Familial mediterranean fever

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]

Familial Mediterranean fever, also known as periodic peritonitis or recurrent polyserositis, is a rare monogenic disease with systemic manifestation.

Familial Mediterranean fever was first described in a Jewish schoolgirl by Janeway and Mosenthal in 1908. In 1955, Dr. Heller called this disorder familial Mediterranean fever, which refers to its high prevalence in this region and the key presenting feature of periodic fever. The disease was life-threatening before the introduction of colchicine in 1972.

There is no established system for the classification of familial Mediterranean fever. However, familial Mediterranean fever may be classified according to phenotypic manifestation into three subtypes/groups: type 1, type 2, and type 3.

The exact pathogenesis of familial mediterranean fever is not fully understood. However, nearly all the cases are due to a mutation in the MEFV gene, which codes for a protein called pyrin. Normally, pyrin regulates the production of interleukin-1β (IL-1β), an important pro-inflammatory cytokine. When mutation occurs, mutated protein is unable to suppress expression of IL-1β, therefore an inflammatory response would develop results in clinical manifestation of FMF. The disease inherits in an autosomal recessive mode. However, there is an increasing number of data reporting the autosomal dominant inheritance.

Familial Mediterranean fever is most often caused by a mutation in the MEFV gene. This gene creates proteins involved in inflammation. There are also reports of FMF cases in the absence of causative gene in the genetic screening.

The incidence of familial mediterranean fever is estimated 100 per 100,000 individuals worldwide. The prevalence of familial mediterranean fever differs widely according to the geographic area. In the non- Ashkenazi Jews, it ranges from 100 to 400 per 100,000 individuals. Patients of all age groups may develop the familial Mediterranean fever (FMF). However, it usually manifests during Childhood. This disorder usually affects individuals of the Turkish, Armenian, Jewish and Arabic communities. However, it is also common among western societies such as Italy, Greece, Crete, France, and Germany.

There are no established risk factors for familial Mediterranean fever. However, there are some factors which have been observed to trigger the attacks.

Common complications of familial Mediterranean fever include amyloidosis and increased risk of vasculitic disorders. The prognosis does not differ from that of the general population. However, renal involvement is the determinant factor of patient survival rate.

Familial Mediterranean fever is primarily diagnosed based on the clinical presentation.

The hallmark of familial Mediterranean fever is periodic fever and serositis. A positive history of periodic fever lasting 1 to 3 days and serositis is suggestive of FMF. Common symptoms of familial Mediterranean fever include abdominal pain, episodic fever, arthralgia, chest pain, myalgia, vomiting, and fatigue.

Common physical examination findings of familial Mediterranean fever include fever, arthritis, and skin rash.

An acute phase response is present during attacks, with high C-reactive protein levels, an elevated white blood cell count and other markers of inflammation.

There are no ECG findings associated with familial Mediterranean fever. An ECG may be helpful in the diagnosis of pericarditis, one of the possible manifestations of FMF. Findings on an ECG suggestive of/diagnostic of pericarditis are described here comprehensively.

There are no x-ray findings associated with familial Mediterranean fever. However, an x-ray may be helpful in the diagnosis of complications of the disease, which include arthritis, dilatation of the small bowel loops, splenomegaly.

There are no echocardiography/ultrasound findings associated with familial Mediterranean fever. However, echocardiography/ultrasound may be helpful in the diagnosis of complications, including pericardial effusion, pleural effusion, and hepatosplenomegaly.

There are no CT scan findings associated with familial Mediterranean fever. However, a CT scan may be helpful in the diagnosis of complications of this disease, which include splenomegaly, hepatomegaly, focal peritonitis, and etc.

There are no MRI findings associated with familial mediterranean fever. However, a MRI may be helpful in the evaluation of complications of this disease, which include hepatosplenomegaly, exertional leg pain, and specifically myalgia.

There are no other imaging findings associated with familial mediterranean fever.

A genetic test is also available now that the disease has been linked to mutations in the MEFV gene. Sequencing of exons 2, 3, 5, and 10 of this gene detects an estimated 97% of all known mutations.

The mainstay of treatment for familial Mediterranean fever is medical therapy with colchicine. Exertional leg pain may be treated with NSAIDs. Glucocorticoids may be indicated in case of protracted febrile myalgia. Although there is no alternative for colchicine in case of colchicine resistance, IL-1-blockade may be useful.

Surgical intervention is not recommended for the management of familial mediterranean fever. However, since peritonitis is one of the most common manifestations of this disorder, it should be differentiated from other possible causes requiring surgical intervention.

There are no established measures for the primary prevention of familial mediterranean fever.

There are no established measures for the secondary prevention of familial mediterranean fever.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]

Familial Mediterranean fever was first described in a Jewish schoolgirl by Janeway and Mosenthal in 1908. In 1955, Dr. Heller called this disorder familial Mediterranean fever, which refers to its high prevalence in this region and the key presenting feature of periodic fever. The disease was life-threatening before the introduction of colchicine in 1972.

• Familial Mediterranean fever was first described in a Jewish schoolgirl by Janeway and Mosenthal in 1908.^[1]
• In 1945, Dr. Siegal, an american allergy specialist, published a case report under the title of benign paroxysmal peritonitis and defined this disorder.^[2]
• In 1948, Dr. Reimann, first used the term periodic fever.
• In 1955, Dr. Heller called this disorder familial Mediterranean fever, which refers to its high prevalence in this region and the key presenting feature of periodic fever.^[3]
• In 1997, MEFV mutations were first implicated in the parthenogenesis of familial Mediterranean fever.^[4]

• The disease was life-threatening before the introduction of colchicine in 1972.^[5]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]

The exact pathogenesis of familial mediterranean fever is not fully understood. However, nearly all the cases are due to a mutation in the MEFV gene, which codes for a protein called pyrin. Normally, pyrin regulates the production of interleukin-1β (IL-1β), an important pro-inflammatory cytokine. When mutation occurs, mutated protein is unable to suppress expression of IL-1β, therefore an inflammatory response would develop results in clinical manifestation of FMF. The disease inherits in an autosomal recessive mode. However, there is an increasing number of data reporting the autosomal dominant inheritance.

• Approximately, all cases are due to a mutation in the MEFV gene, which codes for a protein called pyrin or marenostrin (from the original name of the Mediterranean sea, Marenostrum).^[1]
• Normally, pyrin regulates the production of interleukin-1β (IL-1β), an important pro-inflammatory cytokine.^[2]
• IL-1β has a pivotal role in inflammatory processes such as fever, and septic shock.
• The maturation of IL-1β depends on an enzyme called caspase-1 which is activated within inflammosomes, a cytoplasmic multiprotein platforms.
• Inflammosomes will be activated upon cellular infection or stress.
• Although, it is still not clear, it has been assumed that mutant form of pyrin is unable to suppress, therefore an inflammatory response would develop results in clinical manifestation of FMF.^[3]

• The MEFV gene is located on the short arm of chromosome 16 (16p13) which consists of 10 exons.^[4]
• The majority of mutations occur in exon 10.^[5]
• To date, approximately 300 mutations have been reported in this gene.
• Not all the reported mutations would result in the presention of the disease.
• The E148Q, M680I, M694V, M694I, and V726A mutations have been observed to be responsible for more than 80% of FMF cases in the Middle Eastern region.
• The most common disease associated gene variants are:^[6]
  • M694V
  • V726A
  • M680I
  • M694I
• The disease inherits in an autosomal recessive mode. However, there is an increasing number of data reporting the autosomal dominant inheritance.^[7][8][9]
• The incidence of mutations may differ according to the ethnicity. For example M694V is the most frequently seen mutation in turkish population.^[10]

Conditions associated with Familial Mediterranean fever include:

• Certain type of vasculitis such as:^[11]
  • IgA vasculitis
  • PAN-like vasculitis with more perirenal bleeding and CNS involvement
• Hereditary angioedema^[12]
• FMF has been associated with some neurological disorders such as:
  • Multiple sclerosis^[13]
  • Stroke^[14][15]
  • Recurrent aseptic meningitis^[16]
• Whether these disorders are a manifestation of FMF or not still need to be cleared.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]

Familial Mediterranean fever is most often caused by a mutation in the MEFV gene. This gene creates proteins involved in inflammation. There are also reports of FMF cases in the absence causative gene in the genetic screening.

• Familial Mediterranean fever is caused by a mutation in the MEFV gene.^[1]
• There are reported cases of FMF in the absence of known genetic mutation in their genetic analysis. These studies explain that, in these cases, either mutation occurred in non-coding region or the disease were developed due to unknown causes.^[2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]

Familial mediterranean fever must be differentiated from other diseases that cause fever, fatigue, weight loss, arthralgia, myalgia, rash and soft tissue swelling.

