Secondary amyloidosis, as opposed to primary amyloidosis, is a complication of an already existing infection or inflammatory chronic disease. The localization of protein deposits varies and may assume a regional or systemic pattern.

The predominant symptoms caused by secondary amyloidosis pertain to renal dysfunction [1]. Proteinuria, gradually developing organ insufficiency, peripheral edema, fatigue, weight loss and nephrotic syndrome are direct results of renal involvement [2] [3]. Hypertension is another symptom that often perplexes the clinical picture, and it is yet to be confirmed if it is a type of renal hypertension or if a different pathophysiological mechanism underlies its onset.

Cardiac function may also be compromised due to secondary amyloidosis, although it is not a common sign; congestive heart failure may develop [4]. Other organs targeted by the disease are the thyroid gland, viscera, and blood vessels. A clinical picture resembling bowel obstruction and malabsorption may be extremely uncommon but are yet possible. Peritonitis is a potential complication of protein deposits on bowel walls and gastrointestinal bleeding can be caused by vascular amyloid presence [5]. Thyroid gland involvement leads to the development of goiter; some other patients may present with hepatosplenomegaly. Peripheral neuropathy is another possible manifestation of secondary amyloidosis.

The clinical picture is completed by the symptoms manifested due to the underlying disease itself, such as deformed extremities due to rheumatic arthritis and a variety of other symptoms not related directly to amyloidosis.

• Splenomegaly

  Hepatomegaly, splenomegaly, and autonomic neuropathy frequently occur as the disease progresses; cardiomyopathy occurs rarely. [bu.edu]

  Oedema accompanied by proteinuria was present in 88% of the cases, hepatomegaly in 17%, and splenomegaly in 11%. The mean systolic and diastolic blood pressures were 115 /-26 and 73 /-15 mmHg respectively. [ncbi.nlm.nih.gov]

  The appearance of hepatosplenomegaly in a patient with ongoing inflammation should prompt investigation for amyloidosis, although some patients with severe RA develop splenomegaly with subsequent Felty syndrome (splenomegaly and neutropenia or pancytopenia [emedicine.medscape.com]

  Others may include splenomegaly, pleuritis, pericarditis, and hepatic abnormalities 1 ). [kjim.org]

  Hepatomegaly occurs in 25% of patients, whereas splenomegaly is present in less than 5% and macroglossia in only 10%. Anemia is infrequent unless multiple myeloma, renal insufficiency, or gastrointestinal bleeding occurs. [circ.ahajournals.org]

• Anemia

  Laboratory examination revealed normocytic anemia, renal dysfunction, and proteinurea. He had been suffering from arthralgia and joint deformity, for 8 years. [ci.nii.ac.jp]

  Laboratory tests showed an increase of inflammatory reactants, anemia, hypocalcemia, and severe hypoalbuminemia and hypoproteinemia. [ncbi.nlm.nih.gov]

  P74 ) Endocrine, nutritional and metabolic diseases E70-E88 2019 ICD-10-CM Range E70-E88 Metabolic disorders Type 1 Excludes androgen insensitivity syndrome ( E34.5- ) congenital adrenal hyperplasia ( E25.0 ) Ehlers-Danlos syndrome ( Q79.6 ) hemolytic anemias [icd10data.com]

  Biochemical analysis showed mild anemia (124 g/L) and leukocytosis (12.7 x 10 9 /L) with lymphocytosis (5.75 x 10 9 /L). C-reactive protein was elevated at 71 mg/L. [acgcasereports.gi.org]

  Patients with 10% clonal plasma cells should be tested to see if they meet criteria for multiple myeloma, including screening for lytic bone lesions, anemia, renal insufficiency, and hypercalcemia. [msdmanuals.com]

• Fever of Unknown Origin

  Giant cell (temporal) arteritis (GCA) may be a cause of fever of unknown origin (FUO) in elderly patients. The development of secondary (reactive) amyloidosis is an unusual complication of the disease. [ncbi.nlm.nih.gov]

• Recurrent Diarrhea

  In this report, we discuss the association of CVID and tuberculosis to secondary amyloidosis and recurrent diarrhea. [ncbi.nlm.nih.gov]

• Periodontitis

  Periodontal health and disease were evaluated using gingival index (GI), papillary bleeding index (PBI), plaque index (PI), and periodontal disease index (PDI). [ncbi.nlm.nih.gov]

• Hepatomegaly

  Hepatomegaly, splenomegaly, and autonomic neuropathy frequently occur as the disease progresses; cardiomyopathy occurs rarely. [bu.edu]

  Oedema accompanied by proteinuria was present in 88% of the cases, hepatomegaly in 17%, and splenomegaly in 11%. The mean systolic and diastolic blood pressures were 115 /-26 and 73 /-15 mmHg respectively. [ncbi.nlm.nih.gov]

  Rarely, a more specific symptom, such as abdominal fullness or right upper quadrant discomfort (reflecting hepatomegaly), might bring the patient to the physician. [emedicine.medscape.com]

  Hepatomegaly (enlarged liver). Systemic amyloidosis Lichen amyloidosis Also called papular amyloidosis Lichen amyloidosis is the most common form of primary localised cutaneous amyloidosis. [dermnetnz.org]

  Systemic Amyloidosis Symptoms of nephrotic-range proteinuria (nondiabetic), cardiomyopathy (no ischemic history), hepatomegaly (no contrast dye filling defect by imaging) and/or peripheral neuropathy (nondiabetic) should prompt an investigation for extraocular [eyewiki.aao.org]

• Hepatosplenomegaly

  Thyroid gland involvement leads to the development of goiter; some other patients may present with hepatosplenomegaly. Peripheral neuropathy is another possible manifestation of secondary amyloidosis. [symptoma.com]

