Acute adrenal insufficiency caused by antiphospholipid syndrome

Yunfei Feng,Weibin Zhou,Daiqiong Fang

Department of Endocrinology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003,China

Antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) are frequently discussed together and considered two closely related diseases.APS involves multiple organ systems,but APSrelated endocrine manifestations are rare.[1]Among them,adrenal insufficiency (AI) is the first endocrine manifestation of APS.The prompt diagnosis of AI is critical,as this disorder has high morbidity and mortality if left untreated.Here,we report a rare case of acute AI caused by APS secondary to SLE.

CASE

In August 2022,a 39-year-old woman without a significant family history of medical diseases presented to our emergency department (ED) for low back pain,nausea,anorexia,fatigue,hypoglycemia,and hypotension.One month prior,she had fatigue,loss of appetite,low back pain,cough with sputum,and fever.Through direct inquiry,no blunt abdominal or thoracic trauma was reported.She was diagnosed with community-acquired pneumonia and was treated with ceftriaxone and moxif loxacin at a local hospital.

When she was treated for pneumonia a month prior,abdominal computed tomography (CT) was performed and showed that the left adrenal gland was enlarged at approximately 1 cm and surrounded by f luid,indicating a possibility of adrenal hemorrhage (Figure 1A).The activated partial thromboplastin time (APTT) was 56.2 s (reference range [RR] 23.9-33.5 s),and hemoglobin was 90 g/L (RR 113-151 g/L).After 9 d,she was discharged with a normal temperature and relief of cough and sputum.However,she continued to complain of anorexia,weight loss,fatigue,and intermittent vomiting.Gastroscopy revealed chronic nonatrophic gastritis with erosion.The patient presented to our ED with hypoglycemia (glucose of 1.8 mmol/L),hyponatremia(serum sodium 134 mmol/L),and hypotension (60/40 mmHg [1 mmHg=0.133 kPa]).An abdominal contrastenhanced CT scan revealed bilateral adrenal enlargement with cystic changes,which was consistent with glandular hemorrhagic infarction (Figure 1B).A diagnosis of primary hypoadrenalism was conf irmed by low cortisol (1.24 μg/dL,normal 5.00 to 25.00 μg/dL) and high corticotrophin (847 pg/mL,normal 0 to 46 pg/mL) at 8 a.m.The patient was treated with electrolytes and hydrocortisone for acute adrenal crisis,followed by oral hydrocortisone,and her clinical symptoms improved significantly.

On physical examination,the patient had skin hyperpigmentation in her face,finger,and lingual mucosa.The arterial blood pressure was low (96/50 mmHg),despite previous repletion of electrolytes.She was pregnant five times,with three miscarriages and two full-term deliveries.There was no documented history of pathological miscarriage due to AI or APS.She had a history of anemia of unknown etiology for ten years.Her hemoglobin level was 86 g/L,white blood cell count was 2.53×109/L,and platelet count was normal.Plasma coagulation factor activities of Ⅶ,Ⅸ,Ⅺ,and Ⅻ were low (58.8% [normal 70%-120%],49.2%[normal 70%-120%],51.1% [normal 70%-120%],and 54.7% [normal 70%-150%],respectively);however,Ⅱ,V,Ⅷ,X factors were normal.The prothrombin time and thrombin time were normal,but the APTT was consistently elevated on repeated occasions.Antinuclear(1:160),double-stranded DNA (anti-dsDNA),soluble nucleoprotein,SSA60,SSB,Ro52,nucleosome and histone were positive.Anti-mitochondrial,antismooth muscle,anti-neutrophil cytoplasmic antibodies(ANCA),and rheumatoid factor (RF) were negative.The anticardiolipin (aCL) antibody was positive at a high titer with aCL immunoglobin G (aCL-IgG) of 132.02 GPL/mL(normal 0-20 GPL/mL),aCL immunoglobulin M (aCLIgM) of 75.9 MPL/mL (normal 0-20 MPL/mL),and aCL immunoglobulin A (aCL-IgA) of 9.87 APL/mL (normal 0-20 APL/mL).

Fur the rtests showed β2-glycoprote in Iimmunoglobulin G (β2GPI-IgG) of 142.34 SGU units(normal 0-20 SGU units),β2GPI-IgM of 9.64 SMU units (normal 0-20 SMU units),and β2GPI-IgA of 43.54 SAU units (normal 0-20 SAU units).These findings were all conf irmed 12 weeks later.Serum IgG was 2,107 mg/dL (normal 860-1,740 mg/dL),serum IgA was 311 mg/dL (normal 100-420 mg/dL),serum IgM was 156 mg/dL (normal 50-280 mg/dL),and C3 and C4 were at low levels (63 mg/dL [normal 70-140 mg/dL],5 mg/dL[normal 10-40 mg/dL]).The lupus screening ratio (1.50,normal ＜1.20) and standardized lupus ratio (1.26,normal＜1.20) for lupus anticoagulant were both higher than the reference range.Ultrasound examination showed no signs of thrombosis in the lower limb veins.

The patient was diagnosed with AI caused by APS secondary to SLE,which met the classification criteria of the 2012 Systemic Lupus International Collaborating Clinics (SLICC).[2]Subsequently,the patient received an appropriate amount of warfarin to maintain the international normalized ratio (INR) between 2.5 and 3.0 and received high-dose glucocorticoids.The patient was then treated with immunosuppressive agents,belimumab,hydroxychloroquine,and anticoagulant antiplatelet therapy.

