What are the other Names for this Condition? (Also known as/Synonyms)

• Amyloidosis-Associated Lymph Disease
• Lymph Node Amyloidosis
• Lymphatic Vessel Amyloidosis

What is Lymphatic Amyloidosis? (Definition/Background Information)

• Amyloidosis is a group of disorders in which the ‘amyloid protein’ builds up in many organs and tissues of the body. The term “amyloid” is used for protein molecules of any type that stick together owing to misfolding (or incorrect formation of the proteins)
• These protein aggregates are abnormally-formed and arranged into fibrils (slender fibers). An amyloid build-up can occur locally in only one organ, or may occur throughout the body. Under certain conditions, the amyloid proteins may get deposited in the lymph nodes and vessels, causing Lymphatic Amyloidosis
  • The lymphatic system is network of lymph nodes and vessels in the body that is primarily associated with fighting pathogens and disease
  • The lymph vessels carry the lymph, which is a clear liquid rich in white blood cells that are the agents that offer immunity against pathogens
• Amyloidosis is divided into 5 major subtypes, namely:
  • AL amyloidosis that occurs when bone marrow produces too much amyloid protein, creating light (L) chains
  • AA amyloidosis, when amyloid proteins build up secondary to a chronic disease
  • Hereditary amyloidosis: It is an inherited form of the disease; the amyloid build-up primarily affects the kidneys and nerves
  • Wild-type ATTR amyloidosis: This form leads to amyloid protein deposits in elderly adults, particularly in the heart and tendons
  • Dialysis-related amyloidosis: This occurs in individuals who have undergone dialysis for a long time. The amyloid protein tends to get deposited in the tendons and joints
• Lymphatic Amyloidosis can either occur as primary, localized disease of the AL type, or as a manifestation of systemic AL amyloidosis. The condition may also be associated with AA- and hereditary- subtypes of amyloidosis. Typically, the disorder affects older adults
• Lymphatic Amyloidosis may present with symptoms of lymph node swelling, overall swelling of the body, pain in limbs, and tightening or hardening of skin, among other symptoms
• Generally, amyloidosis affecting any system including Lymphatic Amyloidosis, is a progressive disorder with no cure and the prognosis is guarded

Who gets Lymphatic Amyloidosis? (Age and Sex Distribution)

• Lymphatic Amyloidosis is a rare disorder reported worldwide
• The condition can occur at any age and it typically affects older male and female adults. Men may be more frequently affected than women
• However, when the condition occurs as a manifestation of hereditary amyloidosis, both genders may be equally affected

What are the Risk Factors for Lymphatic Amyloidosis? (Predisposing Factors)

The following are some known risk factors for developing Lymphatic Amyloidosis:

• Advancing age
• Male gender
• A family history of amyloidosis
• Any condition that affects the antibody-producing cells in the body, including benign monoclonal gammopathy, malignant lymphoma, and multiple myeloma
• Chronic inflammatory conditions such as
  • Arthritis, including rheumatoid arthritis, juvenile inflammatory arthritis, psoriatic arthritis and ankylosing spondylitis
  • Inflammatory bowel disease (IBD) such as ulcerative colitis
  • Chronic infections, including
  • Tuberculosis
  • Leprosy
  • Bronchiectasis
  • Osteomyelitis
  • Skin infections (especially in drug abusers, who use needles to inject themselves)
  • Chronic infection in skin with burns
  • Chronic kidney infections (pyelonephritis)
  • Whipple’s disease
• Uncontrolled diabetes
• Infectious diseases such as HIV/AIDS
• Cystic fibrosis; individuals with this condition are prone to repeat infections
• Certain cancers such as Hodgkin’s lymphoma and renal cell carcinoma
• Family history of certain hereditary disorders that may include:
  • Familial Mediterranean fever (FMF)
  • Tumor necrosis factor (TNF) receptor associated periodic syndrome (TRAPS)
  • Hyperimmunoglobulin D syndrome and periodic fever syndrome (HIDS)
  • Cryopyrin-associated periodic syndrome (CAPS)

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Lymphatic Amyloidosis? (Etiology)

• Lymphatic Amyloidosis may be caused as a localized, primary form of AL amyloidosis, or as a consequence of systemic amyloidosis (which may be of AL, AA, or hereditary subtypes)
• In majority of cases, inherited Lymphatic Amyloidosis is associated with mutation(s) in the TTR gene. The mutations are inherited in an autosomal dominant manner

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

What are the Signs and Symptoms of Lymphatic Amyloidosis?

