Q: My cousin was diagnosed with a G4 immunoglobulin disease. Can you explain what this is so I can understand it?

A: It sounds like you are referring to IgG4-related disease (IgG4-RD), a rare condition diagnosed in only around 60 per million people; however, since this condition has only recently been identified as a specific disease entity (in 2003), the true prevalence may be higher. IgG4-RD is most commonly diagnosed in middle-aged men, although it occurs in women and at other ages as well.

The underlying specific cause(s) of this disease are not well understood. However, there is evidence supporting an autoimmune component (where the body’s immune system attacks some of its own organs and/or tissues), and there is also some evidence that there may be an allergic component as well. IgG4-RD typically manifests with IgG4-positive cell infiltration of the affected organ(s) and/or tissue, often leading to fibrosis (thickening and scarring) and other cellular responses (for example eosinophil infiltration, similar to what may be seen in certain allergic reactions, and/or other inflammatory changes). The total IgG4 count in the blood is elevated in up to 70 percent of patients (although there can be technical issues in doing the IgG4 level measurement, so sometimes the sample must be diluted).

IgG4-RD patients may develop acute or subacute organ involvement (multiple organs are affected in over two thirds of patients), including organ inflammation, fibrosis, enlargement and/or other manifestations. Symptoms depend on the organ involved and the type of involvement, and may include:

Pancreas: autoimmune pancreatitis (inflammation of the pancreas) with left upper quadrant abdominal pain (often radiating to the back), nausea/vomiting, and/or other symptoms.
Lymph glands: these may become swollen and/or tender.
Gallbladder: sclerosing cholangitis may have symptoms of right upper quadrant abdominal pain, nausea/vomiting and/or jaundice (yellowing of the skin, the white parts of the eyes, other).
Salivary and lacrimal glands: this may cause pain and/or swelling of the parotid glands (‘spit’ glands by the sides of the face), especially when salivating, as well as other symptoms.
Retroperitoneal space: the area in the back of the abdomen may develop fibrosis, causing pain and involvement of the some of the organs there (such as inflammation of the aorta).
Thyroid: inflammation of the thyroid can cause increased (and subsequently decreased) production of thyroid hormone.
Kidneys: there can be inflammation and/or fibrosis of the kidneys causing pain, changes in urination and even kidney failure.
Lungs: lung inflammation and/or fluid in the sac around the lungs (the pleura) can cause breathing problems, chest pain (sometimes more pronounced with a deep breath), cough (sometimes with bloody sputum) and/or other symptoms.
Eyes: including possible vision changes and/or inability of the eyes to be able to move normally (potentially causing double vision).
Other: including skin, liver, stomach, heart, prostate, ovaries, the central nervous system and other organ systems may be involved.

There has been work done to establish formal guidelines for the diagnosis of IgG4-RD, but presently the diagnosis is based on examination of a biopsy of the affected organ tissue, and is supported by finding an increased level of IgG4 in the blood as well as specific tests confirming involvement of the affected organ(s).

The standard treatment for IgG4-RD is steroids, and most patients seem to respond, at least initially, to this treatment. Other immune modulation treatments have been tried, but so far the data on the response to these is limited.

The nonspecific nature of IgG4-RD (specifically the variability of the possible organs involved, as well as the variable symptoms that may manifest), the newness of identification (and probably the rareness) of the condition, as well as the lack of formal diagnostic criteria, make the diagnosis of this condition challenging. Correct diagnosis is important to help guide treatment, as well as to decide on what follow up is indicated.

Jeff Hersh, Ph.D., M.D., can be reached at DrHersh@juno.com