Diagnosis of amyloidosis requires tissue biopsy. The biopsy is assessed for evidence of characteristic amyloid deposits. The tissue is treated with various stains. The most useful stain in the diagnosis of amyloid is Congo red, which, combined with polarized light, makes the amyloid proteins appear apple-green on microscopy. Also, thioflavin T stain may be used.

Tissue can come from any involved organ, but in systemic disease the first-line site of the biopsy is subcutaneous abdominal fat, known as a "fat pad biopsy," due to its ease of acquisition versus biopsy of the rectum, salivary gland or internal organs. An abdominal fat biopsy is not completely sensitive, and sometimes, biopsy of an involved organ (such as the kidney) is required to achieve a diagnosis. For example, in AL amyloidosis only 85% of people will have a positive fatpad biopsy using Congo red stain. By comparison, rectal biopsy has sensitivity of 74–94%.

The type of the amyloid protein can be determined in various ways: the detection of abnormal proteins in the bloodstream (on protein electrophoresis or light chain determination); binding of particular antibodies to the amyloid found in the tissue (immunohistochemistry); or extraction of the protein and identification of its individual amino acids. Immunohistochemistry can identify AA amyloidosis the majority of the time, but can miss many cases of AL amyloidosis. Laser microdissection with mass spectrometry is the most reliable method of identifying the different forms of amyloidosis.

AL is the most common form of amyloidosis, and a diagnosis often begins with a search for plasma cell dyscrasia, memory B cells producing aberrant immunoglobulins or portions of immunoglobulins. Immunofixation electrophoresis of urine or serum is positive in 90% of people with AL amyloidosis. Immunofixation electrophoresis is more sensitive than regular electrophoresis but may not be available in all centers. Alternatively immunohistochemical staining of a bone marrow biopsy looking for dominant plasma cells can be sought in people with a high clinical suspicion for AL amyloidosis but negative electrophoresis.

ATTR, or familial transthyretin-associated amyloidosis, is suspected in people with family history of idiopathic neuropathies or heart failure who lack evidence of plasma cell dyscrasias. ATTR can be identified using isoelectric focusing which separates mutated forms of transthyretin. Findings can be corroborated by genetic testing to look for specific known mutations in transthyretin that predispose to amyloidosis.

AA is suspected on clinical grounds in individuals with longstanding infections or inflammatory diseases. AA can be identified by immunohistochemistry staining.

Median survival for patients diagnosed with AL amyloidosis was 13 months in the early 1990s, but had improved to c. 40 months a decade later.

Prognosis varies with the type of amyloidosis. Prognosis for untreated AL amyloidosis is poor with median survival of one to two years. More specifically, AL amyloidosis can be classified as stage I, II or III based on cardiac biomarkers like troponin and BNP. Survival diminishes with increasing stage, with estimated survival of 26, 11 and 3.5 months at stages I, II and III, respectively.

Outcomes in a person with AA amyloidosis depend on the underlying disease and correlate with the concentration of serum amyloid A protein.

People with ATTR have better prognosis and may survive for over a decade.

Senile systemic amyloidosis was determined to be the primary cause of death for 70% of people over 110 who have been autopsied.

Both blood and the urine can be tested for the light chains, which may form amyloid deposits, causing disease. However, the diagnosis requires a sample of an affected organ.

In a healthy individual, the median plasma concentration of SAA is 3 mg per liter. This can increase to over 2000 mg per liter during an acute phase response and a sustained overproduction of SAA is required for the creation of the AA deposits that define AA amyloidosis. High levels of SAA, however, is not a sufficient condition for the development of systemic AA amyloidosis and it remains unclear what triggers the accumulation of AA.

The AA protein is mainly deposited in the liver, spleen and kidney, and AA amyloidosis can lead to nephrotic syndrome and ESRD. Natural history studies show, however, that it is the renal involvement that drives the progression of the disease. In general, old age, reduced serum albumin concentration, end stage renal failure, and sustained elevated SAA concentration are all associated with poor prognosis.

