The major organ lesions are summarized in Table 391e-1. IgG4-RD usually presents subacutely, and most patients do not have severe constitutional symptoms. Fevers and dramatic elevations of C-reactive protein are unusual; however, some patients report substantial weight loss occurring over periods of months. Clinically apparent disease can evolve over months, years, or even decades before the manifestations within a given organ becomes sufficiently severe to bring the patient to medical attention. Some patients have disease that is marked by the appearance and then resolution or temporary improvement in symptoms within a particular organ. Other patients accumulate new organ involvement as their disease persists in previously affected organs. Many patients with IgG4-RD are misdiagnosed as having other conditions, particularly malignancies, or their findings are attributed initially to nonspecific inflammation. The disorder is often identified incidentally through radiologic findings or unexpectedly in pathology specimens.
TABLE 391e-1Organ Manifestations of IgG4-Related Disease ||Download (.pdf) TABLE 391e-1 Organ Manifestations of IgG4-Related Disease
|Organ ||Major Clinical Features |
|Orbits and periorbital tissues ||Painless eyelid or periocular tissue swelling; orbital pseudotumor; dacryoadenitis; dacryocystitis; orbital myositis; and mass lesions extending into the pterygopalatine fossa and infiltrating along the trigeminal nerve |
|Ears, nose, and sinuses ||Allergic phenomena (nasal polyps, asthma, allergic rhinitis, peripheral eosinophilia); nasal obstruction, rhinorrhea, anosmia, chronic sinusitis; occasional bone-destructive lesions |
|Salivary glands ||Submandibular and/or parotid gland enlargement (isolated bilateral submandibular gland involvement more common); minor salivary glands sometimes involved |
|Meninges ||Headache, radiculopathy, cranial nerve palsies, or other symptoms resulting from spinal cord compression; tendency to form mass lesions; magnetic resonance imaging shows marked thickening and enhancement of dura |
|Hypothalamus and pituitary ||Clinical syndromes resulting from involvement of the hypothalamus and pituitary, e.g., anterior pituitary hormone deficiency, central diabetes insipidus, or both; imaging reveals thickened pituitary stalk or mass formation on the stalk, swelling of the pituitary gland, or mass formation within the pituitary |
|Lymph nodes ||Generalized lymphadenopathy or localized disease adjacent to a specific affected organ; the lymph nodes involved are generally 1–2 cm in diameter and nontender |
|Thyroid gland ||Riedel’s thyroiditis; fibrosing variant of Hashimoto’s thyroiditis |
|Lungs ||Asymptomatic finding on lung imaging; cough, hemoptysis, dyspnea, pleural effusion, or chest discomfort; associated with parenchymal lung involvement, pleural disease, or both; four main clinical syndromes: inflammatory pseudotumor, central airway disease, localized or diffuse interstitial pneumonia, and pleuritis; pleural lesions have severe, nodular thickening of the visceral or parietal pleura with diffuse sclerosing inflammation, sometimes associated with pleural effusion |
|Aorta ||Asymptomatic finding on radiologic studies; surprise finding at elective aortic surgery; aortic dissection; clinicopathologic syndromes described include lymphoplasmacytic aortitis of thoracic or abdominal aorta, aortic dissection, periaortitis and periarteritis, and inflammatory abdominal aneurysm |
|Retroperitoneum ||Backache, lower abdominal pain, lower extremity edema, hydronephrosis from ureteral involvement, asymptomatic finding on radiologic studies |
|Kidneys ||Tubulointerstitial nephritis; membranous glomerulonephritis in a small minority; asymptomatic tumoral lesions, typically multiple and bilateral, are sometimes detected on radiologic studies; renal involvement strongly associated with hypocomplementemia |
|Pancreas ||Type 1 autoimmune pancreatitis, presenting as mild abdominal pain; weight loss; acute, obstructive jaundice, mimicking adenocarcinoma of the pancreas (including a pancreatic mass); between 20 and 50% of patients present with acute glucose intolerance; imaging shows diffuse (termed “sausage-shaped pancreas”) or segmental pancreatic enlargement, with loss of normal lobularity; a mass often raises the suspicion of malignancy |
|Biliary tree ||Obstructive jaundice associated with autoimmunity in most cases; weight loss; steatorrhea; abdominal pain; and new-onset diabetes mellitus; mimicker of primary sclerosing cholangitis |
|Liver ||Painless jaundice associated with mild to moderate abdominal discomfort, weight loss, steatorrhea; new-onset diabetes mellitus; mimicker of primary sclerosing cholangitis and cholangiocarcinoma |
|Other organs involved ||Gallbladder, breast (pseudotumor), prostate (prostatism), pericardium (constrictive pericarditis), mesentery (sclerosing mesenteritis), mediastinum (fibrosing mediastinitis), skin (erythematous or flesh-colored papules), peripheral nerve (perineural inflammation) |
Multiorgan disease may be evident at diagnosis but can also evolve over months to years. Some patients have disease confined to a single organ for many years. Others have either known or subclinical organ involvement at the same time as the major clinical feature. Patients with type 1 AIP may have their major disease focus in the pancreas; however, thorough evaluations by history, physical examination, blood tests, urinalysis, and cross-sectional imaging may demonstrate lacrimal gland enlargement, sialoadenitis, lymphadenopathy, a variety of pulmonary findings, tubulointerstitial nephritis, hepatobiliary disease, aortitis, retroperitoneal fibrosis, or other organ involvement. Spontaneous improvement, sometimes leading to clinical resolution of certain organ system manifestations, is reported in a small percentage of patients.
Two common characteristics of IgG4-RD are allergic disease and the tendency to form tumefactive lesions that mimic malignancies (Fig. 391e-1). Many IgG4-RD patients have allergic features such as atopy, eczema, asthma, nasal polyps, sinusitis, and modest peripheral eosinophilia. IgG4-RD also appears to account for a significant proportion of tumorous swellings—pseudotumors—in many organ systems. Some patients undergo major surgeries (e.g., Whipple procedures or thyroidectomy) for the purpose of resecting malignancies before the correct diagnosis is identified. Frequent sites of pseudotumors are the major salivary glands, lacrimal glands, lungs, and kidneys; however, nearly all organs have been affected with this manifestation.
A major clinical feature of IgG4-related disease is its tendency to form tumefactive lesions. Shown here are mass lesions of the lacrimal glands (A) and the submandibular glands (B).
IgG4-RD often causes major morbidity and can lead to organ failure; however, its general pattern is to cause damage in a subacute manner. Destructive bone lesions in the sinuses, head, and middle ear spaces that mimic granulomatous polyangiitis (formerly Wegener’s granulomatosis) also occur in IgG4-RD; less aggressive lesions are the rule in most organs. In regions such as the retroperitoneum, substantial fibrosis often occurs before the diagnosis is established, leading to ureteral entrapment, hydronephrosis, postobstructive uropathy, renal atrophy, and chronic pain, possibly resulting from the encasement of peripheral nerves by the inflammatory process. Undiagnosed or undertreated IgG4-related cholangitis can lead to hepatic failure within months. Similarly, IgG4-related aortitis, believed to be associated with between 10 and 50% of cases of inflammatory aortitis, can cause aneurysms and dissections. Substantial renal dysfunction and even renal failure can ensue from IgG4-related tubulointerstitial nephritis, and renal atrophy is a frequent sequel to this disease complication.