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Familial Renal Amyloidosis Workup

  • Author: Helen J Lachmann, MD, MRCP; Chief Editor: Vecihi Batuman, MD, FACP, FASN  more...
 
Updated: Aug 21, 2015
 

Laboratory Studies

No blood or urine test result is diagnostic of amyloidosis, but lab findings that exclude chronic inflammation or a monoclonal gammopathy in a patient with renal amyloid accumulation support the possibility of FRA. Lab tests also have a vital role in evaluating and monitoring amyloidotic organ function.

Protein-to-creatinine (Pr/Cr) ratio in random urine samples was strongly correlated with  24 hour urine protein excretion in a study of 44 patients with amyloidosis, and may be useful for screening for renal involvement. The optimal cut-off point of the Pr/Cr ratio for predicting renal involvement was 715 mg/g, with a sensitivity and specificity of 91.8% and 95.5%, respectively.[8]

Once the creatinine clearance has fallen to less than 20%, progression to end-stage renal failure is almost inevitable, although the rate of decline often does not accord with predictions and may be remarkably slow. On the other hand, step-wise deteriorations in renal function occur quite frequently, even in the absence of any identifiable intercurrent renal insult such as dehydration, infection, or venous thrombosis.

Liver function test results tend to remain normal until the liver has been extensively infiltrated by amyloid, and even marked hepatomegaly may be accompanied by only a modest elevation in serum alkaline phosphatase. Liver function in those with FRA is often well preserved for decades, and elevations of serum bilirubin and transaminase levels occur at a very late stage. A bilirubin value of just twice the upper limit of normal is associated with a very poor prognosis and incipient liver failure.

Hematological indices and coagulation tend to be unremarkable, although a hyposplenic picture can occur. Occult GI blood loss should be considered in patients with anemia that is not secondary to renal impairment.

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Imaging Studies

Anatomical imaging modalities (eg, plain radiography, computed tomography [CT] scan, magnetic resonance imaging [MRI], ultrasonography) typically yield nonspecific findings in patients with systemic amyloidosis. However, a study by Barreiros et al suggests that ultrasonography can reveal signs of amyloidosis in various organs.[9] In an examination of 30 patients with systemic amyloidosis, including 19 suffering from familial amyloid polyneuropathy, the investigators found the following ultrasonographic indications of amyloidosis:

  • Heart - Myocardial thickness, pericardial and pleural effusion, and typical echorich subendocardial depositions
  • Liver and spleen - Spontaneous subcapsular hemorrhages
  • Intestine - Inhomogeneous, patchy-like depositions
  • Kidney - Somewhat unspecific results in this organ
  • Amyloidotic organs may be enlarged in the late stage of the disease, but kidney size varies and may be normal or even small at presentation.
  • Amyloid deposits are rich in calcium, and areas of calcification may develop.

Scintigraphy

Radionuclide tracers used for bone scintigraphy occasionally localize in amyloidotic organs.

Serum amyloid P (SAP) component scintigraphy was introduced in 1987 and is a sensitive, specific, and noninvasive method of quantitatively imaging amyloid deposits in vivo.[10] All amyloid fibrils bind the normal plasma protein SAP by virtue of a specific calcium-dependent ligand-protein interaction. In patients with amyloidosis, iodine I123 –labeled SAP localizes rapidly and specifically to the amyloid deposits.[2] The technique has a high diagnostic sensitivity and is the only method available for serial monitoring of the progression or regression of amyloid throughout the body.

SAP scintigraphy is eminently suitable as a screening test in patients thought to be at risk for systemic amyloid deposition, including those with known amyloidogenic mutations. However, the technique is not yet available commercially.

Serial SAP scans have shown that accumulation of amyloid tends to be much slower in patients with FRA than in those with acquired AA and AL types, and progression may not be evident, even over the course of a decade. In all types of acquired and hereditary amyloidosis that have been studied, SAP scans have also shown that amyloid deposits are often cleared gradually when the supply of amyloid fibril precursor proteins can be reduced.[11]

Scintigraphic image findings are depicted below.

