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Q: My uncle has just been diagnosed with amyloidosis. He is 76 years old. What are his options and prognosis?

Dr. Keti:

Amyloidosis by definition is accumulation in the tissues of various insoluble fibrillar proteins (amyloid) in amounts sufficient to impair normal function. Amyloidosis is a bone marrow disease. It is not a single disease entity but rather a diverse group of disease processes characterized by extracellular tissue deposits, in one or many organs, of protein materials which are generically termed amyloid. Amyloid is an abnormal protein. These proteins are fragments of immunoglobulin (antibody) molecules which are normally present in the blood to give protection against bacteria and other infectious agents. Normally, antibody molecules are constantly being synthesized by cells of the immune system and then, after a finite life span, degraded so that there is a balance between production and degradation.
Amyloid deposition may be either a primary process without known antecedent or secondary to some other condition. It can be localized to one specific site or generalized throughout the body (systemic), usually with fatal consequences. Secondary amyloidosis mainly affects organs, such as spleen, kidneys, liver, and adrenals.
Amyloid deposits typically contain three components. Amyloid protein fibrils account for about 90% of the amyloid material. In addition, amyloid deposits are associated with the glycoprotein related to normal serum amyloid P (SAP), and are closely associated with sulfated glycosaminoglycans (GAG), complex carbohydrates of connective tissue.
Systemic forms of amyloid are derived from circulating protein precursors by conversion from soluble into insoluble (fibrillar) form. The classification of amyloidosis is based upon several factors: the tissue distribution of amyloid deposits (local or systemic amyloidosis), the absence or presence of preexisting disease (primary or secondary amyloidosis), and the chemical type of amyloid protein fibril.
Examples of Systemic amyloidosis are in: Multiple myeloma. Examples of Primary Type: Heredofamilial amyloidosis, __Familial Mediterranean_Fever, Familial amyloid polyneuropathy Examples of Secondary type amyloidosis is in:
Chronic inflammatory disease, Rheumatoid arthritis, Tuberculosis, Skin and lung abscesses, Cancer, Hodgkin's disease, Hemodialysis for CRF(*) Examples of localized amyloidosis: Senile cardiac amyloidosis, Senile cerebral amyloidosis:_Alzheimer's disease, Endocrine tumors:Medullary carcinoma of thyroid gland.
Amyloidosis Related to Monoclonal Ig Light Chains: AL type of amyloidosis may be primary or may occur secondary to multiple myeloma or some other monoclonal gammopathy (immunocyte dyscrasia). It is the most common type of amyloidosis seen in the U.S. today. AL type of amyloidosis occurs in about 5-10% of patients who have preexisting or coexisting multiple myeloma. Multiple myeloma is seen mainly in patients over 40 years of age (median age of 60 years) and, next to metastatic carcinoma, is the most common malignant tumor of bone. It is a malignant tumor of plasma cells which arises in the bone marrow, permeates the medullary cavity, erodes the bone cortex, and is characterized by multiple osteolytic ("punched out") lesions of vertebrae, skull, ribs, pelvis, and other bones and by narrow-banded electrophoretic peaks of monoclonal IgG in the serum and free light chains of the same kappa or lambda type in the urine (Bence-Jones proteinuria). An identical, patient-specific, free monoclonal light chain protein is also usually present in myeloma serum but, being smaller than albumin molecules, readily passes into the urine. Overall, about 70% of myeloma patients have both serum monoclonal Ig and urinary light chains, and the remaining patients have urinary light chains alone without serum monoclonal Ig.
Noteworthy, the majority of patients who develop AL type of amyloidosis apparently do so in the absence of clinically overt myeloma or other predisposing disease, and such cases are commonly referred to as primary or idiopathic amyloidosis.
Amyloidosis associated with Inflammatory or Infectious Diseases: The amyloid deposits in this form of amyloidosis have a systemic distribution and contain AA (amyloid-associated) fibrils which are related to the nonimmunoglobulin AA protein and its serum protein precursor (SAA), an acute phase reactant synthesized by hepatic cells. Also called reactive or secondary amyloidosis, this form of amyloidosis occurs mainly as a complication of long standing inflammatory diseases, most frequently rheumatoid arthritis (5-10% of rheumatoid patients) and also dermatomyositis, scleroderma, regional enteritis, and ulcerative colitis.
Prior to the antibiotic era, chronic tissue-destructive infectious diseases, such as tuberculosis, chronic osteomyelitis, and bronchiectasis, were the most common antecedants of secondary amyloidosis. Nowdays, amyloidosis often develops as a complication of skin and lung abscesses occurring in subcutaneous heroin abusers.
Reactive-type amyloidosis may also occur in association with cancer, such as Hodgkin's disease and renal cell carcinoma.
Prior to the antibiotic era, chronic tissue-destructive infectious diseases, such as tuberculosis, chronic osteomyelitis, and bronchiectasis, were the most common antecedants of secondary amyloidosis. Nowdays, amyloidosis often develops as a complication of skin and lung abscesses occurring in subcutaneous heroin abusers.
Reactive-type amyloidosis may also occur in association with cancer, such as Hodgkin's disease and renal cell carcinoma.