Familial mediterranean fever (FMF) should be differentiated from other conditions presenting with fever, fatigue, weight loss, arthralgia, myalgia, rash and soft tissue swelling. The differentials include the following:^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]}

Category of Disease	Diseases	Signs and symptoms														Laboratory findings
		Inheritance pattern	Fever duration	Frequency of attacks	Abdominal pain	Arthralgia/Arthritis	Chest pain	Skin rash	Myalgia/Body pain	Diarrhea/Vomiting	Neurologic manifestations	Conjunctivitis	Aphthous stomatitis	Lymphadenopathy	Splenomegaly	Complete blood count (CBC)	C- reactive protein (CRP)
																		Erythrocyte sedimentation rate (ESR)	Other findings	Genetic analysis
Autoinflammatory diseases	Familial mediterranean fever[26][27]	Autosomal recessive/dominant	12-72 h	Weekly or 3-4 times/year	+	+	+	erysipelas-like erythema	+	+	Headache	-/+	-/+	-/+	+	Leukocytosis	↑	↑	High risk for amyloidosis	Mutation in MEFV gene
	Hyper IgD with recurrent fever[27][28][29]	Autosomal recessive	3-7 days	Every 2-12 weeks	+	+	+	Diffuse maculopapular rash Polymorphous rash	+	+	Headache	–	+/-	+/-	+/-	Leukocytosis	↑	↑	Elevated srum level of IgD & IgA Chronic mevalonic aciduria	Mutation in MVK gene
	TNF receptor-associated periodic syndrome[30][31]	Autosomal dominant	3-4 weeks	Variable	+	+	–	Migrating rash with deep pain under the areas with the rash Severe pain follows the rash path in a centrifugal pattern	–	–	Headache	+	–	+/-	+	Leukocytosis	↑	↑	Periorbital edema	Mutation in TNFRSF1A gene
	Muckle-Wells Syndrome[32][33]	Autosomal dominant	2-3 days	More common during cold seasons	+	+	–	Urticaria-like rash	+	+	Headache	+	+	–	–	Leukocytosis	↑	↑	Cold-triggered attacks	Mutation in NLRP3 gene
	Familial cold urticaria[27][34]	Autosomal dominant	12-24 hours, or longer	Common in cold seasons	–	+	–	Urticaria-like rash	–	–	Headache Mild hearing loss	+	+/-	–	–	Leukocytosis	↑	↑	Cold-triggered attacks	Mutation in NLRP3 gene
	Neonatal onset multisystem inflammatory disease[27][35][36]	Autosomal dominant	Continuous	Common in cold seasons	+		+	Urticaria-like rash	+	+	Headache Aseptic meningitis Papilledema Seizure sensorineural hearing loss	+	+/-	Generalized lymphadenopathy	+	Leukocytosis	↑	↑	Intellectual disability Elevated levels of Immunoglobulins Cold-triggered attacks	Mutation in NLRP3 gene
	Pyogenic sterile arthritis, pyoderma gangrenosum, acne (Papa syndrome)[37][38]	Autosomal dominant	Variable	Variable	+/-	Destructive arthritis	+/-	Pyoderma gangrenosum ulcerative lesions Severe cystic acne	+/-	+/-	–	–	–	–	–	Leukocytosis	↑	↑	High neutrophilic content of synovial fluid Negative cultures of bone and skin	Mutation in PSTPIP1 gene
	Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA)[39][40][41]	Unkown	3-6 days	Every 21-28 days	+	+	–	–	+	+	–	–	+	Cervical lymphadenopathy	–	Leukocytosis	↑	↑	Culture negative exudative pharyngitis is a classic finding	Unknown
	Blau syndrome[42][43]	Autosomal dominant	Intermittent or persistent daily fever	Variable	+/-	+	+/-	scaly plaques Non-caseating granulomatous dermatitis in Biopsy	+	+/-	Cranial neuropathies Visual problems in 80% Peripheral neuropathies	–	+	+/-	+	Leukocytosis	↑	↑	Ophthalmologic manifestations are common	Mutation in NOD2 gene

