Before the advent of colchicine prophylaxis, systemic amyloidosis was a common complication of FMF. It is caused by deposition of a fragment of serum amyloid A, an acute-phase reactant, in the kidneys, adrenals, intestine, spleen, lung, and testes (Chap. 15). Amyloidosis should be suspected in patients who have proteinuria between attacks; renal or rectal biopsy is used most often to establish the diagnosis. Risk factors include the M694V homozygous genotype, positive family history (independent of FMF mutational status), the SAA 1 genotype, male gender, noncompliance with colchicine therapy, and having grown up in the Middle East.
Diagnosis
For typical cases, physicians experienced with FMF can often make the diagnosis on clinical grounds alone. Clinical criteria sets for FMF have been shown to have high sensitivity and specificity in parts of the world where the pretest probability of FMF is high. Genetic testing can provide a useful adjunct in ambiguous cases or for physicians not experienced in FMF. Most of the disease-associated FMF mutations are in exon 10 of the gene, with a smaller group ofmutations in exon 2.An updated list of mutations for FMF and other hereditary periodic fevers can be found online at http://fmf.igh.cnrs.fr/infevers/.
Genetic testing has permitted a broadening of the clinical spectrum and geographic distribution of FMF and may be of prognostic value. Most studies indicate that M694V homozygotes have an earlier age of onset and a higher frequency of arthritis, rash, and amyloidosis. In contrast, the E148Q mutation is usually associated with milder disease. E148Q is sometimes found in cis with exon 10 mutations, which complicates the interpretation of genetic test results. Only ~70% of patients with clinically typical FMF have two identifiable mutations in trans, suggesting either that current screening methods do not detect all of the relevant mutations or that one mutation may be sufficient to cause disease under some circumstances. In these cases clinical judgment is very important, and sometimes a therapeutic trial of colchicine may help to confirm the diagnosis. Genetic testing of unaffected individuals is usually inadvisable, because of the possibility of nonpenetrance and the potential impact of a positive test on future insurability.
If a patient is seen during his or her first attack, the differential diagnosis may be broad, although delimited by the specific organ involvement. After several attacks the differential diagnosis may include the other hereditary periodic fever syndromes (Table 14-1); the syndrome of periodic fever with aphthous ulcers, pharyngitis, and cervical adenopathy (PFAPA); systemic-onset juvenile rheumatoid arthritis or adult Still’s disease; porphyria; hereditary angioedema; inflammatory bowel disease; and, in women, gynecologic disorders.
Treatment:
Familial Mediterranean Fever
The treatment of choice for FMF is daily oral colchicine, which decreases the frequency and intensity of attacks and prevents the development of amyloidosis in compliant patients. Intermittent dosing at the onset of attacks is not as effective as daily prophylaxis and is of unproven value in preventing amyloidosis. The usual adult dose of colchicine is 1.2-1.8 mg/d, which causes substantial reduction in symptoms in two-thirds of patients and some improvement in >90%.Children may require lower doses, although not proportionately to body weight.
Common side effects of colchicine include bloating, abdominal cramps, lactose intolerance, and diarrhea. They can be minimized by starting at a low dose and gradually advancing as tolerated, splitting the dose, use of simethecone for flatulence, and avoidance of dairy products. If taken by either parent at the time of conception, colchicine may cause a small increase in the risk of trisomy 21 (Down syndrome). In elderly patients with renal insufficiency,colchicine can cause a myoneuropathy characterized by proximal muscle weakness and elevation of the creatine kinase.Cyclosporine inhibits hepatic excretion of colchicine by its effects on the MDR-1 transport system, sometimes leading to colchicine toxicity in patients who have undergone renal transplantation for amyloidosis. Intravenous colchicine should generally not be administered to patients already taking oral colchicine, because severe, sometimes fatal, toxicity can occur in this setting.