Clinical Aspects
Symptoms of amyloidosis depend on the organs it affects. Symptoms can include: ·
Increased thirst and frequency of urination · Swelling of ankles and legs · Unexplained weight loss · Weakness · Shortness of breath · Numbness or tingling in the hands or feet · Diarrhea · Vomiting · Severe fatigue · Enlarged tongue · Feeling of fullness after eating smaller amounts of food than usual · Dizziness upon standing

The nephrotic syndrome is the most striking early manifestation. In the early stages, only slight proteinuria may be noted; later, the distinctive symptom complex develops with anasarca (a general accumulation of serous fluid in various tissues and body cavities), hypoproteinemia, and massive proteinuria (the presence of excessive amounts of protein in the urine). Hepatic amyloid disease produces hepatomegaly but rarely jaundice. Skin lesions may be waxy or translucent; purpura may result from amyloidosis of small cutaneous vessels.
Gastro Intestinal amyloid may cause esophageal motility abnormalities, gastric atony, motility abnormalities of the small and large intestine, malabsorption, bleeding, or pseudo-obstruction. Macroglossia is common in primary and myeloma-related amyloidoses
A firm, symmetric, nontender goiter resembling Hashimoto's or Riedel's struma may result from amyloidosis of the thyroid gland.
Amyloid arthropathy may mimic rheumatoid arthritis in rare cases of multiple myeloma.
Peripheral neuropathy, which is not an uncommon presenting manifestation, is common in some familial amyloidoses and also occurs in some cases of primary or myeloma-associated amyloidosis.
Lung involvement (mostly in AL amyloidosis) may be characterized by focal pulmonary nodules, tracheobronchial lesions, or diffuse alveolar deposits.
Lichen amyloidosus (LA) is a persistent, pruritic eruption of multiple discreet hyperkeratotic and hyperpigmented papules, which often coalesce to form plaques, frequently distributed over the shins and extensor aspect of the arms. The aetiology remains unknown. Calcipotriol ointment and betamethasonel 7-valerate ointment are equally effective in the treatment of lichen amyloidosus.
Diagnosis
Amyloidosis is suspected on the basis of symptoms and signs described above but can be diagnosed only by biopsy. Laboratory Testing for the diagnosis of amyloidosis is a tissue biopsy staining positive with Congo red and demonstrating apple-green birefringence under polarized light microscopy. Electron microscopy will also show a classical fibrillar appearance in the extracellular matrix. It is extremely important to avoid over-staining the tissue with Congo red as this may give false results Subcutaneous abdominal fat pad aspiration and biopsy of rectal mucosa are the best screening tests. Other useful biopsy sites are gingiva, skin, nerve, kidney, and liver. Tissue sections should be stained with Congo red dye and observed with a polarizing microscope for the characteristic green birefringence of amyloid. Isotopically labeled serum AP has been used in a scintigraphic test to confirm the diagnosis of amyloidosis.
Treatment
Treatment is directed first to the underlying cause; such treatment may arrest amyloidosis. Management of amyloidosis itself is generally symptomatic. Kidney transplantation has been performed in patients with renal amyloid; long-term survival is comparable to that in other renal diseases, but mortality is higher in the early years. Amyloid will ultimately recur in a donor kidney, but several recipients have done very well and have lived up to 10 yr. Current treatment of primary amyloidosis includes a program of prednisone/melphalan or prednisone/melphalan/colchicine Colchicine has been used to prevent the acute attacks of familial Mediterranean fever, and it has been shown that patients so treated develop no new amyloid and established amyloid decreases. It has been shown that in hereditary amyloidosis due to transthyretin mutations, liver transplantation, which removes the site of synthesis of the mutant protein, is very effective.
Prognosis
In secondary amyloidosis, prognosis depends on successful treatment of the underlying disease. All forms of renal amyloidosis have a poor prognosis, but patients may remain stable and even improve with supportive therapy (eg, eradication of pyelonephritis). Dialysis and kidney transplantation have further improved the prognosis. Amyloidosis associated with multiple myeloma has the poorest prognosis; death within 1 yr is common. Localized amyloid tumors may be removed without recurrence. Myocardial amyloidosis is the most common cause of death, primarily due to arrhythmias or intractable heart failure. Prognosis in familial amyloidoses varies.