Category of Disease	Diseases	Signs and symptoms										Laboratory findings
		Fever	Fatigue	Arthralgia	Myalgia	Soft tissue swelling/serositis	Skin rash	Weight loss	Dyspnea	Sore throat	Lymphadenopathy	Complete blood count (CBC)	Liver function tests (LFTs)	Inflammatory markers		Autoantibodies						Diagnostic tests
														Erythrocyte sedimentation rate (ESR)	C- reactive protein (CRP)	Anti-nuclear antibodies (ANA)	Rheumatoid factor (RF)	Anti- glomerular basement membrane (anti-GBM)	Anti-dsDNA	Anti-Jo1/ Anti Mi2	ANCA
Infections	HIV	+	+	+	+	+/-	–	+	+/-	+ /-	+	Leukopenia Anemia Thrombocytopenia	ALT↑ AST↑	↑	↑	–	–	–	–	–	–
	Herpesviridae	+	+	+	+	+	Papular or vesicular Erythematous base Painful	–	–	+/-	+	Leukocytosis	–	↑	↑	–	–	–	–	–	–
	Measles	+	+	+	+	–	3-5 days after fever Erythematous maculopapular rash starts on face spreads to trunk and extremities (centrifugal)	–	–	+	+	Leukocytosis	–	↑	↑	–	–	–	–	–	–
	Viral hepatitis	+	+	–	+/-	–	–	+/-	–	–	+/-	Leukocytosis	ALT↑ AST↑	↑	↑	–	–	–	–	–	–
	Parvovirus B19	+	+	+	+/-	–	Slapped cheek rash	–	–	–	+	Leukopenia Aplastic anemia (low reticulocyte count) Thrombocytopenia	ALT↑ AST↑	↑	↑	–	–	–	–	–	–
	Infective endocarditis	+	+	+	+/-	–	Purpuric	+/-	+	–	+	Leukocytosis	–	↑	↑	–	–	–	–	–	–	Blood cultures, ultrasonography
	Borreliosis, Brucellosis, Yersiniosis	+	+	+	+	–	Target rash (Borrelia) Diffuse maculopapular (Brucellosis) Erythema nodosum (Yersiniosis)	–	–	–	+	Leukocytosis	ALT↑ AST↑	↑	↑	–	–	–	–	–	–	Serology, PCR
	Syphilis and Jarisch-Herxheimer reaction	+	+	+	+	–	Non-pruritic Macular On palms and soles Round Seen in secondary syphilis Penile ulceration (painless)	–	–	+	+	Leukocytosis	ALT↑ (Uncommon) AST↑ (Uncommon)	↑	↑	–	–	–	–	–	–	Serology, PCR
	Toxoplasmosis	+	+	–	+	–	Maculopapular Palms and soles	–	–	+	+	Leukocytosis (eosinophilia)				–	–	–	–	–	–	Serology, PCR
Neoplasia	Malignant lymphoma	+	+	–	+/-	+/-	Purplish scaly rash in cases of cutaneous lymphoma	+	+	–	+	Anemia of chronic disease	In case of liver metastasis (Non-Hodgkin lymphoma): ALT↑ AST↑	↑	↑	–	–	–	–	–	–	CT, PET/CT, Bone marrow examination, lymph node biopsy
	Multicentric Castleman disease	+	+	–	–	+	–	+	+	–	+	Anemia Thrombocytopenia	–	↑	↑	–	–	–	–	–	–	Lymph node biopsy
	Angioimmunoblastic T cell lymphoma	+	+	–	–	–	Maculopapular eruption on the trunk mimicking toxic erythema	+	–	–	+	Lymphocytosis	ALT↑ AST↑	↑	↑	–	–	–	–	–	–	Lymph node biopsy
Drug hypersensitivity	Drug reaction with eosinophilia and systemic symptoms	+	+	+	+	+/-	Utricaria (Immediate type) Maculopapular (Delayed type)	–	+	–	–	Leukocytosis (eosinophilia)	–	↑	↑	–	–	–	–	–	–	Eosinophil count, skin biopsy
Autoimmune conditions	Systemic lupus erythematosus	+	+	+	+/-	+	Butter-fly shaped erythematous malar rash that spares the nasolabial folds Coin-shaped erythematous rash on extremities or trunk	+	+	–	+/-	Leukopenia Hemolytic anemia Thrombocytopenia	ALT↑ AST↑	↑	↑	+	+	–	+	–	–	Antinuclear autoantibodies
	Inflammatory myositis	+	+	–	+ (weakness > pain)	–	Macular red rash over the back of the fingers, elbows or knees (Grotton’s sign) Macular purpish or reddish rash on the upper chest or back  (Shawl-like, heliotrope rash)	–	–	–	+/-	Leukocytosis	–	↑	↑	+/-	+/-	–	–	+	–	Idem, muscle biopsy
	Rheumatoid arthritis	+	+	+	–	+	Purpura Ulcers	–	+	–	+	Anemia of chronic disease Neutropenia (Felty’s syndrome)	–	↑	↑	+/-	+/-	–	–	–	–	Anti-citrullinated peptids autoantibodies, rheumatoid factor
	Systemic vasculitides	+	+	+	–	+	Nasopharyngeal ulceration (Wegner’s granulomatosis) Erythematous rash on palms and soles (Kawasaki disease)	–	+/-	–	+/-	Leukocytosis	–	↑	↑	–	–	+/-	–	–	+	ANCA, tissue biopsy, arteriography
	Familial Mediterranean fever	+	+	+	+	+	Red rash on lower extremities (ankles and knees)	+	+ (due to pain)	–	+/-	Leukocytosis (during acute flares)	–	↑	↑	–	–	–	–	–	–	Familial history, MEFV gene analysis
	Mevalonate kinase deficiency	+	+	+	+	–	Maculopapular rash Aphthous ulcers (or stomatitis)	+	–	+	+	Leukocytosis (during acute flares)	–	↑	↑	–	–	–	–	–	–	Urinary mevalonic acid, mevalonate kinase analysis
	Reactive arthritis	+	+	+	–	–	Keratoderma blennorrhagica (palms, soles, scrotum) Circinate balanitis (penile)	–	+ (Aortic insufficiency)	–	+	Leukocytosis	–	↑	↑	–	–	–	–	–	–	HLA B27, magnetic resonance imaging
Miscellaneous	Sarcoidosis	+	+	+	–	+	Waxy skin plaques Violaceous facial lesions Erythema nodosum	+	+	–	+	Lymphopenia Eosinophilia	Normal ALT, AST ALP ↑ (infiltrative pattern)	↑	↑	–	–	–	–	–	–	Lymph node/Lung biopsy ACE levels FDG-PET

