Bilateral Adrenal Infarction That Developed in Latent Essential Thrombocythemia

Abstract

Bilateral adrenal infarction is an extremely rare disease, and it has been reported that some coagulation abnormalities, including essential thrombocythemia (ET), exist in the background. We herein report a 76-year-old patient in whom the platelet count had been in the normal range at the onset of adrenal infarction but subsequently increased to 102×10⁴/μL at 7 months later, leading to the diagnosis of JAK2V617F-positive ET. As the presence of the JAK2V617F mutation increases the risk of thrombosis, Janus kinase 2 (JAK2) genetic testing should be considered in some cases of nonspecific unknown thrombosis, even if there are no obvious hematological findings, such as clonal hematopoiesis of indeterminate potential (CHIP).

Introduction

Adrenal infarction is a rare adrenal disease, and bilateral adrenal infarction (BAI) can lead to primary adrenal insufficiency, which is a potentially life-threatening condition due to the crucial role of adrenal cortical hormones in many metabolic responses (1). The mechanism underlying BAI is unclear at present, but systemic diseases prone to cause thrombosis, such as antiphospholipid antibody syndrome (APS), heparin-induced thrombocytopenia and thrombosis (HITT), polycytemia vera (PV), essential thrombocythemia (ET) and, recently, coronavirus disease 2019 (COVID-19) infection, are reported as potential causes (1-4).

Recently, the condition “clonal hematopoiesis of indeterminate potential (CHIP)” has been reported, in which myeloproliferative neoplasm (MPN) has not developed despite the MPN driver gene mutation being present at a variant allele frequency exceeding 2% in the peripheral blood (5). In cases of JAK2V617F-positive CHIP, thrombosis often develops as well as MPN (6).

We herein report a case of BAI in which the cause was initially unknown but was later identified to be JAK2V617F-positive ET. In this case, two thromboses had occurred before presenting with thrombocytosis, one of which was BAI, an atypical cause. This case is expected to be valuable when arguing the characteristics and risks of thrombosis due to Janus Kinase 2 (JAK2) mutations and the pathogenic impact of CHIP.

Case Report

A 76-year-old man visited our emergency room with a 3-day history of continuing upper abdominal pain. His medical history included chronic obstructive pulmonary disease (COPD) at 66 years old, pulmonary embolism at 69 years old, and early gastric carcinoma at 72 years old; he had no significant family history and was not taking any anticoagulant therapy. The abdomen was soft and flat, and there was no tenderness. Abdominal X-ray revealed a normal degree of colonic gas. He was diagnosed with reflux esophagitis and treated with a proton pump inhibitor and butyl scopolamine. Two days later, he developed left-sided abdominal pain at midnight and visited our hospital again.

His physical profile was as follows: body height 160.8 cm, body weight 56.9 kg, body temperature 37.4°C, blood pressure 163/91 mmHg, pulse rate 82/min, and consciousness Glasgow Coma Scale (GCS) 15. He had abdominal distension and upper and left abdominal pain. Laboratory data (Table) revealed increased inflammatory markers [white blood cells: 13,890 /μL, C reactive protein (CRP): 8.93 mg/dL] and decreased sodium (Na: 126 mmol/L). The platelet count was normal (24.2×10⁴/μL), and the mean corpuscular volume (MCV) was slightly increased. Electrocardiogram and chest X-ray findings were unremarkable, but expansion of the colon and swelling of the bilateral adrenal gland were noted on abdominal X-ray and computed tomography (CT) (Fig. 1A, B). An endocrinological examination revealed increased adrenocorticotropic hormone (ACTH) levels (70.0 pg/mL) but relatively low cortisol levels (16 μg/dL) under stress. The cortisol response was poor in the rapid ACTH loading test (Fig. 2A). He showed the typical symptoms and laboratory data of adrenal insufficiency, so we immediately started the administration of stress-dose hydrocortisone to prevent adrenal crisis and then gradually reduced it.

Table.

Laboratory Data.