There are no established alternatives for the small number of patients who do not respond to colchicine or cannot tolerate therapeutic dosages, although the IL-1 receptor antagonist and inhibitors of interferon-α and tumor necrosis factor (TNF) are investigational. Bone marrow transplantation has been suggested for refractory FMF, but the risk-benefit ratio is currently regarded as unacceptable.
Other Hereditary Recurrent Fevers
Within 5 years of the discovery of the FMF gene, three additional genes causing five other hereditary periodic fever syndromes were identified, catalyzing a paradigm shift in diagnosis and treatment of these disorders.
TNF Receptor-Associated Periodic Syndrome (TRAPS)
TRAPS is caused by dominantly inherited mutations in the extracellular domains of the 55-kDa TNF receptor (TNFRSF1A, p55). Although originally described in a large Irish family (and hence the name familial Hibernian fever), TRAPS has a broad ethnic distribution. TRAPS episodes often begin in childhood. The duration of attacks ranges from 1-2 days to as long as several weeks, and in severe cases symptoms may be nearly continuous. In addition to peritoneal, pleural, and synovial attacks similar to FMF, TRAPS patients frequently have ocular inflammation (most often conjunctivitis and/or periorbital edema), and a distinctive migratory myalgia with overlying painful erythema may be present. TRAPS patients generally respond better to glucocorticoids than to prophylactic colchicine.About 15% develop amyloidosis.The diagnosis of TRAPS is based on the demonstration of TNFRSF1A mutations in the presence of characteristic symptoms. Leukocytes from patients with certain TRAPS mutations exhibit a defect in TNF receptor-shedding, possibly impairing normal homeostasis. However, a more complex picture is emerging, with a number of functional abnormalities, some of which are ligand independent, contributing to the autoinflammatory phenotype. Etanercept, a TNF inhibitor, ameliorates TRAPS attacks, although its effect on amyloidosis is unproven.
Hyperimmunoglobulinemia D with Periodic Fever Syndrome (HIDS)
HIDS is a recessively inherited recurrent fever syndrome found primarily in individuals of northern European ancestry. It is caused by mutations in mevalonate kinase (MVK), encoding an enzyme involved in the synthesis of cholesterol and nonsterol isoprenoids. Attacks usually begin in infancy, and last 3-5 days. Clinically distinctive features include painful cervical adenopathy, a diffuse maculopapular rash sometimes affecting the palms and soles, and aphthous ulcers; pleurisy is rare, as is amyloidosis. Although originally defined by the persistent elevation of serum IgD, disease activity is not related to IgD levels, and some patients with FMF or TRAPS may have modestly increased serum IgD. Moreover, occasional patients with MVK mutations and periodic fever have normal IgD levels. All patients with mutations have markedly elevated urinary mevalonate levels during their febrile attacks, although the inflammatory manifestations are likely to be due to a deficiency of isoprenoids rather than an excess of mevalonate. There is currently no established treatment for HIDS.
The Cryopyrinopathies
Three hereditary febrile syndromes, familial cold autoin-flammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID), are all caused by mutations in CIAS1, the gene encoding cryopyrin (or NALP3), and represent a clinical spectrum of disease. FCAS patients develop chills, fever, headache, arthralgia, conjunctivitis, and an urticarialike rash in response to generalized cold exposure. In MWS, an urticarial rash is noted, but it is not usually induced by cold; MWS patients also develop fevers, abdominal pain, limb pain, arthritis, conjunctivitis, and, over time, sensorineural hearing loss. NOMID is the most severe of the three disorders, with chronic aseptic meningitis, a characteristic arthropathy, and rash. Like the FMF protein, pyrin, cryopyrin has an N-terminal PYRIN domain. Cryopyrin regulates IL-1 ß production through the formation of a macromolecular complex termed the inflammasome. Macrophages from cryopyrin-deficient mice exhibit decreased IL-1ß production in response to certain gram-positive bacteria, bacterial RNA, and monosodium urate crystals. Patients with all three cryopyrinopathies show a dramatic response to daily injections of anakinra, the IL-1 receptor antagonist.
