A very rare case of Cushing's disease for cesarean section: What the anesthesiololgist needs to know.

Cushing's syndrome is uncommon in pregnancy, and Cushing's disease being the cause for this syndrome is still rare. We had the opportunity to manage such a patient admitted for cesarean section. Here, we describe the evaluation of a patient with Cushing's syndrome in pregnancy along with its anesthetic implications. By describing this case, we intend to emphasize the role of the anaesthesiologist as a peri operative physician.

INTRODUCTION

The first description of Cushing's syndrome in pregnancy was reported by Hunt and Mac Conahey in 1953.[1] Since then, at least 136 cases have been reported worldwide.[2] Of the various causes of Cushing's syndrome, Cushing's disease resulting from pituitary adenoma is still rare.[2-3] Patients with Cushing's disease are characterized by cushingoid features, hypercortisolism and increased adrenocorticotrophic hormone (ACTH) levels resulting from the pituitary adenoma. Complications arising from Cushing's syndrome depend on the levels of increased serum cortisol levels and tissue sensitivity in pregnancy. These complications can be hypertension, diabetes mellitus, impaired wound healing and pulmonary edema.

CASE REPORT

A 26-year-old G2 P2 L1 pregnant full-term female was referred to our hospital for delivery. She gave a history of rapid weight gain, hyperpigmentation, fatigue and weakness, with all complaints beginning in the third trimester. Her first child was born out of full-term cesarean section under spinal anesthesia, the indication being cephalopelvic disproportion and recovery was uneventful. She weighed 60 kg before pregnancy and had gained 30 kg in this pregnancy, the majority of which was gained in the last trimester. She also complained of hyperpigmentation over the arms and the back. No other positive medical or surgery history was elicited.

On examination, she weighed 90kg and had abdominal striae but the colour could not be discriminated because of her dark complexion. She had thin skin, moon facies and buffalo hump too. Her blood pressure was 130/80 mmHg, and her pulse rate was 106/min with a normal systemic examination. Her complaints and cushingoid features demanded serum cortisol levels. We also sent her blood for thyroid function tests and sugars apart from other routine examination.

Thyroid function tests, blood sugars and rest of the hematology were normal. However, serum cortisol was raised which was upto 26.33 μg/dl. Given her clinical features and high serum cortisol, a presumptive diagnosis of Cushing's syndrome was made. But, the case, because of its rarity demanded further investigations to discern the etiology. The most common cause of Cushing's syndrome in pregnancy lies in the adrenal glands; either an adenoma or adrenocarcinoma. An abdominal ultrasonography was performed to rule out adrenal pathology, which was negative. We then sent her urine for urinary free cortisol (UFC) and serum for ACTH levels.

Her values were:

These levels were very high for normal pregnancy and her raised ACTH levels pointed toward a pituitary cause.[4] But, as the patient was brought in full term, we had to accept the patient without further investigations for cesarean section.

Elective cesarean section was planned for our full-term patient in view of previous cesarean and cephalopelvic disproportion. Challenges for anesthesiologists were her weight, with central obesity and fat deposition over the back, buffalo hump and heavy jaw, making regional as well as general anesthesia difficult. Anesthesia plan of action was spinal anesthesia with 1.5 ml 0.5% hyperbaric bupivacaine. Difficult mask ventilation and intubation were anticipated and preparations were made accordingly. The patient received antacid prophylaxis preoperatively.

Spinal anesthesia was given with a 26G Quincke's spinal needle in the L3-L4 interspace at the first attempt but at a greater depth than always. Obstetricians faced difficulty because of excessive fat deposition and adhesions from previous cesarean. A baby weighing 2.5 kg was delivered with an APGAR score of 9. The patient's electrocardiogram, blood pressure and saturation were monitored through out the procedure and were normal except for sinus tachycardia. Post-operative analgesia was given in the form of diclofenac suppository 100 mg per rectal. The rest of the intra- and post-operative period was uneventful.

