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.

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.

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.

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.

There is evidence that eating amyloid fibers may lead to amyloidosis. This evidence is based on studies in cattle, chickens, mice, and cheetahs. Thus, in a sense, SAA amyloidosis may be considered a contagious disease, although whether this occurs or is important in the development of naturally occurring amyloidosis remains unknown. Nevertheless, because amyloid fibers can be detected in muscle in low amounts, it raises some concern about whether people could develop amyloidosis as a result of ingesting meat from an animal with the disease.

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.

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.

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.

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.

It is possible to analyze urine samples in determining albumin, hemoglobin and myoglobin with an optimized MEKC method.

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

Along with obtaining a complete medical history, a series of biochemical tests are required in order to arrive at an accurate diagnosis that verifies the presence of the illness. In addition, imaging of the kidneys (for structure and presence of two kidneys) is sometimes carried out, and/or a biopsy of the kidneys. The first test will be a urinalysis to test for high levels of proteins, as a healthy subject excretes an insignificant amount of protein in their urine. The test will involve a 24-hour bedside urinary total protein estimation. The urine sample is tested for proteinuria (>3.5 g per 1.73 m per 24 hours). It is also examined for urinary casts, which are more a feature of active nephritis. Next a blood screen, comprehensive metabolic panel (CMP) will look for hypoalbuminemia: albumin levels of ≤2.5 g/dL (normal=3.5-5 g/dL). Then a Creatinine Clearance C test will evaluate renal function particularly the glomerular filtration capacity. Creatinine formation is a result of the breakdown of muscular tissue, it is transported in the blood and eliminated in urine. Measuring the concentration of organic compounds in both liquids evaluates the capacity of the glomeruli to filter blood. Electrolytes and urea levels may also be analysed at the same time as creatinine (EUC test) in order to evaluate renal function.

A lipid profile will also be carried out as high levels of cholesterol (hypercholesterolemia), specifically elevated LDL, usually with concomitantly elevated VLDL, is indicative of nephrotic syndrome.

A kidney biopsy may also be used as a more specific and invasive test method. A study of a sample’s anatomical pathology may then allow the identification of the type of glomerulonephritis involved. However, this procedure is usually reserved for adults as the majority of children suffer from minimum change disease that has a remission rate of 95% with corticosteroids. A biopsy is usually only indicated for children that are "corticosteroid resistant" as the majority suffer from focal and segmental glomeruloesclerosis.

Further investigations are indicated if the cause is not clear including analysis of auto-immune markers (ANA, ASOT, C3, cryoglobulins, serum electrophoresis), or ultrasound of the whole abdomen.

Primary systemic amyloidosis (AL amyloidosis or just primary amyloidosis) is a disease that involves the mesenchymal tissue, the tongue, heart, gastrointestinal tract, and skin.

Secondary systemic amyloidosis is a condition that involves the adrenal gland, liver, spleen, and kidney as a result of amyloid deposition due to a chronic disease such as Behçet's disease, ulcerative colitis, etc.

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.

RS3PE responds excellently to low dose corticosteroids, with sustained and often complete remission. Non-steroidal anti-inflammatory drugs (NSAIDs) have also been used. Hydroxychloroquine has proven effective in some cases.

A broad classification of nephrotic syndrome based on underlying cause:

Nephrotic syndrome is often classified histologically:

Conventionally, proteinuria is diagnosed by a simple dipstick test, although it is possible for the test to give a false negative reading, even with nephrotic range proteinuria if the urine is dilute. False negatives may also occur if the protein in the urine is composed mainly of globulins or Bence Jones proteins because the reagent on the test strips, bromophenol blue, is highly specific for albumin. Traditionally, dipstick protein tests would be quantified by measuring the total quantity of protein in a 24-hour urine collection test, and abnormal globulins by specific requests for protein electrophoresis. Trace results may be produced in response to excretion of Tamm–Horsfall mucoprotein.

More recently developed technology detects human serum albumin (HSA) through the use of liquid crystals (LCs). The presence of HSA molecules disrupts the LCs supported on the AHSA-decorated slides thereby producing bright optical signals which are easily distinguishable. Using this assay, concentrations of HSA as low as 15 µg/mL can be detected.

Alternatively, the concentration of protein in the urine may be compared to the creatinine level in a spot urine sample. This is termed the protein/creatinine ratio. The 2005 UK Chronic Kidney Disease guidelines states protein/creatinine ratio is a better test than 24-hour urinary protein measurement. Proteinuria is defined as a protein/creatinine ratio greater than 45 mg/mmol (which is equivalent to albumin/creatinine ratio of greater than 30 mg/mmol or approximately 300 mg/g) with very high levels of proteinuria having a ratio greater than 100 mg/mmol.

Protein dipstick measurements should not be confused with the amount of protein detected on a test for microalbuminuria which denotes values for protein for urine in mg/day versus urine protein dipstick values which denote values for protein in mg/dL. That is, there is a basal level of proteinuria that can occur below 30 mg/day which is considered non-pathology. Values between 30–300 mg/day are termed microalbuminuria which is considered pathologic. Urine protein lab values for microalbumin of >30 mg/day correspond to a detection level within the "trace" to "1+" range of a urine dipstick protein assay. Therefore, positive indication of any protein detected on a urine dipstick assay obviates any need to perform a urine microalbumin test as the upper limit for microalbuminuria has already been exceeded.

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.

Primary cutaneous amyloidosis is a form of amyloidosis associated with oncostatin M receptor. This type of amyloidosis has been divided into the following types:

- Macular amyloidosis is a cutaneous condition characterized by itchy, brown, rippled macules usually located on the interscapular region of the back. Combined cases of lichen and macular amyloidosis are termed biphasic amyloidosis, and provide support to the theory that these two variants of amyloidosis exist on the same disease spectrum.

- Lichen amyloidosis is a cutaneous condition characterized by the appearance of occasionally itchy lichenoid papules, typically appearing bilaterally on the shins.

- Nodular amyloidosis is a rare cutaneous condition characterized by nodules that involve the acral areas.

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.

Because CAPS is extremely rare and has a broad clinical presentation, it is difficult to diagnose, and a significant delay exists between symptom onset and definitive diagnosis. There are currently no clinical or diagnostic criteria for CAPS based solely on clinical presentation. Instead, diagnosis is made by genetic testing for "NLRP3" mutations. Acute phase reactants and white blood cell count are usually persistently elevated, but this is aspecific for CAPS.

Several other illnesses can present with a monoclonal gammopathy, and the monoclonal protein may be the first discovery before a formal diagnosis is made: