causing fat to be burned for energy and the release of ketones into the urine. (13) Microalbuminuria occurs when glomerular function is lost, resulting in albumin in the urine. (13) This is caused by injury to the kidneys' small blood channels. Albumin is a protein found in the blood that is linked to acute renal failure when it is detected in the urine. (13) Other proteins, such albumin, should not be present in the urine; nevertheless, amyloid proteins accumulate in the kidneys during renal amyloidosis, causing proteinuria.
TREATMENT
There are a few things that need to be considered before treatment can begin. A proper patient diagnosis, a review of symptom occurrences, and an assessment of the patient's reaction to colchicine are among these considerations. A diagnosis of FMF is made primarily if the patient exhibits associated clinical symptoms, if the patient has a Mediterranean ancestry, and if genetic test results for MEFV are positive. (2,4,8) More than 35 gene mutations have been identified as being responsible for FMF thus far. (4) These known gene mutations can be discovered using PCR technique (Table 3 identifies the 16 most clinically relevant mutations). After a diagnosis has been obtained and the patient has been determined to be tolerant of colchicine, treatment with the drug can begin. (8)
Colchicine is an FDA-approved medication used to treat conditions like FMF, gout, and Behcet's illness. (14) Microtubule polymerization and actin polymerization are two biological actions of the molecule. (15) Colchicine polymerizes microtubules through attaching to beta-tubulins, one of the microtubule's primary constituents. Mitosis is suppressed and cell motility and activity are altered when tubulins become functionally unavailable due to cochicine binding (beta-tubulin-colchicine complex). Colchicine causes neutrophil cell stiffness by causing actin polymerization. (15) The anti-inflammatory action of these two types of polymerization (microtubule and actin) lowers the inflammation seen in FMF patients. The accumulation of amyloid protein in the tissue can be slowed, and secondary amyloidosis can be avoided or reversed if colchicine treatment is given in a timely manner (dependent on the severity).
For many FMF patients, colchicine is the most effective medication. This drug should be given on a regular basis to reduce the frequency and severity of episodes, as well as to prevent or treat secondary amyloidosis. It works primarily by reducing leukocyte mobility and limiting phagocytosis in inflammatory responses. Colchicine is relatively safe, with only a few side effects such as stomach distress and neutropenia being reported.
Colchicine is relatively safe, with only a few side effects such as stomach distress and neutropenia being reported. In a study of 68 FMF patients with secondary renal amyloidosis, Livneh et al found that the therapeutic dosage is > 1.5 mg/day; nevertheless, the normal dosage administered ranges from 0.5-2 mg/day. (16) Analgesia or non-steroidal anti-inflammatory medicines such as diclofenac, etodolac, or sulindac are further therapy possibilities. (17) Corticosteroids have not been proved to be very effective, and in some situations, they have been shown to be ineffective; however, the reason for corticosteroid ineffectiveness with FMF treatment is still unknown. (2)
CONCLUSION
The patient had been effectively treated for FMF with the development of secondary amyloidosis of his right kidney when he was discharged from the hospital. The results of the tests confirmed the presence of inflammation and kidney failure. The detection of a MEFV mutation by PCR, together with the patient's history, were the major results that led to the diagnosis of FMF. The patient was given a total daily dose of 1.8 mg of colchicine and was closely monitored. The accumulation of amyloid in the kidneys diminished as the inflammation lessened, and function was restored. Because this is a genetic illness, the patient will almost certainly continue to experience FMF episodes. However, by taking colchicine on a regular basis, the frequency and severity of infections should be greatly reduced.
REFERENCES
(1.) National Human Genome Research Institute: Learning About Familial Mediterranean Fever. Available from http://www.genome.gov/12510679. Accessed 2010 Jun 25.
(2.) Thoene J, Doris S, editors. Physician's Guide to Rare Diseases. New Jersey: Dowden Publishing Company; 1992.
(3.) Warrell D, Cox T, editors. Oxford Textbook of Medicine. 4th ed. Oxford University Press: 2005.
(4.) LeBlond R, Brown D, DeGowin R, editors. De Gowin's Diagnostic Examination. 9th ed. New York: McGraw-Hill; 2009.
(5.) Medlej-Hashim M, Loiselet J, Lefranc G, Megarbane A. Familial Mediterranean Fever (FMF): from diagnosis to treatment. Sante. 2004; 14(4):261-6.
(6.) Genetics Home Reference: MEFV. Available from http://ghr.nlm.nih.gov/gene=mefv. Accessed 2010 Jun 25.
(7.) Reed J, editor. Comparative analysis of apoptosis and inflammation genes of mice and humans. Genome Research. 2003; 13(6B):1376-88.