References and More Informative Sites are listed below:

Article by Robert C. Mellors, M.D., Ph.D.
The Mayo Clinic
Merc.com
Silcom.com
IUPUI.edu
Bing SQ, Chang LL, kang LL et al. Primary cutaneou~ amyloidosis. Chinese Med J 1983;96: 185-200.

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Q: My uncle has just been diagnosed with amyloidosis. He is 76 years old. What are his options and prognosis?

Dr. Keti:
Amyloidosis by definition is accumulation in the tissues of various insoluble fibrillar proteins (amyloid) in amounts sufficient to impair normal function. Amyloidosis is a bone marrow disease. It is not a single disease entity but rather a diverse group of disease processes characterized by extracellular tissue deposits, in one or many organs, of protein materials which are generically termed amyloid. Amyloid is an abnormal protein. These proteins are fragments of immunoglobulin (antibody) molecules which are normally present in the blood to give protection against bacteria and other infectious agents. Normally, antibody molecules are constantly being synthesized by cells of the immune system and then, after a finite life span, degraded so that there is a balance between production and degradation. Amyloid deposition may be either a primary process without known antecedent or secondary to some other condition. It can be localized to one specific site or generalized throughout the body (systemic), usually with fatal consequences. Secondary amyloidosis mainly affects organs, such as spleen, kidneys, liver, and adrenals. Amyloid deposits typically contain three components. Amyloid protein fibrils account for about 90% of the amyloid material. In addition, amyloid deposits are associated with the glycoprotein related to normal serum amyloid P (SAP), and are closely associated with sulfated glycosaminoglycans (GAG), complex carbohydrates of connective tissue. Systemic forms of amyloid are derived from circulating protein precursors by conversion from soluble into insoluble (fibrillar) form. The classification of amyloidosis is based upon several factors: the tissue distribution of amyloid deposits (local or systemic amyloidosis), the absence or presence of preexisting disease (primary or secondary amyloidosis), and the chemical type of amyloid protein fibril. Examples of Systemic amyloidosis are in: Multiple myeloma. Examples of Primary Type: Heredofamilial amyloidosis, __Familial Mediterranean_Fever, Familial amyloid polyneuropathy Examples of Secondary type amyloidosis is in: Chronic inflammatory disease, Rheumatoid arthritis, Tuberculosis, Skin and lung abscesses, Cancer, Hodgkin's disease, Hemodialysis for CRF(*) Examples of localized amyloidosis: Senile cardiac amyloidosis, Senile cerebral amyloidosis:_Alzheimer's disease, Endocrine tumors:Medullary carcinoma of thyroid gland. Amyloidosis Related to Monoclonal Ig Light Chains: AL type of amyloidosis may be primary or may occur secondary to multiple myeloma or some other monoclonal gammopathy (immunocyte dyscrasia). It is the most common type of amyloidosis seen in the U.S. today. AL type of amyloidosis occurs in about 5-10% of patients who have preexisting or coexisting multiple myeloma. Multiple myeloma is seen mainly in patients over 40 years of age (median age of 60 years) and, next to metastatic carcinoma, is the most common malignant tumor of bone. It is a malignant tumor of plasma cells which arises in the bone marrow, permeates the medullary cavity, erodes the bone cortex, and is characterized by multiple osteolytic ("punched out") lesions of vertebrae, skull, ribs, pelvis, and other bones and by narrow-banded