The signs and symptoms of Lymphatic Amyloidosis may vary among affected individuals in type and severity. The following are some known signs and symptoms associated with the condition:

• Swelling of lymph nodes, which may or may not be painful
• Obstruction of lymph nodes causing lymphedema leading to the following:
  • Fluid accumulation in the body, causing generalized swelling
  • Ascites or fluid accumulation in the peritoneal cavity, which causes swelling of the abdomen
  • Pleural effusion, which is the accumulation of fluid in the lining between the lungs and chest. This can lead to chest pain, cough and difficulty breathing

The following signs and symptoms pertaining to systemic Amyloidosis may be present, and some of the symptoms may overlap with Lymphatic Amyloidosis:

• Fatigue
• Swelling in the ankles and legs
• Unintended weight loss
• Pain in hands and feet; joint pain
• Skin rashes, which may be purple or red spots
• Rash around eyes; eyes that appear puffy
• Anemia
• Clay-colored stools
• Bleeding disorders; problems with proper clotting of blood

How is Lymphatic Amyloidosis Diagnosed?

Lymphatic Amyloidosis is diagnosed on the basis of the following tests and exams:

• A thorough physical examination
• Evaluation of personal and family medical history
• Assessment of the presenting signs and symptoms
• Imaging tests to assess amyloid deposits in the body/organs, and to assess damage to the organs, tissues, and bones, which include:
  • X-ray of the affected region
  • Ultrasound imaging
  • Computed tomography scanning
  • Magnetic resonance imaging
• Serum amyloid protein (SAP) scintigraphy scan: In this procedure, a small amount of radiolabeled (radioactive iodine) SAP is introduced through injection into the body. After several hours, individuals are scanned with a whole body gamma scanner to check for amyloid deposits in the tissues and organs. Individuals undergoing this procedure ingest potassium iodide before and after the procedure, to prevent the thyroid glands from absorbing the radioactive iodine
• Tissue biopsy: A biopsy of affected skin area is performed and sent to a laboratory for a pathological examination. A pathologist examines the biopsy sample under a microscope. After putting together clinical findings, special studies on tissues (if needed) and with microscope findings, the pathologist arrives at a definitive diagnosis. Examination of the biopsy sample under a microscope by a pathologist is considered to be gold standard in arriving at a conclusive diagnosis. In case of amyloidosis,
• Immunohistochemical analysis of tissue samples using anti-AA serum may be performed, to identify the type of amyloidosis an individual has
• Amyloid deposit from affected tissue is detected using a staining procedure. When stained with Congo red stain, the amyloid protein deposits appear green under a special type of microscope (polarizing microscope)

In addition to the above tests, the following may be required to assess damage to other tissues and organs, owing to systemic amyloidosis:

• Blood tests to assess the following:
• Assess abnormal antibodies
• Check heart function (cardiac biomarkers for stress on the heart)
• “Freelite assay”, a measurement of light chain immunoglobulins
• Immunoglobulin by immunofixation electrophoresis
• Measure alkaline phosphatase enzyme levels
• Urine tests:
• To check for excess protein (a 24-hour urine test is usually done)
• Immunoglobulin by immunofixation electrophoresis
• Bone marrow aspiration for checking the type of abnormal immunoglobulin light chains
• Electrocardiography and echocardiography for checking heart functions
• Molecular genetic testing to check for mutation(s) in the TTR gene
• Molecular testing to check the type of proteins in amyloid deposits (AL or AA chains) through mass spectrophotometry

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Lymphatic Amyloidosis?

The potential complications of Lymphatic Amyloidosis include:

• Severe infection of lymph vessels
• Bacterial infection of skin
• Development of a type of tumor known as lymphangiosarcoma (due to longstanding lymphedema)

How is Lymphatic Amyloidosis Treated?

Currently, there are no treatment options to cure Lymphatic Amyloidosis. However, treatments may be available to ease the symptoms of the condition and slow its progression. The treatment provided is typically unique to each individual and it depends on the organs affected. The treatment options may include:

• Surgical excision of affected lymph node(s)
• Autologous bone marrow transplantation following surgery

In addition, treatments to address systemic amyloidosis (which may manifest as lymphatic neuropathy) and any underlying cause are often necessary.

How can Lymphatic Amyloidosis be Prevented?

• Currently, there are no specific methods or guidelines to prevent Lymphatic Amyloidosis
• Seeking prompt medical attention for pre-existing conditions that can lead to systemic amyloidosis, which consequently causes Lymphatic Amyloidosis is advisable
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are highly recommended.

What is the Prognosis of Lymphatic Amyloidosis? (Outcomes/Resolutions)

• The prognosis of Lymphatic Amyloidosis is determined by a number of factors, such as the extent of disease, organs affected, overall health of the affected individual, and his/her response to treatment
• All types of amyloidosis are progressive disorders. In Lymphatic Amyloidosis, if complications, such as severe infection of lymph vessels or lymphangiosarcoma develop, or if there is involvement of major organs, then the prognosis may be guarded

Additional and Relevant Useful Information for Lymphatic Amyloidosis:

• Approximately, 30 different proteins with a tendency to form amyloids have been identified. These are known as precursor proteins or amyloidogenic proteins
• The misfolding of proteins can occur due to a number of reasons, including aberrant formation, improper breakdown, or accumulation beyond a critical concentration in serum