Antiphospholipid Antibody Syndrome. Rare Diseases of the Immune System

13. Additional Organs Involved in Antiphospholipid Syndrome: Eye, Ear-Nose-Throat, Lung, Gastroenteric System, Endocrine Glands

Maria De Santis1, 2, Angela Ceribelli1, 2 and Carlo Selmi1, 2  

(1)

Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy

(2)

BIOMETRA Department, University of Milan, Milan, Italy

Carlo Selmi

Email: carlo.selmi@unimi.it

13.1 General Terms

Antiphospholipid (PL) syndrome (APS) is a multiorgan disease and as such, albeit in rare cases, its manifestations can be found in the eye, ear-nose-throat district, lung, gastrointestinal system, and endocrine glands. In these cases, particularly when they represent the first manifestation, the diagnosis can be challenging. Moreover, due to the frequent association of APS and systemic lupus erythematosus (SLE), it is often difficult to establish if a clinic manifestation is primarily related to APS, SLE, or both. In the present chapter we will review the available reports, mostly represented by single cases or small series, of these additional less obvious organs involved in APS (Fig. 13.1).

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Fig. 13.1

The potential involvement of the eye, ear-nose-throat, lung, gastrointestinal system, and endocrine glands in APS is illustrated

13.2 Eye Involvement in APS

While the eye involvement is uncommon in APS, ocular structures are more commonly affected in SLE and this is generally associated with a disease flare or central nervous system involvement. In SLE the main ophthalmological manifestations include hemorrhage, retinal cotton wool spots, microangiopathy, and vasoocclusion based on immune complex-mediated vasculopathy and complement activation [1]. Eye involvement has been described in young women with anti-PL as optic neuritis or retinal or choroidal vasoocclusive disease [24]. The few reported cases show unilateral or bilateral pattern, and they generally have an acute onset. In some patients, these manifestations in APS were secondary to SLE, while in other cases they were associated to the presence of lupus anticoagulant (LAC) and were the first manifestation of APS. This is important in particular for the early identification of young patients with thrombotic eye disease with still unknown diagnosis of APS. Another interesting aspect is that other coagulation abnormalities can be associated to thrombotic eye involvement, especially when ischemic optic neuropathy is diagnosed [5]. This implies that not only anti-PL can be responsible for the ischemic process (in particular LAC), but also deficiency of anticoagulant protein C, protein S, and antithrombin may be present [5]. In all cases, the presence of an ocular thrombotic disease requires to initiate an anticoagulant therapy to improve the prognosis of these patients.

13.3 Ear-Nose-Throat and Pulmonary Involvement in APS

The involvement of the ear-nose-throat district in APS is considered rare, and in fact no cases of hearing loss or cochleovestibular involvement directly associated with APS have been reported [6]. On the contrary in SLE patients, a significant percentage of patients has hearing or vestibular dysfunctions [7]. However, one case report describes the unusual association between relapsing polychondritis (RPC) and APS [8]. RPC is the immune-mediated inflammation of cartilaginous structures of ears, nose, eyes and joints, and in about one third of cases, RPC is associated with other connective tissue diseases. Among these, a case report suggests that RPC could be a preclinical condition for APS, even if no other literature supports this link between the two diseases [8].