FMF must be differentiated from other causes of secondary peritonitis

Differentiating FMF from other causes of peritonitis

Disease		Prominent clinical findings	Lab tests	Tratment
Primary peritonitis	Spontaneous bacterial peritonitis	Absence of GI perforation, most closely associated with cirrhosis and advanced liver disease. Presents with abrupt onset of fever, abdominal pain, distension, and rebound tenderness.	Most have clinical and biochemical manifestations of advanced cirrhosis or nephrosis like leukocytosis,hypoalbuminemia, Prolonged prothrombin time. SAAG >1.1 g/dL, increased serum lactic acid level, or a decreased ascitic fluid pH (< 7.31) supports the diagnosis. Gram staining reveals bacteria in only 25% of cases. Diagnosed by analysis of the ascitic fluid which reveals WBC > 500/ML, and PMN >250cells/ml. Culture of ascitic fluid inoculated immediately into blood culture media at the bedside usually reveals a single enteric organism, most commonly Escherichia coli, Klebsiella, or streptococci.	Once diagnosed,it is treated with Ceftriaxone.
	Tuberculous peritonitis	Seen in 0.5% of new cases of tuberculosis particularly in young women in endemic areas as a primary infection. Presents with abdominal pain and distension, fever, night sweats, weight loss, and altered bowel habits.	Ascites is present in about half of cases. Abdominal mass may be felt in a third of cases. The peritoneal fluid is characterized by a protein concentration > 3 g/dL with < 1.1 g/dL SAAG and lymphocyte predominance of WBC. Definitive diagnosis in 80% of cases is by culture. Most patients presenting acutely are diagnosed only by laparotomy.	Combination antituberculosis chemotherapy is preferred in chronic cases.
	Continuous Ambulatory Peritoneal Dialysis (CAPD peritonitis)	Peritonitis is one of the major complications of peritoneal dialysis & 72.6% occurred within the first six months of peritoneal dialysis. Historically, coagulase-negative staphylococci were the most common cause of peritonitis in CAPD, presumably due to touch contamination or infection via the pericatheter route. Treatment for peritoneal dialysis-associated peritonitis consists of antimicrobial therapy, in some cases catheter removal is also warranted. Additional therapies for relapsing or recurrent peritonitis may include fibrinolytic agents and peritoneal lavage. Most episodes of peritoneal dialysis-associated peritonitis resolve with outpatient antibiotic treatment.	Majority of peritonitis cases are caused by bacteria (50%-due to gram positive organisms, 15% to gram negative organisms,20% were culture negative.2% of cases are caused by fungi, mostly Candida species. Polymicrobial infection in 4%.Exit-site infection was present in 13% and a peritoneal fluid leak in 3 % and M.tuberculosis 0.1%.	Initial empiric antibiotic coverage for peritoneal dialysis-associated peritonitis consists of coverage for gram-positive organisms (by vancomycin or a first-generation cephalosporin) and gram-negative organisms (by a third-generation cephalosporin or an aminoglycoside). Subsequently, the regimen should be adjusted based on culture and sensitivity data. Cure rates are approximately 75%.
Secondary peritonitis	Acute bacterial secondary peritonitis	Occurs after perforating, penetrating, inflammatory, infectious, or ischemic injuries of the GI or GU tracts. Most often follows disruption of a hollow viscus?chemical peritonitis?bacterial peritonitis(polymicrobial, includes aerobic gram negative {E coli, Klebsiella, Enterobacter, Proteus mirabilis} and gram positive { Enterococcus, Streptococcus} and anaerobes {Bacteroides, clostridia}). Presents with abdominal pain, tenderness, guarding or rigidity, distension, free peritoneal air, and diminished bowel sounds. Signs that reflect irritation of the parietal peritoneum resulting ileus. Systemic findings include fever, chills or rigors, tachycardia, sweating, tachypnea, restlessness, dehydration, oliguria, disorientation, and, ultimately, refractory shock.		Peritoneal lavage, Laparoscopy are the treatment of choice.