Progression of amyloid deposits in a patient with Progression of amyloid deposits in a patient with amyloidosis associated with fibrinogen A alpha-chain Glu526Val. These serial posterior, whole-body, scintigraphic images were obtained following intravenous injection of iodine-123 (123I)–labeled human serum amyloid P component into a 48-year-old man with hereditary amyloidosis associated with fibrinogen A alpha-chain Glu526Val in whom asymptomatic proteinuria had been identified. Both parents were alive and well and older than age 80 years. The scan at diagnosis (left) showed modest abnormal uptake into renal amyloid deposits, which increased at follow-up 3 years later (right). The remainder of the image represents a normal distribution of tracer throughout the blood pool.
Regression of amyloidosis associated with fibrinog Regression of amyloidosis associated with fibrinogen A alpha-chain Glu526Val following hepatorenal transplantation. The pictures are serial anterior, whole-body, scintigraphic images obtained following intravenous injection of iodine-123 (123I)–labeled human serum amyloid P component into a patient with amyloidosis associated with fibrinogen A alpha-chain Glu526Val. Prior to hepatorenal transplantation (left), heavy amyloid deposition was present in an enlarged liver and spleen. No amyloid deposits were identified in a follow-up study obtained 42 months after hepatorenal transplantation (right); only a normal distribution of tracer is present throughout the blood pool.
Regression of amyloidosis associated with apolipop Regression of amyloidosis associated with apolipoprotein AI Gly26Arg following hepatorenal transplantation. These serial anterior, whole-body, scintigraphic images were obtained following intravenous injection of iodine-123 (123I)–labeled human serum amyloid P component into a patient with hereditary amyloidosis associated with apolipoprotein AI Gly26Arg. Prior to hepatorenal transplantation (left), heavy amyloid deposition was present in the liver, obscuring the kidneys. Two years after combined hepatorenal transplantation (right), a follow-up scan was normal, showing tracer distributed evenly throughout the background blood pool, including the transplanted organs. Splenic amyloid deposits that were evident initially in posterior scans had regressed at follow-up.

Echocardiography

Amyloid causes diastolic dysfunction with well-preserved contractility until a very late stage. Significant cardiac amyloid deposition is relatively unusual in patients with FRA, especially in patients with lysozyme and fibrinogen types. When it is present, however, it confers a poor prognosis.

Cardiac amyloidosis is best evaluated by a combination of echocardiography, electrocardiography (ECG), and measurement of the N-terminal of the prohormone brain natriuretic peptide (NT-pro BNP).The classic findings with 2-dimensional Doppler echocardiography are as follows:

  • Concentric biventricular wall thickening
  • Increased myocardial echodensity
  • Thickened but pliable valves
  • A restrictive filling pattern

ECG findings may be normal in patients with substantial cardiac amyloidosis, but reduced voltages, pathological Q waves (ie, pseudoinfarct pattern) in the anterior chest leads, and conduction abnormalities usually signify advanced disease.

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Other Tests

DNA analysis

DNA analysis is mandatory in all patients with systemic amyloidosis who cannot be confirmed absolutely to have the AA or AL type. Appreciating that the presence of a chronic inflammatory disease or a monoclonal gammopathy may be incidental is important.

Numerous mutations have been identified in most of the genes associated with hereditary amyloidosis, and new variants are being found regularly. Therefore, performing gene sequencing is better than using methods such as restriction fragment length polymorphism analysis, which is directed at particular known mutations.

The results of DNA analysis are not, by themselves, definitive proof of the presence of amyloid or the amyloid fibril type. These findings must be interpreted in light of other clinical and histologic findings.

Fibril protein sequencing

In cases in which identifying the amyloid fibril type by more conventional means is not possible, isolation of amyloid fibrils from a sample of fresh amyloidotic tissue enables amino acid sequencing of the fibril subunit peptide. This requires technical expertise and is time consuming but can be achieved using very small tissue samples. It is the most definitive method for typing amyloid deposits.

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Procedures

The definitive diagnosis of amyloid accumulation requires histologic confirmation; however, biopsy procedures carry an increased risk of hemorrhage in patients with amyloidosis, and bleeding may be substantial and even life-threatening in 5% of patients who undergo biopsies. This is due to the increased fragility of amyloidotic blood vessels and the reduced elasticity of severely affected organs.

Less-invasive alternatives include fine-needle aspiration of subcutaneous fat and rectal or labial salivary gland biopsy. In experienced hands, these screening biopsies can yield positive results in as many as 80% of cases; however, in routine practice, sensitivity is only approximately 50%. Also, fat aspirates are usually not suitable for immunohistochemical typing.

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Histologic Findings

Many cotton dyes, fluorescent stains such as thioflavine-T, and metachromatic stains have been used, but Congo red staining and its resultant green birefringence when viewed with high-intensity cross-polarized light has the best specificity and is the criterion standard histochemical test for amyloidosis. The stain is unstable and must be freshly prepared at least every 2 months. A section thickness of 5-10 µm and inclusion in every staining run of a positive-control tissue containing modest amounts of amyloid are critical to ensure specificity and quality control.[12]

Other problems in histologically based diagnoses include obtaining adequate tissue samples and an unavoidable element of sampling error. Biopsies cannot reveal the extent or distribution of amyloid accumulation, and failure to demonstrate amyloid in one or even several biopsies does not exclude the diagnosis.