Two months and four months later,the patient underwent abdominal magnetic resonance imaging(MRI) and CT scans,and the results still showed bilateral adrenal atrophy (Figures 1 C and D).During the 10-month follow-up,she was still receiving the same treatments.

DISCUSSION

AI is a life-threatening disorder in severe cases due to the inability of the adrenal cortex to secrete glucocorticoids or mineralocorticoids.[3]The patient in this study had low cortisol and high corticotrophin at 8 a.m.,indicating primary AI due to adrenal gland pathologies.The most common cause of primary AI is autoimmune adrenalitis (80%-90%),while other causes include drugs,congenital adrenal hyperplasia,infectious or invasive diseases,adrenal metastasis,adrenoleukodystrophy,and in rare cases,bleeding or infarction caused by APS.[3]

APS is a disease characterized by recurrent venous and arterial thrombotic events associated with antibodies targeting phospholipid-protein complexes.[4]The main antibodies found in APS are aCL,anti-β-2 glycoprotein I and lupus anticoagulant (LA).The diagnostic criteria for APS include at least one clinical sign (vascular thrombosis or pregnancy complications) and one laboratory criterion (two or more positive aCL-IgG or aCLIgM,LA IgG or IgM,with a minimum interval of 12 weeks).[4]The clinical manifestations of APS are diverse and may affect almost every organ in the body.AI is one of the rare manifestations of APS.[5]Our patient presented with bilateral adrenal hemorrhage as the first manifestation of a hypercoagulable state caused by APS.The pathogenesis of hypoadrenalism in APS is thrombosis-mediated occlusion of the adrenal vein,leading to glandular edema,arterial obstruction and subsequent hemorrhagic infarction.[5]The second proposed mechanism of AI in APS patients is spontaneous (without thrombosis) adrenal hemorrhage.[5]In most cases,adrenal thrombosis/hemorrhage in APS patients is bilateral,but in a small number of patients,there is a period of time between the onset of adrenal bleeding on each side.Therefore,the time from the hemorrhagic event to acute AI may be crucial for formulating a correct diagnosis.Our case report suggests that adrenal hemorrhage is likely to be overlooked,and bilateral adrenal damage may lead to a life-threatening adrenal crisis.

Figure 1.Images of computed tomography (CT) and magnetic resonance imaging (MRI).A: in July 2022,CT showed that the left adrenal gland was enlarged at approximately 1 cm and surrounded by f luid;B: in August 2022,CT revealed bilateral adrenal enlargement with cystic changes;C and D: MRI in October 2022 and CT in December 2022 showed bilateral adrenal atrophy.

In our patient,the diagnosis of APS was finally confirmed after the diagnosis of AI was made.In such patients,differential diagnosis may be difficult,especially in the absence of a history of thromboembolism or miscarriage.If APS patients present symptoms such as abdominal discomfort,weakness,or asthenia,their blood pressure and serum sodium and potassium levels should be carefully evaluated,and additional diagnostic tests and treatment should be conducted promptly.[6]On the other hand,for patients with an unknown etiology of AI,even if there is no thrombotic disease,APS testing should be performed.[6]Anticoagulation and glucocorticoids should be started after a diagnosis is made.

Based on the patient’s clinical and serological results,the etiology of our patient may be SLE-induced APS,which can also explain the patient’s leukopenia,positive antinuclear antibodies,positive anti-dsDNA antibodies,positive antiphospholipid antibodies,and low complement.The clinical characteristics of SLE are heterogeneous,including endocrine derangements,such as autoimmune thyroid disease (3%-24%),diabetes,increased fracture risks,vitamin D deficiency and AI,although these characteristics are not included in the diagnostic criteria of SLE.The association between AI and SLE has not been fully studied,mainly because the coexistence of SLE and AI is rare,and only a few cases have thus far been reported.[7]

The radiological imaging techniques used for diagnosing adrenal hemorrhage include CT and MRI.[8]Abdominal CT remains the preferred method for the early diagnosis of adrenal diseases.Acute hemorrhage appears as highdensity shadows on CT scans,leading to enlargement of one or both adrenal glands.However,at the early stages of hemorrhage,CT scans may not reveal any abnormalities and should be repeated to search for any changes when symptoms persist.[9]In our patient,AI was not confirmed even after the CT scan.MRI is specific for staging adrenal hemorrhage of any cause.At the acute phase of hemorrhage,the T1-weighted image shows an iso-to slightly low signal,while the T2-weighted image shows a significantly low signal.In the subacute phase,initial rim hyperintensities were observed on T1-weighted images,and the T2 sequence at this stage showed hyperintensities.In the chronic phase,both hemosiderin and calcification can cause low signal on T1-and T2-weighted images.[9]

There are some limitations of our work.First,we cannot completely rule out the possibility of adrenal autoimmune damage,as we did not perform testing for 21-hydroxylase antibodies.Second,the lack of adrenal nodule aspiration and pathological diagnosis was another limitation of this case.Third,MRI can detect adrenal hemorrhage,but we only performed adrenal CT in the early stage without MRI.

CONCLUSION

I n patients experiencing abdominal discomfort,weakness or fatigue,AI may be a cause and can be evaluated by assessment of blood pressure,serum cortisol,adrenocorticotropin,sodium and potassium levels a nd adrenal CT scan.In primary AI,even in patients without previous thrombotic events or obstetric complications,APS may be the underlying cause,and LA and aCL antibodies may be screened.

Funding:None.

Ethical approval:Not needed.

Conflicts of interest:The authors declare that there are no conf licts of interest.

Contributors:YFF and WBZ contributed equally to this work.All authors contributed substantially to the writing and revision of this manuscript and approved its contents.