There are currently no approved treatments for systemic AA amyloidosis. The current standard of care includes treatments for the underlying inflammatory disease with anti-inflammatory drugs, immunosuppressive agents or biologics. AA amyloidosis patients are also receiving treatments to slow down the decline of their renal function, such as angiotensin II receptor blockers or angiotensin converting enzyme inhibitors.

Kiacta - (eprodisate disodium) is in 2015 being evaluated as a protector of renal function in AA amyloidosis. Kiacta, inhibits the formation and deposition of the amyloid A fibrils into the tissues.

LECT2 amyloidosis is diagnosed by a kidney biopsy which reveals two key findings: a) histological evidence of Congo red staining material deposited in the interstitial, mesangial, glomerular, and/or vascular areas of the kidney and b) the identification of these deposits as containing mainly ALECT2 as identified by proteomics methodologies. Kidney biopsy shows the presence of LECT2-based amyloid predominantly in the renal cortex interstitium, glomeruli, and arterioles. LECT2 amyloidosis can be distinguished from AL amyloidosis, the most common form of amyloidosis (~85% of total cases), by testing their blood for the presence of high levels of a clonal immunoglobulin light chain. If the patient tests negative for this light chain, positive Congo Red staining of the kidney biopsy strongly suggests LECT2 amyloidosis.

Based on studies conducted in the United States, the prognosis for individuals with ALECT2 amyloidosis is guarded, particularly because they are elderly and their kidney disease is usually well-advanced at the time of presentation. End-stage renal disease develops in 1 out of 3 patients and has a median renal survival of 62 months. A suggested prognostic tool is to track creatinine levels in ALect2 patients. The attached Figure gives survival plotss for individuals with LECT2 renal amyloidosis and serum creatinine levels less than 2 mg/100 ml versus 2 mg/100 ml or greater than 2 mg/100 ml. The results show that afflicted individuals with lower creatinine levels have a ~four-fold higher survival rate.

A diagnosis of Waldenström's macroglobulinemia depends on a significant monoclonal IgM spike evident in blood tests and malignant cells consistent with the disease in bone marrow biopsy samples. Blood tests show the level of IgM in the blood and the presence of proteins, or tumor markers, that are the key symptoms of WM. A bone marrow biopsy provides a sample of bone marrow, usually from the back of the pelvis bone. The sample is extracted through a needle and examined under a microscope. A pathologist identifies the particular lymphocytes that indicate WM. Flow cytometry may be used to examine markers on the cell surface or inside the lymphocytes.

Additional tests such as computed tomography (CT or CAT) scan may be used to evaluate the chest, abdomen, and pelvis, particularly swelling of the lymph nodes, liver, and spleen. A skeletal survey can help distinguish between WM and multiple myeloma. Anemia is typically found in 80% of patients with WM. A low white blood cell count, and low platelet count in the blood may be observed. A low level of neutrophils (a specific type of white blood cell) may also be found in some individuals with WM.

Chemistry tests include lactate dehydrogenase (LDH) levels, uric acid levels, erythrocyte sedimentation rate (ESR), kidney and liver function, total protein levels, and an albumin-to-globulin ratio. The ESR and uric acid level may be elevated. Creatinine is occasionally elevated and electrolytes are occasionally abnormal. A high blood calcium level is noted in approximately 4% of patients. The LDH level is frequently elevated, indicating the extent of Waldenström's macroglobulinemia–related tissue involvement. Rheumatoid factor, cryoglobulins, direct antiglobulin test and cold agglutinin titre results can be positive. Beta-2 microglobulin and C-reactive protein test results are not specific for Waldenström's macroglobulinemia. Beta-2 microglobulin is elevated in proportion to tumor mass. Coagulation abnormalities may be present. Prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen tests should be performed. Platelet aggregation studies are optional. Serum protein electrophoresis results indicate evidence of a monoclonal spike but cannot establish the spike as IgM. An M component with beta-to-gamma mobility is highly suggestive of Waldenström's macroglobulinemia. Immunoelectrophoresis and immunofixation studies help identify the type of immunoglobulin, the clonality of the light chain, and the monoclonality and quantitation of the paraprotein. High-resolution electrophoresis and serum and urine immunofixation are recommended to help identify and characterize the monoclonal IgM paraprotein.