	Biliary peritonitis	Most often seen in cases of rupture of pathological gallbladder or bile duct or cholangitic abscess or secondary to obstruction of the biliary tract. Seen in alcoholic patients with ascites.
Tertiary peritonitis		Persistence or recurrence of intraabdominal infection following apparently adequate therapy of primary or secondary peritonitis. Associated with high mortality due to multi organ dysfunction. It presents in a similar way as other peritonitis but is recognized as an adverse outcome with poor prognosis.	Enterococcus, Candida, Staphylococcus epidermidis, and Enterobacter being the most common organisms.	Characterized by lack of response to appropriate surgical and antibiotic therapy due to disturbance in the hosts immune response.
Familial Mediterranean fever (periodic peritonitis, familial paroxysmal polyserositis)		Rare genetic condition which affects individuals of Mediterranean genetic background. Etiology is unclear. Presents with recurrent bouts of abdominal pain and tenderness along with pleuritic or joint pain. Fever and leukocytosis are common.		Colchicine prevents but does not treat acute attacks.
Granulomatous peritonitis		A rare condition caused by disposable surgical fabrics or food particles from a perforated ulcer, eliciting a vigorous granulomatous (delayed hypersensitivity) response in some patients 2-6 weeks after laparotomy. Presents with abdominal pain, fever, nausea and vomiting, ileus, and systemic complaints, mild and diffuse abdominal tenderness.	Diagnosed by the demonstration of diagnostic Maltese cross pattern of starch particles.	The disease is self-limiting. Treated with corticosteroids or anti-inflammatory agents.
Sclerosing encapsulating peritonitis		Seen in conditions associated with long term peritoneal dialysis, shunts like VP shunts, history of abdominal surgeries, liver transplantation. Symptoms include nausea, abdominal pain, diarrhea, anorexia, bloody ascites.
Intraperitoneal abscesses		Most common etiologies being Gastrointestinal perforations, postoperative complications, and penetrating injuries. Signs and symptoms depend on the location of the abscess within the peritoneal cavity and the extent of involvement of the surrounding structures. Diagnosis is suspected in any patient with a predisposing condition. In a third of cases it occurs as a sequela of generalized peritonitis. The pathogenic organisms are similar to those responsible for peritonitis, but anaerobic organisms occupy an important role. The mortality rate of serious intra-abdominal abscesses is about 30%.	Diagnosed best by CT scan of the abdomen.	Treatment consists of prompt and complete CT or US guided drainage of the abscess, control of the primary cause, and adjunctive use of effective antibiotics. Open drainage is reserved for abscesses for which percutaneous drainage is inappropriate or unsuccessful.
Peritoneal mesothelioma		Arises from the mesothelium lining the peritoneal cavity. Its incidence is approximately 300-500 new cases being diagnosed in the United States each year. As with pleural mesothelioma, there is an association with an asbestos exposure. Most commonly affects men at the age of 50-69 years. Patients most often present with abdominal pain and later increased abdominal girth and ascites along with anorexia, weight loss and abdominal pain. Mean time from diagnosis to death is less than 1 year without treatment.	CT with intravenous contrast typically demonstrates the thickening of the peritoneum. Laparoscopy with tissue biopsy or CT guided tissue biopsy with immunohistochemical staining for calretinin, cytokeratin 5/6, mesothelin, and Wilms tumor 1 antigen remain the gold standard for diagnosis.	At laparotomy the goal is cytoreduction with excision. Debulking surgery and intraperitoneal chemotherapy improves survival in some cases.
peritoneal carcinomatosis		Associated with a history of ovarian or GI tract malignancy. Symptoms include ascites, abdominal pain, nausea, vomiting.