electrophoretic peaks of monoclonal IgG in the serum and free light chains of the same kappa or lambda type in the urine (Bence-Jones proteinuria). An identical, patient-specific, free monoclonal light chain protein is also usually present in myeloma serum but, being smaller than albumin molecules, readily passes into the urine. Overall, about 70% of myeloma patients have both serum monoclonal Ig and urinary light chains, and the remaining patients have urinary light chains alone without serum monoclonal Ig. Noteworthy, the majority of patients who develop AL type of amyloidosis apparently do so in the absence of clinically overt myeloma or other predisposing disease, and such cases are commonly referred to as primary or idiopathic amyloidosis. Amyloidosis associated with Inflammatory or Infectious Diseases: The amyloid deposits in this form of amyloidosis have a systemic distribution and contain AA (amyloid-associated) fibrils which are related to the nonimmunoglobulin AA protein and its serum protein precursor (SAA), an acute phase reactant synthesized by hepatic cells. Also called reactive or secondary amyloidosis, this form of amyloidosis occurs mainly as a complication of long standing inflammatory diseases, most frequently rheumatoid arthritis (5-10% of rheumatoid patients) and also dermatomyositis, scleroderma, regional enteritis, and ulcerative colitis. Prior to the antibiotic era, chronic tissue-destructive infectious diseases, such as tuberculosis, chronic osteomyelitis, and bronchiectasis, were the most common antecedants of secondary amyloidosis. Nowdays, amyloidosis often develops as a complication of skin and lung abscesses occurring in subcutaneous heroin abusers. Reactive-type amyloidosis may also occur in association with cancer, such as Hodgkin's disease and renal cell carcinoma. Prior to the antibiotic era, chronic tissue-destructive infectious diseases, such as tuberculosis, chronic osteomyelitis, and bronchiectasis, were the most common antecedants of secondary amyloidosis. Nowdays, amyloidosis often develops as a complication of skin and lung abscesses occurring in subcutaneous heroin abusers. Reactive-type amyloidosis may also occur in association with cancer, such as Hodgkin's disease and renal cell carcinoma.		Clinical Aspects Symptoms of amyloidosis depend on the organs it affects. Symptoms can include: · Increased thirst and frequency of urination · Swelling of ankles and legs · Unexplained weight loss · Weakness · Shortness of breath · Numbness or tingling in the hands or feet · Diarrhea · Vomiting · Severe fatigue · Enlarged tongue · Feeling of fullness after eating smaller amounts of food than usual · Dizziness upon standing The nephrotic syndrome is the most striking early manifestation. In the early stages, only slight proteinuria may be noted; later, the distinctive symptom complex develops with anasarca (a general accumulation of serous fluid in various tissues and body cavities), hypoproteinemia, and massive proteinuria (the presence of excessive amounts of protein in the urine). Hepatic amyloid disease produces hepatomegaly but rarely jaundice. Skin lesions may be waxy or translucent; purpura may result from amyloidosis of small cutaneous vessels. Gastro Intestinal amyloid may cause esophageal motility abnormalities, gastric atony, motility abnormalities of the small and large intestine, malabsorption, bleeding, or pseudo-obstruction. Macroglossia is common in primary and myeloma-related amyloidoses A firm, symmetric, nontender goiter resembling Hashimoto's or Riedel's struma may result from amyloidosis of the thyroid gland. Amyloid arthropathy