The light chain of the monoclonal protein is usually the kappa light chain. At times, patients with Waldenström's macroglobulinemia may exhibit more than one M protein. Plasma viscosity must be measured. Results from characterization studies of urinary immunoglobulins indicate that light chains (Bence Jones protein), usually of the kappa type, are found in the urine. Urine collections should be concentrated.

Bence Jones proteinuria is observed in approximately 40% of patients and exceeds 1 g/d in approximately 3% of patients. Patients with findings of peripheral neuropathy should have nerve conduction studies and antimyelin associated glycoprotein serology.

Criteria for diagnosis of Waldenström's macroglobulinemia include:

1. IgM monoclonal gammopathy that excludes chronic lymphocytic leukemia and Mantle cell lymphoma

2. Evidence of anemia, constitutional symptoms, hyperviscosity, swollen lymph nodes, or enlargement of the liver and spleen that can be attributed to an underlying lymphoproliferative disorder.

The condition is suspected in an elderly person, especially male, presenting with symptoms of heart failure such as shortness of breath or swollen legs, and or disease of the electrical system of the heart with ensuing slow heart rate, dizziness or fainting spells. The diagnosis is confirmed on the basis of a biopsy, which can be treated with a special stain called Congo Red that will be positive in this condition, and immunohistochemistry.

In the absence of symptoms, many clinicians will recommend simply monitoring the patient; Waldenström himself stated "let well do" for such patients. These asymptomatic cases are now classified as two successively more pre-malignant phases, IgM monoclonal gammopathy of undetermined significance (i.e. IgM MGUS) and smoldering Waldenström's macroglobulinemia.

But on occasion, the disease can be fatal, as it was to the French president Georges Pompidou, who died in office in 1974. Mohammad Reza Shah Pahlavi, the Shah of Iran, also suffered from Waldenström's macroglobulinemia, which resulted in his ill-fated trip to the United States for therapy in 1979, leading to the Iran hostage crisis.

Long-term haemodialysis results in a gradual accumulation of β microglobulin, a serum protein, in the blood. It accumulates because it is unable to cross the dialysis filter.

Affected individuals usually present after 5 years of dialysis rarely before that. The tendency of haemodialysis-associated amyloidosis is to be articular in general affecting the joints.

The median time to progression to end stage renal disease is 2.7 years. After 5 years, about 37% of patients with LCDD are alive and do not have end stage renal disease.

Paraproteinemias may be categorized according to the type of monoclonal protein found in blood:

- Light chains only (or Bence Jones protein). This may be associated with multiple myeloma or AL amyloidosis.

- Heavy chains only (also known as "heavy chain disease");

- Whole immunoglobulins. In this case, the paraprotein goes under the name of "M-protein" ("M" for monoclonal). If immunoglobulins tend to precipitate within blood vessels with cold, that phenomenon takes the name of cryoglobulinaemia.

The three types of paraproteins may occur alone or in combination in a given individual. Note that while most heavy chains or whole immunoglobulins remain within blood vessels, light chains frequently escape and are excreted by the kidneys into urine, where they take the name of Bence Jones protein.

It is also possible for paraproteins (usually whole immunoglobulins) to form polymers by aggregating with each other; this takes the name of macroglobulinemia and may lead to further complications. For example, certain macroglobulins tend to precipitate within blood vessel with cold, a phenomenon known as cryoglobulinemia. Others may make blood too viscous to flow smoothly (usually with IgM pentamer macroglobulins), a phenomenon known as Waldenström macroglobulinemia.

There is no standard treatment for LCDD. High-dose melphalan in conjunction with autologous stem cell transplantation has been used in some patients. A regimen of bortezomib and dexamethasone has also been examined.

Haemodialysis-associated amyloidosis is a form of systemic amyloidosis associated with chronic kidney failure.

No drug has been shown to be able to arrest or slow down the process of this condition. There is promise that two drugs, tafamidis and diflunisal, may improve the outlook, since they were demonstrated in randomized clinical trials to benefit patient affected by the related condition FAP-1 otherwise known as transthyretin-related hereditary amyloidosis. Permanent pacing can be employed in cases of symptomatic slow heart rate (bradycardia). Heart failure medications can be used to treat symptoms of difficulty breathing and congestion.

