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.

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.

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.

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.

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.

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.

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

Other than identifying and treating any underlying conditions in secondary livedo, idiopathic livedo reticularis may improve with warming the area.

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.

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.

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.

Heredofamilial amyloidosis is an inherited condition that may be characterized by systemic or localized deposition of amyloid in body tissues.

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.

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.

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.

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.

Suggested diagnostic criteria for cryoglobulinemic disease fall into the following obligatory and additional categories:

- Obligatory criteria: 1) cold sensitivity; 2) cutaneous symptoms (i.e. urticaria, purpura, Raynaud phenomenon, ulceration/necrosis/gangrene, and/or livedo reticularis); 3) arterial and/or venous thrombotic events; fever; 4) arthralgia/myalgia; 5) neuritis in >1 site; and 6) renal disorder.

- Additional criteria: 1) typical biopsy findings at site(s) of involvement and 2) angiogram evidence of occlusion in one or more small to medium sized arteries.

The diagnosis of secondary cryofibrinogenemia also requires evidence for the cited infectious, malignant, premalignant vasculitis, and autoimmune disorders while the diagnosis of primary cryofibriongenemia requires a lack of evidence for 1) the cited associated disorders, 2) other vascular occlusive diseases, and 3) cryoglobulinemia.

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.

Livedoid vasculopathy (also known as "livedoid vasculitis", "livedo reticularis with summer/winter ulceration" and "segmental hyalinizing vasculitis") is a chronic cutaneous disease seen predominantly in young to middle-aged women. One synonym used to describe its features is "Painful purpuric ulcers with pattern of the lower extremities" (PURPLE).

It can be divided into a primary (or idiopathic) form and a secondary form, which has been associated with a number of diseases, including chronic venous hypertension and varicosities.

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.

Amyloid purpura affects a minority of individuals with amyloidosis. For example, purpura is present early in the disease in approximately 15% of patients with primary systemic amyloidosis.

Success in treating the primary disease has been reported using blood clot lysing agents such as anabolic steroids (e.g. danazol or stanozolol which is no longer available in the USA), streptokinase, and streptodornase; anticoagulants such as heparin and warfarin, and immunosuppressive drug regimens such as a corticosteroid (e.g. prednisone) combined with either azathioprine of chlorambucil. Very moderate cases may do well by simply avoiding cold exposure. Treatment with a corticosteroid plus low-dose aspirin followed by maintenance therapy with an anabolic steroid where necessary are recommended for moderately severe cases. Very severe cases generally require an immunosuppressive drug regimen and if extreme or life threatening require resorting to plasmaphoresis or plasma exchange. Cryofiltration apheresis, a method to remove plasma agents by removing cold-induced precipitated material, may be an effective alternative to plasmaphoresis and plasma exchange but is still regarded as second-line therapy for cryofibirnogenemic disease treatment.

During the several years following its initial diagnosis, some 27-47% of primary cryofibrinoginemic diseases are complicated by the development of a B-cell or T-cell lymphoma. That is, the cryofibrinoginemic disease may appear to precede by years the malignant disorder to which it is associated. Accordingly, patients require careful follow-up not only to treat their primary cryofibrinoginemic disease but also to monitor them for movement to the diagnosis of secondary cryofibrinoginemic disease caused by the development of one of these hematological malignancies.

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.