Hemogram

Blood chemistry

Endocrinology

WBC

13,890

/μL

TP

6.9

g/dL

ACTH

70.0

pg/mL

Neut

68.4

%

Alb

3.7

g/dL

Cortisol

16.2

μg/dL

Lymp

16.3

%

AST

30

IU/L

PAC

81.4

pg/mL

Mono

14.3

%

ALT

29

IU/L

PRA

0.9

ng/mL/h

Eos

0.7

%

γ-GTP

51

IU/L

Ad

0.12

ng/mL

Baso

0.3

%

ALP

194

IU/L

NAd

0.68

ng/mL

RBC

408×104

/μL

Amy

59

IU/L

Hb

15.0

g/dL

CK

33

IU/L

Autoimmunity

MCV

105.4

fl

CRP

8.93

mg/dL

ANA

<40

Plt

24.2×104

/μL

PCT

0.2

ng/mL

Anti-DNA Ab

0.9

ng/mL/h

LDH

351

IU/L

aCL

<8

U/mL

Coagulation Examination

BUN

15

mg/dL

C-ANCA

<1.0

U/mL

PT-INR

1.08

Crea

0.56

mg/dL

P-ANCA

<1.0

U/mL

APTT

116.4

%

Na

126

mmol/L

anti-CL･β2GPI Ab

<1.2

U/mL

D-dimer

3.20

μg/mL

K

4.0

mmol/L

Fibrinogen

667.0

mg/dL

Cl

91

mmol/L

Urynalysis

FDP

7.3

μg/mL

Glucose

102

mg/dL

Glu

-

Protein C act.

115

%

IgG4

27.6

mg/dL

Pro

2+

Protein S act.

62.5

%

sIL-2

646

U/mL

Keton

2+

AT3

114

%

ACE

6.8

U/L

WBC-Es

-

LAC

1.2

LAC: lupus anticoagulant, PAC: plasma aldosterone concentration, PRA: plasma renin activity, Ad: adrenaline, NAd: noradrenaline, DA: dopamine, MN: metanephrine, NMN: normetanephrine, DHEA-S: dehydroepiandrostendione sulphate, aCL: anti-cardiolipin antibody, anti-CL･β2GPI Ab: anti-cardiolipin β2-glycoproteinI complex antibody

Figure 1.

(A) Contrast-enhanced CT demonstrates expansion of the colon and swelling of the bilateral adrenal glands. (B-C) MRI T2 (B) and DWI (C) show a high signal intensity of the right adrenal gland (arrows). (D) Contrast-enhanced CT shows the thrombus attached to the abdominal aorta (arrowhead). (E) Contrast-enhanced CT shows the improvement of the adrenal gland enlargement.

Figure 2.

Results of the adrenocorticotropic hormone (ACTH) stimulation test. The dashed line indicates the aldosterone level, and the solid line indicates the cortisol level. (A) On admission, the results reveal a low cortisol response. (B) Before discharge, ACTH stimulation did not increase the cortisol level.

At Day 7, there was no excess accumulation in the bilateral adrenal gland on fluorodeoxyglucose-positron emission tomography (PET)-CT. The right adrenal gland had a high signal on magnetic resonance imaging (MRI; T2 and diffusion-weighted imaging) (Fig. 1C, D), and we detected clotting at his aortic wall on follow-up CT (Fig. 1E). Based on these imaging findings and the hypercoagulability in blood tests (Table), we diagnosed the patient with BAI and started the administration of acetylsalicylic acid (aspirin).

We suspected antiphospholipid syndrome (APS), an infection, or a congenital disease as the cause of thrombosis, but examinations for these entities proved negative (Table). On day 22, a rapid ACTH loading test revealed complete adrenal insufficiency (Fig. 2B), and he was discharged with antiplatelet therapy and glucocorticoid replacement therapy. We followed the patient carefully in an outpatient setting, and adrenal enlargement improved (Fig. 1F). However, his platelet count gradually increased to 112×10⁴/μL at day 205 (Fig. 3).

Figure 3.

Clinical course. The patient was first treated with high-dose glucocorticoids, which were gradually reduced. Administration of acetylsalicylic acid (aspirin) was started on day 9. His platelet count gradually increased to 112×10⁴/μL, and a genetic analysis revealed the JAK2 V617F mutation. Hydroxyurea was added.

Bone marrow aspiration and a biopsy showed the marked proliferation of megakaryocytes and no dysplasia involving one or more myeloid lineages, and the grade of bone marrow fibrosis was MF-1. A chromosome examination revealed 46, XY, +1, der (1; 7) (q 10; p 10) in 20 of 20 cells. A genetic analysis revealed the JAK2 V617F mutation, which finally led to a diagnosis of ET according to WHO criteria (7). After this diagnosis, we started antiplatelet and glucocorticoid replacement therapy. Glucocorticoid replacement was started with 20 mg of hydrocortisone and then reduced to 15 mg per day. On Day 156, the cortisol level was slightly high, and ACTH suppression was observed, so the hydrocortisone dose was reduced to 10 mg (Fig. 3).