Organ-limited amyloidosis is a category of amyloidosis where the distribution can be associated primarily with a single organ. It is contrasted to systemic amyloidosis, and it can be caused by several different types of amyloid.

In almost all of the organ-specific pathologies, there is significant debate as to whether the amyloid plaques are the causal agent of the disease or instead a downstream consequence of a common idiopathic agent. The associated proteins are indicated in parentheses.

Ultrasonography and magnetic resonance imaging of the hands and/or feet have been proposed as useful diagnostic investigations in RS3PE.

Some studies linked RS3PE to HLA-B27 whereas others have not.

Some myeloma centers now employ genetic testing, which they call a “gene array.” By examining DNA, oncologists can determine if patients are high risk or low risk of the cancer returning quickly following treatment.

Cytogenetic analysis of myeloma cells may be of prognostic value, with deletion of chromosome 13, non-hyperdiploidy and the balanced translocations t(4;14) and t(14;16) conferring a poorer prognosis. The 11q13 and 6p21 cytogenetic abnormalities are associated with a better prognosis.

Prognostic markers such as these are always generated by retrospective analyses, and it is likely that new treatment developments will improve the outlook for those with traditionally "poor-risk" disease.

SNP array karyotyping can detect copy number alterations of prognostic significance that may be missed by a targeted FISH panel. In MM, lack of a proliferative clone makes conventional cytogenetics informative in only ~30% of cases.

1. Virtual karyotyping identified chromosomal abnormalities in 98% of MM cases

2. del(12p13.31) is an independent adverse marker

3. amp(5q31.1) is a favorable marker

4. The prognostic impact of amp(5q31.1) over-rides that of hyperdiploidy and also identifies patients who greatly benefit from high-dose therapy.

Array-based karyotyping cannot detect balanced translocations, such as t(4;14) seen in ~15% of MM. Therefore, FISH for this translocation should also be performed if using SNP arrays to detect genome-wide copy number alterations of prognostic significance in MM.

The diagnosis is clinically made on the basis of the history of typical attacks, especially in patients from the ethnic groups in which FMF is more highly prevalent. 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. In patients with a long history of attacks, monitoring the kidney function is of importance in predicting chronic kidney failure.

A genetic test is also available to detect mutations in the "MEFV" gene. Sequencing of exons 2, 3, 5, and 10 of this gene detects an estimated 97% of all known mutations.

A specific and highly sensitive test for FMF is the "Metaraminol Provocative Test (MPT)," whereby a single 10 mg infusion of Metaraminol is administered to the patient. A positive diagnosis is made if the patient presents with a typical, albeit milder, FMF attack within 48 hours. As MPT is more specific than sensitive, it does not identify all cases of FMF. Although a positive MPT can be very useful.

The diagnostic examination of a person with suspected multiple myeloma typically includes a skeletal survey. This is a series of X-rays of the skull, axial skeleton and proximal long bones. Myeloma activity sometimes appears as "lytic lesions" (with local disappearance of normal bone due to resorption), and on the skull X-ray as "punched-out lesions" (pepper pot skull). lesions man also be sclerotic which is seen as radiodense. Magnetic resonance imaging (MRI) is more sensitive than simple X-ray in the detection of lytic lesions, and may supersede skeletal survey, especially when vertebral disease is suspected. Occasionally a CT scan is performed to measure the size of soft tissue plasmacytomas. Bone scans are typically not of any additional value in the workup of myeloma patients (no new bone formation; lytic lesions not well visualized on bone scan).

A bone marrow biopsy is usually performed to estimate the percentage of bone marrow occupied by plasma cells. This percentage is used in the diagnostic criteria for myeloma. Immunohistochemistry (staining particular cell types using antibodies against surface proteins) can detect plasma cells which express immunoglobulin in the cytoplasm and occasionally on the cell surface; myeloma cells are typically CD56, CD38, CD138, CD319 positive and CD19 and CD45 negative. Cytogenetics may also be performed in myeloma for prognostic purposes, including a myeloma-specific FISH and virtual karyotype.