Although many amyloid fibril proteins can be identified immunohistochemically, the demonstration of potentially amyloidogenic proteins in tissues does not, on its own, establish the presence of amyloid. Congo red staining and green birefringence are always required, and immunostaining may then enable the amyloid to be classified. Antibodies to serum amyloid A protein are commercially available and always stain AA deposits. However, in patients with AL amyloid, the deposits are stainable with standard antisera to kappa or lambda only in approximately half of all cases. This is probably because the light-chain fragment in the fibrils is usually the N-terminal variable domain, which is largely unique for each monoclonal protein.

Immunohistochemistry produces variable results in patients with FRA; the staining is typically weak in patients with fibrinogen A alpha-chain amyloid but is more reliable in patients with lysozyme and apolipoprotein AI types. Including positive tissue and absorption controls in each run is vital for optimal interpretation of the results.

The appearance of amyloid fibrils in tissues under the electron microscope is not always completely specific, and, sometimes, they cannot be identified convincingly. Although electron microscopy should be more sensitive than light microscopy, it is not sufficient by itself to confirm the diagnosis of amyloidosis.

A recent advance in diagnostic techniques is the use of laser microdissection and mass spectrometry to directly identify the components of the amyloid deposits. A large, single center study has demonstrated that proteomics can be successfully used to type amyloid deposits with more accuracy than conventional immunohistochemistry.[13]

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Contributor Information and Disclosures
Author

Helen J Lachmann, MD, MRCP Senior Lecturer, Department of Medicine, National Amyloidosis Centre, Royal Free and University College Medical School, England

Helen J Lachmann, MD, MRCP is a member of the following medical societies: Royal College of Physicians

Disclosure: Nothing to disclose.

Coauthor(s)

Philip N Hawkins, MBBS, PhD, FRCP Clinical Director of National Amyloidosis Centre, Professor, Department of Medicine, Royal Free and University College Medical School

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

George R Aronoff, MD Director, Professor, Departments of Internal Medicine and Pharmacology, Section of Nephrology, Kidney Disease Program, University of Louisville School of Medicine

George R Aronoff, MD is a member of the following medical societies: American Federation for Medical Research, American Society of Nephrology, Kentucky Medical Association, National Kidney Foundation

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FACP, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System

Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, International Society of Nephrology

Disclosure: Nothing to disclose.

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Proposed mechanism for amyloid fibril formation. The drawing depicts a generic amyloid fibril precursor protein (I) in equilibrium with a partially unfolded, molten, globulelike form of the protein (II) and its completely denatured state (III). Autoaggregation through the beta domains initiates fibril formation (IV), providing a template for ongoing deposition of precursor proteins and for the development of the stable, mainly beta-sheet, core structure of the fibril. The amyloidogenic precursor proteins in patients with familial renal amyloidosis are thought to be less stable than their wild-type counterparts, causing them to populate intermediate, molten, globulelike states more readily.
An extended kindred with hereditary amyloidosis associated with fibrinogen A alpha-chain Glu526Val; disease penetrance is high in this particular family.
Partial DNA sequence of the gene associated with fibrinogen A alpha-chain Glu526Val in a patient with familial renal amyloidosis, and a sequence from a healthy control. The mutation, which alters codon 526 from glutamic acid to valine, is marked with an arrow.
Progression of amyloid deposits in a patient with amyloidosis associated with fibrinogen A alpha-chain Glu526Val. These serial posterior, whole-body, scintigraphic images were obtained following intravenous injection of iodine-123 (123I)–labeled human serum amyloid P component into a 48-year-old man with hereditary amyloidosis associated with fibrinogen A alpha-chain Glu526Val in whom asymptomatic proteinuria had been identified. Both parents were alive and well and older than age 80 years. The scan at diagnosis (left) showed modest abnormal uptake into renal amyloid deposits, which increased at follow-up 3 years later (right). The remainder of the image represents a normal distribution of tracer throughout the blood pool.
Regression of amyloidosis associated with fibrinogen A alpha-chain Glu526Val following hepatorenal transplantation. The pictures are serial anterior, whole-body, scintigraphic images obtained following intravenous injection of iodine-123 (123I)–labeled human serum amyloid P component into a patient with amyloidosis associated with fibrinogen A alpha-chain Glu526Val. Prior to hepatorenal transplantation (left), heavy amyloid deposition was present in an enlarged liver and spleen. No amyloid deposits were identified in a follow-up study obtained 42 months after hepatorenal transplantation (right); only a normal distribution of tracer is present throughout the blood pool.
Regression of amyloidosis associated with apolipoprotein AI Gly26Arg following hepatorenal transplantation. These serial anterior, whole-body, scintigraphic images were obtained following intravenous injection of iodine-123 (123I)–labeled human serum amyloid P component into a patient with hereditary amyloidosis associated with apolipoprotein AI Gly26Arg. Prior to hepatorenal transplantation (left), heavy amyloid deposition was present in the liver, obscuring the kidneys. Two years after combined hepatorenal transplantation (right), a follow-up scan was normal, showing tracer distributed evenly throughout the background blood pool, including the transplanted organs. Splenic amyloid deposits that were evident initially in posterior scans had regressed at follow-up.
Table. Recognized Genotypes and Their Associated Phenotypes in Familial Renal Amyloidosis
Amyloid Fibril Precursor Protein Organs/Tissues Predominantly Affected by Amyloid and Common Clinical Features Ethnic Origin of Affected Kindreds
Lysozyme Ile56Thr Renal - Proteinuria and renal failure



