Monoclonal Immunoglobulin Deposition Disease - Causes, Clinical Symptoms, Diagnosis and Treatment

Introduction

Monoclonal immunoglobulin deposition disease (MIDD) is a rare systemic disorder of the plasma cells characterized by tissue deposition of abnormal monoclonal antibody chains. Its incidence in western countries is reported to be one in one million per year. The chance of developing MIDD is more in males than females. It is predominantly seen in people of the age group between 55 to 65 years. Its occurrence as a single entity is extremely rare and is often seen in association with other types of plasma cell disorders like multiple myeloma, lymphoproliferative disorders, and monoclonal gammopathy of undetermined significance.

What Is Meant by Monoclonal Immunoglobulin Deposition Disease?

Plasma cells present in the bone marrow, are a subtype of white blood cells (differentiated B-lymphocytes) that produce immunoglobulins (antibodies) for immunity. A single clone (specific group) of plasma cells synthesizes and produces only a single type of immunoglobulins (Ig). These antibodies are called monoclonal immunoglobulins (mIg). Altered clonal proliferation of these plasma cells results in increased secretion of defective monoclonal immunoglobulins into the blood plasma. These abnormal and defective monoclonal Ig fragments get accumulated in various tissues leading to diverse organ dysfunctions.

Monoclonal immunoglobulin deposition disease (MIDD) is a rare systemic disease that is caused by the abnormal clonal proliferation and release of monoclonal immunoglobulins (mIg) and its eventual deposition in the tissues of the body. It is not a malignant condition but presents with similar clinical symptoms. MIDD is considered a benign immunoproliferative disorder that causes excessive accumulation of monoclonal immunoglobulins in various organs in the body. The most predominantly affected organ is the kidney.

MIDD is further classified into three types according to the type of immunoglobulins produced.

• Light-Chain Deposition Disease - The most common type of MIDD characterized by deposition of only monoclonal free light chains which constitute kappa light chains.

• Light-And-Heavy Chain Deposition Disease - Here deposition of both light chains and heavy chains occurs. This type is frequently associated with multiple myeloma.

• Heavy-Chain Deposition Disease - Deposition of only heavy chains are seen. It is the most uncommon type of MIDD.

How Does Monoclonal Immunoglobulin Deposition Disease Develop?

Excessive monoclonal immunoglobulins are seen in blood when the abnormal proliferation of plasma cells occurs. Production of these monoclonal immunoglobulins is the underlying cause of the development of MIDD. The following features are associated with the pathogenesis of monoclonal immunoglobulin deposition disease.

• Monoclonal immunoglobulins get deposited in the renal tissues (basement membrane of the kidney) leading to renal impairment.

• MIDD also affects other organs such as the liver, lungs, heart, skin, and peripheral nerves.

• The damage to the functional structures in the kidney affects protein reabsorption leading to the wastage of protein in the urine (renal insufficiency).

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• Monoclonal plasma cells which are seen in different types of plasma cell dyscrasias such as monoclonal gammopathies of undetermined significance (MGUS), multiple myeloma, and macroglobulinemia also lead to the development of MIDD.

What Are the Signs and Symptoms of Monoclonal Immunoglobulin Deposition Disease?

The clinical manifestations of MIDD are commonly related to the dysfunction of the affected organ which accumulates the monoclonal immunoglobulins. The extent of organ damage determines the severity of monoclonal immunoglobulin deposition disease. Since the kidney is predominantly affected, individuals with MIDD present with symptoms associated with renal impairment. Extrarenal (organs other than kidney) MIDD deposits are also reported. The following clinical symptoms are seen in MIDD.

• Proteinuria.

• Renal insufficiency.

• Chronic nephrotic syndrome.

• Acute renal failure.

• Hematuria (blood in urine).

• Hypertension.

• Generalized edema is characterized by swollen ankles and puffy eyes.

• Glomerulosclerosis (scar tissue formation in the filtering structures of the kidney).

• Deposition of monoclonal immunoglobulins in the liver (hepatic sinusoids) causes liver dysfunction.

• Hepatomegaly.

• Peripheral neuropathy (inflammation of the nerves) occurs if peripheral nerves (choroid plexus) are damaged.

• Myocardial (heart muscle cells) damage leads to heart failure.

• Cardiomyopathy.

• Lung involvement is presented with cystic pneumopathy and chronic obstructive pulmonary disease (COPD).

• Nephropathy (inflammation of the kidney).

• Light chain type of MIDD is occasionally seen in minor salivary glands which causes pain and swelling in the oral cavity.

• MIDD deposits in the skin cause itchiness and pruritus.

How Is Monoclonal Immunoglobulin Deposition Disease Diagnosed?

Monoclonal immunoglobulin deposition disease is often associated with renal problems. For an accurate and definitive diagnosis, a renal biopsy is required. Microscopic and immunofluorescence studies demonstrate MIDD deposits which are valuable for its confirmatory diagnosis. Some of the diagnostic tests that help in the accurate detection of MIDD are as follows -

• Low serum albumin is detected by biochemical tests.

• Protein electrophoresis of serum and urine demonstrates a narrow band or M-spike which is characteristic of monoclonal immunoglobulins.

• Serum and urine immunofixation of MIDD deposits.

• Measurement of serum-free light chains using immunoassay.

• The renal biopsy helps to differentiate other forms of plasma disorders from MIDD.

• All biopsy samples are examined under light and immunofluorescence (IF) microscopy.

• Immunofluorescence detects the type of protein deposits in the basement membrane and helps in identifying the MIDD subtypes.

• Mass spectroscopy helps in distinguishing various abnormal protein deposits.

• Immunohistochemical staining detects the types of monoclonal immunoglobulins.

• Congo Red staining is used to differentiate amyloidosis from MIDD (MIDD deposits show negative staining).

• Electron microscopy detects granular and powdery continuous electron-dense deposits in the basement membrane of renal tissue suggestive of monoclonal immunoglobulin deposition disease.

• Elevated liver enzymes and bilirubin levels are seen in hepatic impairment.

How Is Monoclonal Immunoglobulin Deposition Disease Treated?

Prevention or reduction of irreversible damage to the organs particularly the kidney is the prime concern in treating MIDD. It is possible only in early detection and intervention.

• Administration of Bortezomib decreases the monoclonal immunoglobulin levels in the blood.

• High doses of Melphalan reduce the production of monoclonal immunoglobulins.

• Organ transplant is recommended in end-stage renal failure. However, there is a greater risk of developing MIDD even after transplantation if the production of monoclonal immunoglobulins is not treated effectively.

• Autologous stem cell transplantation is performed where the healthy and normal stem cells from the patient are used as stem cell grafts to replace the defective stem cells in the same patient’s bone marrow.

• Targeted chemotherapy specific to the underlying altered clone shows better recovery outcomes.

• Combined regimens of Bortezomib along with thalidomide or lenalidomide are recommended in the current therapeutic management of MIDD.

• Rituximab-based therapy along with steroids is also effective in controlling the excessive production of monoclonal immunoglobulins.

Conclusion

Monoclonal immunoglobulin deposition disease is an uncommon plasma cell disorder characterized by the accumulation of abnormal monoclonal immunoglobulins in organs such as the kidney, liver, and heart. This leads to diverse clinical symptoms related to organ impairment. Early detection and accurate treatment help to reduce fatal complications and enhance better prognostic outcomes.