Classification of acute abdomen based on etiology		Presentation	Symptoms			Signs			Diagnosis		Comments
			Fever	Abdominal Pain	Jaundice	Guarding	Rebound Tenderness	Bowel sounds	Lab Findings	Imaging
Common causes of Peritonitis	Primary Peritonitis	Spontaneous bacterial peritonitis	+	Diffuse	–	–	–	Hypoactive	Ascitic fluid PMN>250 cells/mm³ Culture: Positive for single organism	Ultrasound for evaluation of liver cirrhosis	–
	Secondary Peritonitis	Perforated gastric and duodenal ulcer	+	Diffuse	–	+	+	N	Ascitic fluid LDH > serum LDH Glucose < 50mg/dl Total protein > 1g/dl	Air under diaphragm in upright CXR	Upper GI endoscopy for diagnosis
		Acute cholangitis	+	RUQ	+	–	–	N	Abnormal LFT	Ultrasound shows biliary dilatation	Biliary drainage (ERCP) + IV antibiotics
		Acute cholecystitis	+	RUQ	+	–	–	Hypoactive	Hyperbilirubinemia Leukocytosis	Ultrasound shows gallstone and evidence of inflammation	Murphy’s sign
		Acute pancreatitis	+	Epigastric	+/-	–	–	N	Increased amylase / lipase	Ultrasound shows evidence of inflammation	Pain radiation to back
		Acute appendicitis	+	RLQ	–	+	+	Hypoactive	Leukocytosis	Ultrasound shows evidence of inflammation	Nausea & vomiting, decreased appetite
		Acute diverticulitis	+	LLQ	+/-	+	–	Hypoactive	Leukocytosis	CT scan and ultrasound shows evidence of inflammation
		Acute salpingitis	+	LLQ/ RLQ	–	+/-	+/-	N	Leukocytosis	Pelvic ultrasound	Vaginal discharge
Hollow Viscous Obstruction		Small intestine obstruction	–	Diffuse	–	+	+/-	Hyperactive then absent	Leukocytosis	Abdominal X ray	Nausea & vomiting associated with constipation, abdominal distention
		Volvulus	–	Diffuse	–	+	–	Hypoactive	Leukocytosis	CT scan and abdominal X ray	Nausea & vomiting associated with constipation, abdominal distention
		Biliary colic	–	RUQ	+	–	–	N	Increased bilirubin and alkaline phosphatase	Ultrasound	Nausea & vomiting
		Renal colic	–	Flank pain	–	–	–	N	Hematuria	CT scan and ultrasound	Colicky abdominal pain associated with nausea & vomiting
Vascular Disorders	Ischemic causes	Mesenteric ischemia	+/-	Periumbilical	–	–	–	Hyperactive	Leukocytosis and lactic acidosis	CT scan	Nausea & vomiting, normal physical examination
		Acute ischemic colitis	+/-	Diffuse	–	+	+	Hyperactive then absent	Leukocytosis	CT scan	Nausea & vomiting
	Hemorrhagic causes	Ruptured abdominal aortic aneurysm	–	Diffuse	–	–	–	N	Normal	CT scan	Unstable hemodynamics
		Intra-abdominal or retroperitoneal hemorrhage	–	Diffuse	–	–	–	N	Anemia	CT scan	History of trauma
Gynaecological Causes	Ovarian Cyst Complications	Torsion of the cyst	–	RLQ / LLQ	–	+/-	+/-	N	Increased ESR and CRP	Ultrasound	Sudden onset sever pain with nausea and vomiting
		Cyst rupture	–	RLQ / LLQ	–	+/-	+/-	N	Increased ESR and CRP	Ultrasound	Sudden onset sever pain with nausea and vomiting
	Pregnancy	Ruptured ectopic pregnancy	–	RLQ / LLQ	–	–	–	N	Positive pregnancy test	Ultrasound	History of missed period and vaginal bleeding