may mimic rheumatoid arthritis in rare cases of multiple myeloma. Peripheral neuropathy, which is not an uncommon presenting manifestation, is common in some familial amyloidoses and also occurs in some cases of primary or myeloma-associated amyloidosis. Lung involvement (mostly in AL amyloidosis) may be characterized by focal pulmonary nodules, tracheobronchial lesions, or diffuse alveolar deposits. Lichen amyloidosus (LA) is a persistent, pruritic eruption of multiple discreet hyperkeratotic and hyperpigmented papules, which often coalesce to form plaques, frequently distributed over the shins and extensor aspect of the arms. The aetiology remains unknown. Calcipotriol ointment and betamethasonel 7-valerate ointment are equally effective in the treatment of lichen amyloidosus. Diagnosis Amyloidosis is suspected on the basis of symptoms and signs described above but can be diagnosed only by biopsy. Laboratory Testing for the diagnosis of amyloidosis is a tissue biopsy staining positive with Congo red and demonstrating apple-green birefringence under polarized light microscopy. Electron microscopy will also show a classical fibrillar appearance in the extracellular matrix. It is extremely important to avoid over-staining the tissue with Congo red as this may give false results Subcutaneous abdominal fat pad aspiration and biopsy of rectal mucosa are the best screening tests. Other useful biopsy sites are gingiva, skin, nerve, kidney, and liver. Tissue sections should be stained with Congo red dye and observed with a polarizing microscope for the characteristic green birefringence of amyloid. Isotopically labeled serum AP has been used in a scintigraphic test to confirm the diagnosis of amyloidosis. Treatment Treatment is directed first to the underlying cause; such treatment may arrest amyloidosis. Management of amyloidosis itself is generally symptomatic. Kidney transplantation has been performed in patients with renal amyloid; long-term survival is comparable to that in other renal diseases, but mortality is higher in the early years. Amyloid will ultimately recur in a donor kidney, but several recipients have done very well and have lived up to 10 yr. Current treatment of primary amyloidosis includes a program of prednisone/melphalan or prednisone/melphalan/colchicine Colchicine has been used to prevent the acute attacks of familial Mediterranean fever, and it has been shown that patients so treated develop no new amyloid and established amyloid decreases. It has been shown that in hereditary amyloidosis due to transthyretin mutations, liver transplantation, which removes the site of synthesis of the mutant protein, is very effective. Prognosis In secondary amyloidosis, prognosis depends on successful treatment of the underlying disease. All forms of renal amyloidosis have a poor prognosis, but patients may remain stable and even improve with supportive therapy (eg, eradication of pyelonephritis). Dialysis and kidney transplantation have further improved the prognosis. Amyloidosis associated with multiple myeloma has the poorest prognosis; death within 1 yr is common. Localized amyloid tumors may be removed without recurrence. Myocardial amyloidosis is the most common cause of death, primarily due to arrhythmias or intractable heart failure. Prognosis in familial amyloidoses varies. References and More Informative Sites are listed below: Article by Robert C. Mellors, M.D., Ph.D. The Mayo Clinic Merc.com Silcom.com IUPUI.edu Bing SQ, Chang LL, kang LL et al. Primary cutaneou~ amyloidosis. Chinese Med J 1983;96: 185-200.

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