Amyloidosis
General Principles
Amyloidosis is a term for diseases that are due to the extracellular deposition of insoluble polymeric protein fibrils in tissues and organs. These diseases are a subset of a growing group of disorders caused by misfolding of proteins. Among these are Alzheimer’s disease and other neurodegenerative diseases, transmissible prion diseases, and some genetic diseases caused by mutations that lead to misfolding and protein loss of function, such as certain of the cystic fibrosis mutations. Amyloid fibrils share a common ß-pleated sheet structural conformation that confers unique staining properties. The name amyloid is attributed to the pathologist Virchow, who in 1854 thought such deposits were cellulose-like.
Amyloid diseases are defined by the biochemical nature of the protein in the fibril deposits and are classified according to whether they are systemic or localized, acquired or inherited, and by their clinical patterns (Table 15-1).The accepted nomenclature is AX, where A indicates amyloidosis and X represents the protein in the fibril. AL is amyloid composed of immunoglobulin (Ig) light chains (LCs), and is called primary systemic amyloidosis; it arises from a clonal B cell disorder, usually myeloma. AF groups the familial amyloidoses, most commonly due to transthyretin, the transport protein for thyroid hormone and retinol binding protein. AA amyloid is composed of the acute phase reactant serum amyloid A protein and occurs in the setting of chronic inflammatory or infectious diseases. The disease associated with AA amyloid is called secondary amyloidosis. Aß2M is amyloid composed of ß2-microglobulin and occurs in individuals with end-stage renal disease (ESRD) of long duration. Aß is the most common form of localized amyloidosis. Aß is in the brain in Alzheimer’s disease and is derived from abnormal proteolytic processing of the amyloid precursor protein (APP).
Diagnosis and treatment of the amyloidoses rests upon the pathologic diagnosis of amyloid deposits and immunohistochemical or biochemical identification of amyloid type (Fig. 15-1). In the systemic amyloidoses, the involved organs can be biopsied, but amyloid deposits may be found in any tissue of the body. Historically, blood vessels of the gingiva or rectal mucosa were examined, but the most easily accessible tissue, positive in more than 80% of patients with systemic amyloid, is fat. After local anesthesia, needle aspiration of fat from the abdominal wall can be expelled onto a slide and stained, avoiding even a minor surgical procedure. If this material is negative, kidney biopsy, endomyocardial biopsy, liver biopsy, or an endoscopic biopsy can be considered. The regular ß sheet structure of amyloid deposits exhibits a unique green birefringence by polarized light microscopy when stained with Congo red dye; the 10-nm diameter fibrils can be seen by electron microscopy. Once amyloid is found, the protein type must be determined, usually by immunohistochemistry or immunoelectron microscopy. Careful evaluation of the patient profile and clinical presentation, including age and ethnic origin, organ system involvement, underlying diseases, and family history should provide a clue to the type of amyloid.