Historically, the CD138 has been used to isolate myeloma cells for diagnostic purposes. However, this antigen disappears rapidly ex vivo. Recently, however, it was discovered that the surface antigen CD319 (SLAMF7) is considerably more stable and allows robust isolation of malignant plasma cells from delayed or even cryopreserved samples.

Other useful laboratory tests include quantitative measurement of IgA, IgG, IgM (immunoglobulins) to look for immune paresis, and beta-2 microglobulin which provides prognostic information. On peripheral blood smear, the rouleaux formation of red blood cells is commonly seen, though this is not specific.

The recent introduction of a commercial immunoassay for measurement of free light chains potentially offers an improvement in monitoring disease progression and response to treatment, particularly where the paraprotein is difficult to measure accurately by electrophoresis (for example in light chain myeloma, or where the paraprotein level is very low). Initial research also suggests that measurement of free light chains may also be used, in conjunction with other markers, for assessment of the risk of progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma.

This assay, the serum free light chain assay, has recently been recommended by the International Myeloma Working Group for the screening, diagnosis, prognosis, and monitoring of plasma cell dyscrasias.

The prognosis varies widely depending upon various risk factors. The Mayo Clinic has developed a risk-stratification model termed Mayo Stratification for Myeloma and Risk-adapted Therapy (mSMART) which divides people into high-risk and standard-risk categories. People with deletion of chromosome 13 or hypodiploidy by conventional cytogenetics, t(4;14), t(14;16) or 17p- by molecular genetic studies, or with a high plasma cell labeling index (3% or more) are considered to have high-risk myeloma .

Liver transplantation has proven to be effective for ATTR familial amyloidosis due to Val30Met mutation.

Alternatively, a European Medicines Agency approved drug Tafamidis or Vyndaqel now exists which stabilizes transthyretin tetramers comprising wild type and different mutant subunits against amyloidogenesis halting the progression of peripheral neuropathy and autonomic nervous system dysfunction.

Currently there are two ongoing clinical trials undergoing recruitment in the United States and worldwide to evaluate investigational medicines that could possibly treat TTR.

Paraproteinemia, also known as monoclonal gammopathy, is the presence of excessive amounts of paraprotein or single monoclonal gammaglobulin in the blood. It is usually due to an underlying immunoproliferative disorder or hematologic neoplasms, especially multiple myeloma. It is sometimes considered equivalent to plasma cell dyscrasia.

Blood tests show a high concentration of specific gamma-globulins (monoclonal gammopathy) of the IgM type. It almost always has light chains of the κ-type. A variant in which IgG is raised has been described, which appears to be ten times as rare. The immunoglobulins may show up in the urine as Bence Jones proteins. Signs of inflammation are often present: these include an increased white blood cell count (leukocytosis) and a raised erythrocyte sedimentation rate and C-reactive protein. There can be anemia of chronic disease. Bone abnormalities can be seen on radiological imaging (often increased density or osteosclerosis) or biopsy.

Because it is such a rare condition (as of September 2014, only 281 cases have been reported), it is important to rule out other conditions which can cause periodic fevers, paraproteins or chronic hives. These include (and are not limited to) autoimmune or autoinflammatory disorders such as adult-onset Still's disease, angioedema, hematological disorders such as lymphoma or monoclonal gammopathy of undetermined significance, other causes of hives, cryoglobulinemia, mastocytosis, chronic neonatal onset multisystem inflammatory disease or Muckle–Wells syndrome.

It is however possible to have more than one rare condition as seen by a patient with Schnitzler's syndrome and cold induced urticaria.

A meeting of experts, including Dr Liliane Schnitzler (then retired) took place in Strasbourg in May 2012 and drew up diagnostic criteria known as the "Strasbourg Criteria". These included two obligate criteria (chronic urticarial rash and monoclonal IgM or IgG) and several minor criteria; a definite diagnosis requires the two obligate criteria and two minor criteria if IgM, three if IgG; a probable diagnosis requires the two obligate criteria and one (IgM) or two (IgG) minor criteria.