Skin - Petechial rashes



Liver and spleen - Organomegaly (usually well-preserved function)



2 British families



(possibly related)



Lysozyme Asp67His Renal - Proteinuria and renal failure



GI tract - Bleeding and perforation



Liver and spleen - Organomegaly and hepatic hemorrhage



Salivary glands – Sicca syndrome



Single British family
Lysozyme Try64Arg Renal - Proteinuria and renal failure



GI tract - Bleeding and perforation



Salivary glands – Sicca syndrome



Single French family
Apolipoprotein AI



wild type



Amyloid deposits in human aortic atherosclerotic plaques 20-30% of elderly individuals at autopsy
Apolipoprotein AI



Gly26Arg



Renal - Proteinuria and renal failure



Gastric mucosa - Peptic ulcers



Peripheral nerves - Progressive neuropathy



Liver and spleen - Organomegaly (usually well-preserved function)



Multiple families



(mostly of northern European extraction)



Apolipoprotein AI



Trp50Arg



Renal - Proteinuria and renal failure



Liver and spleen - Organomegaly and liver failure



Single Ashkenazi family
Apolipoprotein AI



Leu60Arg



Renal - Proteinuria and renal failure



Liver and spleen - Organomegaly (usually well-preserved function)



Cardiac (rarely) - Heart failure



British and



Irish kindreds



Apolipoprotein AI



deletion 60-71



insertion 60-61



Liver - Liver failure Single Spanish family
Apolipoprotein AI



Leu64Pro



Renal - Proteinuria and renal failure



Liver and spleen - Organomegaly



Single Canadian-Italian family
Apolipoprotein AI



deletion 70-72



Renal - Proteinuria and renal failure



Liver and spleen - Organomegaly (usually well-preserved function)



Retina - Central scotoma



Single family of British origin
Apolipoprotein AI



Leu75Pro



Renal - Proteinuria and



renal failure



Liver and spleen - Organomegaly



Italy – Variable penetrance
Apolipoprotein AI



Leu90Pro



Cardiac - Heart failure



Larynx - Dysphonia



Skin – Infiltrated yellowish plaques



Single French family
Apolipoprotein AI



deletion Lys107



Aortic intima - Aggressive early-onset ischemic heart disease Single Swedish patient at autopsy
Apolipoprotein AI



Arg173Pro



Cardiac - Heart failure



Larynx - Dysphonia



Skin - Acanthosis nigricans-like plaques



British and American families
Apolipoprotein AI



Leu174Ser



Cardiac - Heart failure Single Italian family
Apolipoprotein AI



Ala175Pro



Larynx - Dysphonia



Testicular - Infertility



Single British family
Apolipoprotein AILeu178His Cardiac - Heart failure



Larynx – Dysphonia



Skin - Infiltrated plaques



Peripheral nerves – Neuropathy



Single French family
Apolipoprotein AII



Stop78Gly



Renal - Proteinuria and renal failure American family
Apolipoprotein AIIStop78Ser Renal - Proteinuria and renal failure American family
Apolipoprotein AIIStop78Arg Renal - Proteinuria and renal failure Russian family, Spanish family(different nucleotide substitutions in the two kindreds)
Fibrinogen A alpha-chain Arg554Leu Renal - Proteinuria and renal failure Peruvian,



African American and



French families



Fibrinogen A alpha-chain



frame shift at codon 522



Renal - Proteinuria and renal failure Single French family
Fibrinogen A alpha-chain



frame shift at codon 524



Renal - Proteinuria and renal failure Single American family
Fibrinogen A alpha-chain Glu526Val Renal - Proteinuria and renal failure



Late-onset liver (rarely) - Organomegaly and liver failure



Multiple families



(northern European extraction,



variable penetrance)



Fibrinogen A alpha-chain Gly540Val Renal - Proteinuria and renal failure Single German family
Fibrinogen A alpha-chain Indel 517-522 Renal - Proteinuria and renal failure Single Korean child
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