(8.) McPhee S, Papadakis M, Tierng L, editors. Current Medical Diagnosis & Treatment. 47th ed. New York, Chicago, San Francisco: McGraw-Hill; 2008.
(9.) Wallach J, editor. Interpretation of Diagnostic Tests: A Synopsis of Laboratory Medicine. 5th ed. Boston: Little, Brown and Company; 1992.
(10.) Koopman W, editor. Clinical Primer Of Rheumatology. Philadelphia: Lippincott Williams & Wilkins; 2003.
(11.) Stevens C, editor. Clinical Immunology and Serology. 2nd ed. Philadelphia: F.A. Davis Company; 2003.
(12.) Genetics Home Reference: Familial Mediterranean Fever. Available from http://ghr.nlm.nih.gov/condition=familialmediterraneanfever. Accessed 2010 Jun 25.
(13.) Strasinger S, editor. Urinalysis And Body Fluids. 3rd ed. Philadelphia: F.A. Davis Company; 1989.
(14.) U.S. Food and Drug Administration: News and Events. Available from http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm174620.htm. Accessed 2010 Jun 25.
(15.) Tsai MA, Waugh RE, Keng PC. Passive mechanical behavior of human neutrophils: effects of colchicine and paclitaxel. Biophysical Journal. 1998; 74(6):3282-91.
(16.) Livneh A, Zemer D, Langevitz P, Laor A, Sohar E, Pras M. Colchicine treatment of AA amyloidosis of familial Mediterranean fever. An analysis of factors affecting outcome. Arthritis Rheum. 1994; 37(12):1804-11.
(17.) Merck: Amyloidosis. Available from http://www.merck.com/mmhe/sec25/ch304/ch304a.html. Accessed 2010 Jun 25.
Christopher Larrimore, North Annapolis, MD 21409
Address for correspondence: Christopher Larrimore, 1006 Commander's Way North Annapolis, MD 21409, (410) 725-6609, cwlarrimore@hotmail.com
Table 1. Hematology and Chemistry Laboratory Results
Analyte (1) Adm Day 1 Day 2 Day 3 (2) Ref Range
Hematology:
Band Neutrophils 8 9 7 5 2 -6 %
Neutrophils 75 74 72 69 50 -70 %
Lymphocytes 10 12 14 19 20 -44 %
Monocytes 3 3 4 5 2 -9 %
Eosinophils 4 2 3 2 0 -4 %
Basophils 0 0 0 0 0 -2 %
4.7-6.1 x
RBC count 3.8 4.0 4.5 4.9 (10.sup.12)/L
Reticulocytes 2.5 2.4 1.9 1.4 0.5-2.0 %
150-400 x
Platelets 215 225 219 223 [10.sup.9]/L
(3) Sed Rate 19 17 14 13 0-15 mm/hr
4.8-10.8 x
WBC count 12.5 12.3 11.9 11.0 [10.sup.9]/L
Hematocrit 39 39 40 42 42-52 %
Hemoglobin 13 13 13 14 14-18 g/dL
Chemistry:
Creatinine 1.3 1.2 1.0 1.0 0.6-1.2 mg/dL
BUN 10 11 13 12 8-21 mg/dL
C-Reactive Protein 250 100 20 0.7 0.5 mg/dL
Serum Amyloid-A 25.3 13 4 0.9 0.03 mg/dL
eGFR 28 27 45 59 > 60 ml/min
(1) Adm = Admission,
(2) Ref = Reference,
(3) Sed = Sedimentation
Table 2. Urine and PCR Laboratory Results
Analyte (1) Adm Day 1 Day 2 Day 3 (2) Ref Range
Urine:
Urine RBC 2 1 0 0 0-5/hpf
Urine Leukocyte Neg Neg Neg Neg Neg
0.1-1.0
Urobilinogen 2.2 2.0 1.3 0.8 E.U./dL
Urine Bilirubin Neg Neg Neg Neg Neg
Specific Gravity 1.030 1.026 1.010 1.009 1.005-1.030
pH 7.10 7.13 7.25 7.26 5.0-8.0
Glucose Neg Neg Neg Neg Neg
Protein + 2 +2 Neg Neg Neg
Ketones Trace Neg Neg Neg Neg
Microalbumin Present Present Neg Neg Neg
PCR:
Mutations V726A
(1) Adm = Admission, (2) Ref = Reference
Table 3. Clinically Relevant Mutations of MEFV
Exon Mutation
2 E148Q, E167D, T267I
3 P369S
5 R408Q, F479L
10 M680I (x2), T681I, 1692del, M694del, M694V,
M694I, K695R, V726A, A744S, R761H