TABLE 15-1
|
AMYLOID FIBRIL PROTEINS AND THEIR PRECURSORS |
|||
|
AMYLOID PROTEIN |
PRECURSOR |
SYSTEMIC (S) OR LOCALIZED (L) |
SYNDROME OR INVOLVED TISSUES |
|
AL |
Immunoglobulin light chain |
S, L |
Primary |
|
Myeloma-associated |
|||
|
AH |
Immunoglobulin |
S, L |
Primary |
|
heavy chain |
Myeloma-associated |
||
|
ATTR |
Transthyretin |
S |
Familial |
|
Senile systemic |
|||
|
L? |
Tenosynovium |
||
|
Aß2M |
ß2-microglobulin |
S |
Hemodialysis |
|
L? |
Joints |
||
|
AA |
(Apo)serum AA |
S |
Secondary, reactive |
|
AApoAI |
Apolipoprotein AI |
S |
Familial |
|
L |
Aortic |
||
|
AApoAII |
Apolipoprotein AII |
S |
Familial |
|
AGel |
Gelsolin |
S |
Familial |
|
ALys |
Lysozyme |
S |
Familial |
|
AFib |
Fibrinogen α-chain |
S |
Familial |
|
ACys |
Cystatin C |
S |
Familial |
|
ABria |
ABriPP |
L, S? |
Familial dementia, British |
|
ADana |
ADanPP |
L |
Familial dementia, Danish |
|
Aß |
Aß protein precursor (AßPP) |
L |
Alzheimer’s disease, aging |
|
APrP |
Prion protein |
L |
Spongiform encephalopathies |
|
ACal |
(Pro)calcitonin |
L |
C-cell thyroid tumors |
|
AIAPP |
Islet amyloid |
L |
Islets of Langerhans |
|
polypeptide |
Insulinomas |
||
|
AANF |
Atrial natriuretic factor |
L |
Cardiac atria |
|
APro |
Prolactin |
L |
Aging pituitary |
|
Prolactinomas |
|||
|
Alns |
Insulin |
L |
Iatrogenic |
|
AMed |
Lactadherin |
L |
Senile aortic, media |
|
AKer |
Kerato-epithelin |
L |
Cornea; familial |
|
A(tbn)b |
tbnb |
L |
Pindborg tumors |
|
ALac |
Lactoferrin |
L |
Cornea; familial |
a ADan is coming from the same gene as ABri and has identical N-terminal sequence. It will be a matter of further discussion whether ADan should be included in the nomenclature as a separate protein (see text).
b To be named.
Note: Proteins in italics are preliminary.
The mechanisms of fibril formation and tissue toxicity remain controversial. A common underlying mechanism involves formation of intermolecular dimers by trans β sheet interactions of partially unfolded APP, leading to the formation of multimers and higher-order polymers. Factors that contribute to fibrillogenesis include variant or unstable protein structure; extensive β-sheet conformation of the precursor protein; proteolytic processing of the precursor protein; association with components of the serum or extracellular matrix (e.g., amyloid P-component, “amyloid enhancing factor” in spleen extracts, apolipoprotein E, or glycosaminoglycans), and local physical properties, including pH of the tissue. Once the fibrils reach a critical size, they become insoluble and deposit in extracellular tissue sites. These macromolecular deposits interfere with organ function, at least in part due to cellular uptake of oligomeric amyloid precursors producing toxicity to target cells.
The clinical syndromes of the amyloidoses are associated with relatively nonspecific alterations in routine laboratory tests. Blood counts are usually normal, although the erythrocyte sedimentation rate is frequently elevated.
FIGURE 15-1
Algorithm for the diagnosis of amyloidosis and determination of type: Clinical suspicion: unexplained nephropathy, cardiomyopathy, neuropathy, enteropathy, arthropathy, and macroglossia. ApoAI, apolipoprotein AI; ApoAII, apolipoprotein AII; GI, gastrointestinal.
Patients with renal involvement will usually have proteinuria, which can be as much as 30 g/d, producing hypoalbuminemia lower than 1 g/dL. Patients with cardiac involvement will often have elevation of brain naturietic peptide (BNP), pro-BNP, and troponin. These can be useful for monitoring disease activity and have been proposed as prognostic factors; they can be falsely elevated in the presence of renal insufficiency. Patients with liver involvement, even when it is advanced, usually develop cholestasis with an elevated alkaline phosphatase but minimal elevation of the transaminases and preservation of synthetic function. In AL amyloidosis, endocrinopathies can occur, with laboratory testing demonstrating hypothyroidism, hypoad-renalism, or even hypopituitarism. These findings are not specific for amyloidosis. Diagnosis of amyloidosis rests upon two pillars: the identification of fibrillar deposits in tissues and the typing of the amyloid.