  The appearance of hepatosplenomegaly in a patient with ongoing inflammation should prompt investigation for amyloidosis, although some patients with severe RA develop splenomegaly with subsequent Felty syndrome (splenomegaly and neutropenia or pancytopenia [emedicine.medscape.com]

  These symptoms depend on the organ involved, and include nephrotic syndrome, hepatosplenomegaly, congestive heart failure, carpal tunnel syndrome, gastrointestinal (GI) symptoms and macroglossia [ 2 ]. [intechopen.com]

• Hypertension

  Rarely, primary amyloidosis may present with evidence of portal hypertension or hepatic failure. [ncbi.nlm.nih.gov]

  Hypertension is another symptom that often perplexes the clinical picture, and it is yet to be confirmed if it is a type of renal hypertension or if a different pathophysiological mechanism underlies its onset. [symptoma.com]

  Physical Examination Patients with amyloid renal disease are commonly hypertensive, although whether the hypertension is associated with the renal amyloidosis or is a coincidental finding is not always clear. [emedicine.medscape.com]

• Facial Swelling

  She later presented to our tertiary care centre with facial swelling, flushing and bilateral pedal swelling for 3 months. Along with generalized body swelling she had frothy urine. [ncbi.nlm.nih.gov]

• Quadriplegia

  There have been few reported cases of progression to frank quadriplegia. Secondary amyloidosis refers to the deposition of amyloid in various tissues due to an underlying chronic inflammatory state. [ncbi.nlm.nih.gov]

Secondary amyloidosis constitutes a diagnostic challenge, mainly because it always appears as a complication of an underlying pathology and no specific laboratory finding can ascertain the diagnosis; its initial inclusion in the differential diagnosis is, in itself, a challenge as well.

Since the primary finding is related to renal function, urinalysis is expected to show elevated protein. Serum creatinine is usually elevated, exceeding 2 mg/dL. The presence of an acidic blood pH after blood gas analysis and hypo- or hyperkalemia is indicative of renal tubular acidosis early in the course of renal dysfunction. Another pathological laboratory finding may be diminished serum albumin, less than 2.5 mg/dL. In general, the presence of proteinuria and signs of renal decompensation in a patient suffering from a known inflammatory disease, such as Chron's disease or rheumatic disorders should raise suspicion of secondary amyloidosis.

Other pathological blood parameters include polyclonal hypergammaglobulinemia, which is attributed to the underlying inflammatory process, and increased serum amyloid A precursor, which is unfortunately not pathognomonic of secondary amyloidosis in these cases.

Iodine-123–labeled serum amyloid P (SAP) component scintigraphy is a promising imaging modality which can illustrate the primary regions where amyloid deposits are organized; it is, however, not widely available [6]. Cardiac involvement can be evaluated with the use of echocardiography, electrocardiography, and catheterization [7].

A definitive diagnosis still requires deep organ biopsy for a 100% accurate result. However, since the late 20th century, subcutaneous fat tissue aspiration is opted for as the initial, noninvasive method to obtain biopsy samples in many institutions [8]. It has shown a specificity of up to 100% and sensitivity ranging between 50-80%, while the rectal mucosa biopsy, also used as a successful noninvasive technique, exhibits a similar sensitivity [9] [10]. Finally, a minor salivary gland biopsy maintains an up to 100% sensitivity in the detection of amyloid buildup [11] [12].

1. Scarpioni R, Ricardi M, Albertazzi V. Secondary amyloidosis in autoinflammatory diseases and the role of inflammation in renal damage. World J Nephrol. 2016 Jan 6;5(1):66–75.
2. Kang SJ, Yi JH, Hong HS, et al. Secondary Amyloidosis Associated with Multiple Sclerosis. J Clin Neurol. 2009 Sep;5(3):46–148.
3. Enríquez R, Sirvent AE, Padilla S, et al. Nephrotic syndrome and AA amyloidosis revealing adult-onset cryopyrin-associated periodic syndrome. Ren Fail. 2013;35(5):738-41.
4. Dubrey SW, Cha K, Simms RW, Skinner M, Falk RH. Electrocardiography and Doppler echocardiography in secondary (AA) amyloidosis. Am J Cardiol. 1996;77:313-315.
5. Sattianayagam PT, Gillmore JD, Pinney JH, et al. Inflammatory bowel disease and systemic AA amyloidosis. Dig Dis Sci. 2013 Jun;58(6):1689-97.
6. Wall JS, Williams A, Richey T, et al. A binding-site barrier affects imaging efficiency of high affinity amyloid-reactive peptide radiotracers in vivo. PLoS One. 2013;8(6):e66181.
7. Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation. 2005 Sep 27;112(13):2047-60.
8. Westermark P, Stenkvist B. A new method for the diagnosis of systemic amyloidosis. Arch Intern Med. 1973;132(4):522–523.
9. van Gameren II, Hazenberg BP, Bijzet J, Van Rijswijk MH. Diagnostic accuracy of subcutaneous abdominal fat tissue aspiration for detecting systemic amyloidosis and its utility in clinical practice. Arthritis Rheum. 2006;54(6):2015–2021.
10. Hachulla E, Grateau G. Diagnostic tools for amyloidosis. Joint Bone Spine. 2002;69(6):538–545.
11. Caporali R, Bonacci E, Epis O, Bobbio-Pallavicini F, Morbini P, Montecucco C. Safety and usefulness of minor salivary gland biopsy: retrospective analysis of 502 procedures performed at a single center. Arthritis Rheum. 2008;59(5):714–720.
12. de Asúa DR, Costa R, Galván JM, Filigheddu MT, Trujillo D, Cadiñanos J. Systemic AA amyloidosis: epidemiology, diagnosis, and management. Clin Epidemiol. 2014;6:369–377.