Discussion

Bilateral adrenal gland swelling is seen in cases of congenital adrenal hyperplasia, metastasis of malignant tumors, infectious diseases, bleeding, and infarction. In this case, the adrenal gland expanded too rapidly to be congenital adrenal hyperplasia or metastasis of a malignant tumor. Although the mild CRP increase suggested adrenal gland infection, blood cultures, a tuberculosis test, a the β-D glucan levels were negative, suggesting that bilateral adrenal infection, including tuberculosis and fungal infection, were unlikely. CT and MRI showed no bleeding but a clot on the lumen of the aorta and findings suggestive of adrenal infarction (8). In addition, the D-dimer level was high, so we concluded that BAI had occurred.

BAI, which can be hemorrhagic or nonhemorrhagic, is rare and usually occurs in hypercoagulable states, such as antiphospholipid antibody syndrome (2). The pathophysiology of adrenal infarction is not fully understood but is suspected to be based on its unique vascular anatomy with multiple arteries and only one draining vein, which form a vascular plexus called a “vascular dam.” This structure is assumed to be hemodynamically associated with the formation of thrombosis (8).

Espinosa et al. reported that symptoms of adrenal insufficiency in adrenal infarction or adrenal hemorrhaging patients with APS included abdominal pain and hypotension in half, with other symptoms, such as a fever, nausea or vomiting, weakness, and fatigue, also being observed (9). However, not all patients developed adrenal insufficiency. Baseline cortisol levels at the diagnosis were decreased in 98% of patients, and ACTH hormone levels were increased in 96% of patients. Our case did not show hypotension but presented with abdominal pain, vomiting, and fatigue. Furthermore, his ACTH level was elevated, and his cortisol level was relatively low at the onset, and the dosage of hydrocortisone was able to be titrated with improvement of adrenal swelling. Although there is no literature describing either the imaging course of adrenal infarction or the course of adrenal insufficiency to date, in our case, it was conceivable that the adrenocortical function might have recovered with improvement of the adrenal infarction.

There have been few reports of BAI caused by essential thrombocythemia (1,10-12). In our case, blood tests showed no abnormalities other than a high MCV value at first. According to the diagnostic criteria for ET, one of the major criteria is a platelet count of ≥45.0×10⁴/μL (7). Several cases of latent ET have been reported, but in those cases, platelet counts were normalized by the consumption of platelets with splenomegaly and splenic vein thrombosis (13-15). As our patient did not have splenomegaly or splenic vein thrombosis, we suspected that he might be in a precursor state for ET at the onset of BAI. Recently, the concept of CHIP has been proposed, involving the presence of clonally expanded hematopoietic stem cells caused by at least one driver mutation in elderly individuals without evidence of hematologic disease (5). CHIP carriers have a significantly increased incidence of blood tumors and are associated with chronic inflammation that leads to cardiovascular disease (16). The JAK2 gene abnormality is an independent thrombogenic factor that is associated with conditions such as venous thrombosis, which occur before the diagnosis of chronic myeloproliferative neoplasms (6). Furthermore, JAK2V617F CHIP carriers demonstrate an increased incidence of deep vein thrombosis and pulmonary embolus in population studies (17). As our patient had a pulmonary embolism 7 years ago (69 years old), even if he had not been genetically tested at that time, he might have had JAK2V617F-positive clonal hematopoiesis since then. In addition, the patient had a derivative chromosome (1; 7), which was reported to be present at a high frequency in Japanese myelodysplastic syndrome (MDS) patients (18), so his bone marrow might have already transitioned to MDS. However, his bone marrow showed no findings of dysplasia.

There have been no reports of patients presenting with BAI prior to the onset of ET. The diagnostic criteria for ET include four major criteria and one minor criterion (5). Aside from platelet counts, the criteria involve a special test and are thus not usually performed in daily practice. Therefore, when the platelet count is normal, JAK2V617F mutation carriers may be overlooked in daily medical care. Even in cases where the platelet count is normal, if atypical thrombosis is present, we should be aware of the possibility of potential hematologic disease, and bone marrow examinations and genetic tests should be considered.

The authors state that they have no Conflict of Interest (COI).