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]

The incidence of familial mediterranean fever is estimated 100 per 100,000 individuals worldwide. The prevalence of familial mediterranean fever differs widely according to the geographic area. In the non- Ashkenazi Jews, it ranges from 100 to 400 per 100,000 individuals. Patients of all age groups may develop the familial Mediterranean fever (FMF). However, it usually manifests during childhood. This disorder usually affects individuals of the Turkish, Armenian, Jewish and Arabic communities. However, it is also common among western societies such as Italy, Greece, Crete, France, and Germany.

• The incidence of familial mediterranean fever is estimated 100 per 100,000 individuals worldwide. but it has been claimed that it varies according to the ethnicity.^[1]

• The prevalence of familial mediterranean fever differs widely according to geographic area.
• In the non- Ashkenazi Jews, it ranges from 100 to 400 per 100,000 individuals.^[2]
• In Turkey, it ranges from 93 to 253 per 100,000 individuals.^[3]

• Patients of all age groups may develop the familial Mediterranean fever (FMF). However, it usually manifests during childhood.^[4]
• 90% of the individuals present the symptoms before the age of 20 years.
• Only 1% of individuals present the first symptoms after the 40 years of age.^[5] However, this may vary according to the geographical area of the study.^[6]

• FMF usually affects individuals of the Turkish, Armenian, Jewish and Arabic communities.^[7]

• FMF affects men and women equally. However, recent studies showed a slight male preponderance.^[8]

• The majority of FMF cases are reported among the nations of the Mediterranean region.^[7]
• This disorder is most commonly seen in Turkey, followed by Armenia.^[9][10]
• Among western countries, Italy has one of the highest prevalence of FMF.^[11]
• FMF cases has also been reported in in other Mediterranean countries like Greece, Crete, France, and Germany.^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]

There are no established risk factors for familial Mediterranean fever. However, there are some factors which have been observed to trigger the attacks.

There are no established risk factors for familial Mediterranean fever. However, there are some factors which have been observed to trigger the attacks, including:^[1][2]

• Physical or emotional stress
• Menstruation^[3]
• Physical trauma
• Cold exposure
• Infections
• Starvation
• Sleeplessness and tiredness

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]

Common complications of familial Mediterranean fever include amyloidosis and increased risk of vasculitic disorders. The prognosis does not differ from that of the general population. However, renal involvement is the determinant factor of patient survival rate.

• The symptoms of familial Mediterranean fever usually develop in the first two decades of life and start with symptoms such as fever and serositis.^[1]
• Serositis manifests with abdominal pain, and/or chest pain, arthralgia and/or arthritis of the hip, knee or ankle, and erysiplas-like erythema, frequently on the lower limbs.^[2]
• Fever episodes may last 1 to 3 days.
• Patients usually manifest minimal symptoms in between the attacks.
• Even i the same patient, clinical presentation may vary over time.
• If left untreated, 75% of patients with familial Mediterranean fever may progress to develop amyloidosis.^[3]

The most devastating complication of FMF is the development of AA-amyloidosis which may lead to end-stage renal disease.^[4][5]

• The development of amyloidosis has been associated with the following factors:
  • Particular MEFV mutations (M694V, M694I, or M680I)
  • Family history of amyloidosis
  • Male sex

FMF may also be complicated with non-amyloid kidney disease such as:^[6][7]

• Nephrotic syndrome
• Focal segmental glomerular sclerosis
• IgA nephropathy^[8]
• Minimal change disease
• mesangial proliferative glomerulonephritis^[9]

Other complications of FMF include:

• Emergency surgery (usually due to confusion with an acute abdomen of other cause).^[10]
• Band adhesion which may lead to bowel obstruction, pelvic pain, and reduced fertility.^[11]
• Arthritis^[12]

• Prognosis is generally excellent. However, amyloid renal involvement is the determinant factor of patient survival rate.^[4]