The upper airways are not commonly involved in APS, except for a few anecdotic reports [910]. In particular, some cases of epistaxis were described in association to severe thrombocytopenia in APS. Regarding the lower airways, a few cases of pulmonary hemorrhage and acute interstitial pneumonia have been reported in particular during the “catastrophic APS” [910]. This condition is defined as a life-threatening multiple organ thrombosis, due to micro thrombosis, but also large vein and artery involvement, in which there is a high risk of unusual organ involvement [11]. After kidney involvement, pulmonary complications are second in frequency (66 %) in catastrophic APS with development of acute respiratory distress syndrome and pulmonary emboli as main manifestations, followed by pulmonary hemorrhage, microthrombi, pulmonary edema, and infiltrates. Dyspnea is a common presenting symptom in catastrophic APS, so this rare variant should be immediately considered for APS patients rapidly worsening in their pulmonary function to avoid life-threatening consequences [12]. Pulmonary arterial hypertension (PAH) due to APS chronic thromboembolism can be a complication of primary APS or APS secondary to SLE. This latter case was described in an observational study of three patients who developed PAH during pregnancy that caused the death of two patients after delivery. Thus, the high mortality rate must be considered especially when this APS complication develops during pregnancy [12]. Chronic thromboembolic PAH usually requires surgical treatment, as in the forms due to other thrombotic conditions, through pulmonary thromboendarterectomy. In some cases PAH is due to pulmonary microvascular abnormalities similar to those identified in idiopathic pulmonary hypertension and may also benefit from pharmacotherapy of pulmonary hypertension. However, also in these cases anticoagulation is the first step of patient management because of the high risk of recurrent embolization and local in situ thrombosis [13].

13.4 Gastrointestinal Involvement in APS

Gastrointestinal involvement is uncommon also in SLE patients and when it is not associated with anti-PL-induced thrombotic events, it is due to vasculitis [14]. Gastrointestinal mucosal ulcerations have been described during thrombotic microangiopathy and disseminated intravascular coagulopathy due to APS [1415]. These features may represent the onset of catastrophic APS that predominantly affects and occludes small vessels of intra-abdominal organs such as bowel, liver, and pancreas [16]. Other isolated thromboembolic events involving the gastroenteric tract have been reported in APS patients [17], including portal vein thrombosis [18], Budd-Chiari syndrome [19], and mesenteric thrombosis [20]. Budd-Chiari syndrome may manifest in different ways and these are illustrated in Table 13.1.

Table 13.1

Signs and symptoms of Budd-Chiari syndrome

Clinical presentation

Signs and symptoms

Acute and subacute type

Rapid abdominal pain

Hepatomegaly

Ascites

Jaundice

Kidney failure

Chronic type (most common)

Progressive ascites

No jaundice

50 % kidney failure

Fulminant type (unusual)

Liver decompensation

Hepatomegaly

Ascites

Jaundice

Kidney failure

13.5 Endocrine Gland Involvement in APS

While almost all endocrine glands can be affected in SLE patients, in APS there are a few reports of endocrine alterations associated with the disease. Adrenal insufficiency is considered the most common endocrine manifestation in APS patients [21]. Primary adrenal insufficiency due to bilateral adrenal hemorrhage and infarction was described in a case series of 16 patients affected by APS. This complication may be irreversible in most cases, but the study shows that the adrenal function could be recovered in a few cases and measurement of cortisol levels in the early morning could be used for follow-up of adrenal function [22]. APS should be considered in any patient with adrenal insufficiency even in the absence of other thrombotic manifestations.

Autoimmune thyroid disease can be associated with increased titers of anti-PL antibodies, in particular of anticardiolipin antibodies, in patients affected by autoimmune thyroid diseases, even if not in the context of APS [23]. Hypopituitarism and Sheehan syndrome are increasingly being reported in association with anti-PL, but no complete report or observational studies have been published so far. It is also advisable to assess anti-PL in the sera of patients presenting with pituitary insufficiency [21]. Data regarding the prevalence and significance of anti-PL in diabetic patients remains uncertain, but an increased incidence of anti-PL (anticardiolipin, anti-phosphatidylserine, and anti-phosphatidylethanolamine) in type I and II diabetic patients has been reported. In particular, the incidence of IgA isotype to phosphatidylethanolamine was higher than other isotypes to other phospholipids; moreover, the anti-phosphatidylethanolamine antibodies were associated to proliferative retinopathy in diabetic patients [24]. Subsequently, the presence of anti-phosphatidylinositol and anti-phosphatidylcholine in diabetic sera has been found and appears to be associated with macroangiopathic complications [25]. Finally, only a few cases of ovarian and testicular derangements have been reported [5]. Further studies are needed to clarify the relationship between anti-PL and thyroid disorders and diabetes mellitus.

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