Her placenta was sent to histopathology for examination of any hyperplasia of cells. Two days post operatively the patient was scheduled for magnetic resonance imaging (MRI) of the brain to visualize sella tursica. Her placenta showed a normal picture; however, her MRI brain revealed a 2.7mm nonenhancing foci in the anterior pituitary, which was suggestive of pituitary microadenoma (accompanying MRI picture).

In concise, our patient had cushingoid features associated with hypercortisolism, increased ACTH levels and the MRI brain showed pituitary microadenoma. Thus, in fact, she was a case of Cushing's syndrome, the cause of which was Cushing's disease.

DISCUSSION

We are thorough with normal physiological changes of pregnancy and the hematological, cardiovascular and respiratory changes are well described. However, the endocrine system is always ignored. Normal pregnancy is a state of stimulated hypothalomo-pituitary-adrenal (HPA) axis. With increasing serum cortisol, the ACTH levels should fall because of the negative feed back. But, this does not happen in normal pregnancy, which suggests that an ACTH source exists that is not subject to the negative feed-back. It is postulated that a short mRNA gene encoding POMC (proopioimelanocortin - peptide precursor of ACTH) is present in the placenta that stimulates corticotrophin-releasing hormone (CRH) production from the placenta, which in turn stimulates ACTH release from the pituitary.[5]

Both these mechanisms finally result in an increase in the serum cortisol and UFC levels. Despite these increases, Cushing's syndrome is uncommon in pregnancy and a rise of hormonal level of 2 to 22-times is seen with the reported cases.[6] The reasons for these are that the hypercortisolism in normal pregnancy is not up to an extent to cause Cushing's syndrome. Also, in pregnancy, there is a decrease in the sensitivity of tissue levels to cortisol hormone.[7]

But, when the pregnancy is accompanied with an additional source of cortisol, either through the pituitary, adrenal, ectopic ACTH production (from small cell carcinoma of lung or as a part of MEN type 1) or exogenous administration of steroids (iatrogenic or addictive), it results in Cushing's syndrome. However, she had no usual complications of Cushing's syndrome like hypertension or diabetes because to cause such complications, the pituitary microadenoma should be at least 6mm; our patient was fortunate enough to be diagnosed early with a gland of 2.7 mm.[8] The fetus is generally spared in Cushing's syndrome because of the presence of 11 β OH steroid dehydrogenase enzyme in the placenta that converts glucocorticoids & cortisol into their inactive 11 keto metabolites.[9] However, prematurity, intrauterine growth restriction and intrauterine fetal death have been reported.

Generally, in non-pregnant patients, dexamethasone suppression test (DST) followed by a CRH-stimulation test is performed to confirm the diagnosis. However, in pregnancy, the HPA axis physiology is itself altered and the DST gives false-positive results and the CRH causes contraction of the uterus and carries a risk of premature labor. Hence, both these tests had a limited value in our patient.[10]

A pituitary microadenoma can be a prolactinoma, GH-secreting tumor leading to acromegaly apart from ACTH secreting. To confirm what the adenoma is actually secreting, an invasive inferior petrosal sinus sampling is advised. But, in our case, high levels of ACTH were already demonstrated along with the suggestive cushingoid feature.[11]

Management of Cushing's syndrome in pregnancy involves both surgical and medical treatment. If the cause is pituitary adenoma, trans sphenoidal excision of the gland is the definitive treatment.

Medical management is usually reserved for adrenal causes and involves the use of metyrapone and ketoconazole, both of which are contraindicated in pregnancy. Accompanying HT, DM should be treated.

To conclude, Cushing's disease is a rare condition seen in pregnancy and the diagnosis is often complicated by normal presentation in pregnancy. Hence, a high degree of suspicion is required. In such patients presenting in early pregnancy with a severe form of Cushing's syndrome, surgery may be advocated and hence the anaesthetic implications should be known. Otherwise, in patients like ours, it is of great importance to first evaluate and diagnose such a condition, there-by fulfilling the role of the anaesthesiologist as a peri operative physician. Such patients should then be referred to the respective superspecialty after delivery for further management. If appropriate measures are not taken at the correct time, such patients may land up with rather big microadenomas later in life thus not being amenable to medical therapy.