Case Reportobr_987 560..562

Adrenal insufficiency following bariatric surgery

J. W. Stephens1,2, K. Boregowda2, J. Barry1, D. E. Price2, N. Eyre1 and J. N. Baxter1

1Welsh Institute of Metabolic and Obesity

Surgery, Morriston Hospital, ABM University

Health Board, Swansea, Wales, UK;2Department of Diabetes and Endocrinology,

ABM University Health Board, Swansea,

Wales, UK

Received 9 January 2012; revised 30 January

2012; accepted 31 January 2012

SummaryA 35-year-old woman with morbid obesity and amenorrhoea underwent a bilo-pancreatic diversion (BPD). Surgery was successful with good weight loss, resto-ration of menstruation and almost immediately she conceived for the first time.She was commenced on routine vitamin supplements after surgery but failed toattend follow-up clinic. Five years later, she presented with limb girdle pains,lethargy, night blindness, skin pigmentation, amenorrhoea and dizziness. She hadstopped taking supplements prescribed after the surgery. Investigations showedsevere vitamin A and D deficiency along with iron and calcium deficiency. Hercholesterol was low at 3.5 mmol L-1. Despite aggressive vitamin replacement,she continued to complain of lethargy and dizziness. Subsequently, three shortadrenocorticotropic hormone-stimulation tests were suboptimal (basal cortisol:196, 185 and 223 nmol L-1; 30 min cortisol: 421, 453 and 435 nmol L-1). She wassubsequently commenced on adrenal replacement and her symptoms resolved andshe conceived. We describe for the first time in the literature the unexpectedfinding of adrenal insufficiency following a BPD.

Keywords: Adrenal insufficiency, bariatric surgery, cholesterol, cortisol, obesity,steroid.

obesity reviews (2012) 13, 560–562

Malabsorptive bariatric surgery including bilo-pancreaticdiversion (BPD) may be associated with nutritional defi-ciencies. We describe for the first time in the literature theunexpected finding of adrenal insufficiency following aBPD.

Case report

A 30-year-old woman (body mass index [BMI]: 54 kg m-2)who underwent an uneventful BPD was prescribed forceval,calcichew D3, vitamin B12, ferrous sulfate and multivita-mins. Surgery was successful and associated with the returnof menstruation and she subsequently conceived for the firsttime. Following the birth of a healthy son, she was lost tofollow-up. Five years (BMI: 36 kg m-2) later, she presentedto her physician with left foot pain and proximal leg weak-ness. Ten months later, she was referred to the endocrineclinic. She also complained of lethargy, dizziness, night

blindness, generalized skin pigmentation and amenorrhoea.She had stopped taking ferritin, vitamin D, multivitaminsand forceval from 6 months post-partum. Investigationsshowed: haemoglobin: 9.6 g dL-1; ferritin: 9 ng mL-1 (13–150); vitamin B12: 464 pg mL-1 (191–663); folate:16.8 ng mL-1 (4.6–18.7); corrected calcium: 2.05 mmol L-1;parathyroid hormone: 25.9 pmol L-1 (1.6–6.8); vitaminD: < 5 ng mL-1 (10–50); vitamin A: 0.1 mmol L-1 (1.10–2.60); total cholesterol: 3.5 mmol L-1; and low-densitylipoprotein (LDL) cholesterol: 1.4 mmol L-1. Vitamin C,vitamin E, zinc, copper, gonadotrophins and oestradiol werenormal. She was restarted on calcichew D3 forte (threetablets twice a day containing calcium 500 mg and chole-calciferol 400 U) and vitamin A + D combined supplements(six tablets twice a day of 4,000/400 U) and ferrous sulfate,vitamin B6 and forceval.

Within 6 months, the foot pain and night blindnessimproved. There was a partial improvement in the

obesity reviews doi: 10.1111/j.1467-789X.2012.00987.x

560 © 2012 The Authorsobesity reviews © 2012 International Association for the Study of Obesity13, 560–562, June 2012

tiredness; however, she continued to feel unwell withdizziness. The biochemical investigations had improved(corrected calcium: 2.21 mmol L-1; ferritin: 20 ng mL-1;vitamin A: 0.96 mmol L-1; vitamin E: 21.4 mmol L-1;vitamin D3: 12 ng mL-1; and parathyroid hormone:5.7 pmol L-1). She had three 9 am serum cortisol measure-ments of 52, 130 and 138 nmol L-1 (normal > 550).Subsequently, short 250 mg adrenocorticotropic hormone(ACTH)-stimulation tests showed inadequate responses(basal cortisol: 196, 185 and 223 nmol L-1; 30 min corti-sol: 421, 453 and 435 nmol L-1). Adrenal antibodies and acomputed tomography scan of the adrenal glands wereunremarkable. She was commenced on hydrocortisone20 mg d-1 and fludrocortisone 50 mg d-1 with resolution ofsymptoms and the return of menstrual periods and shesubsequently conceived within 2 months.

Discussion

This patient presented with deficiencies of ferritin,calcium, vitamin D and vitamin A together with evidenceof adrenal insufficiency. We are unable to find any previ-ous reports of adrenal insufficiency following BPD. Thedeficiencies in ferritin, calcium, vitamin D and vitamin Aare likely to be related to malabsorption. However, wespeculate that the deficiencies in vitamin D and steroidhormones may partly be related to relative cholesteroldeficiency. Cholesterol forms the basic structure of manyhormones (e.g. cortisol, aldosterone) (1). Of interest, thispatient had a relatively low total cholesterol and LDLcholesterol. Previously, studies examining LDL-cholesterolturnover after ileal resection have shown a reduction inLDL cholesterol as a result of increased hepatic LDL-cholesterol catabolism mediated by enhanced hepatic LDLreceptor uptake. Of importance (Fig. 1), cholesterol forbile acid synthesis is partly derived from endogenous syn-

thesis and partly derived from the influx of hepatic LDLcholesterol from plasma. In the normal small intestine,newly synthesized bile acids are secreted in bile and thenmainly reabsorbed in the terminal ileum. Therefore,further hepatic bile acid synthesis is mainly dependenton reabsorption from the ileum and only partly bycholesterol supplied by endogenous hepatic synthesis andhepatic LDL-cholesterol receptor-mediated uptake fromthe serum. Following ileal bypass (Fig. 1), there is markedmalabsorption of bile acids and therefore an increase inhepatic bile acid synthesis, which requires greater hepaticLDL-cholesterol receptor-mediated uptake. We wouldhypothesize that this would result in reduced cholesteroland 7-dehydrocholesterol availability for steroid hormoneand vitamin D synthesis, as shown in Fig. 2. Whilst thishypothesis is speculative, other conditions associated withlow serum LDL-cholesterol levels have also been associ-ated with adrenal insufficiency. For example, Smith-Lemli-Opitz syndrome is associated with deficient conversionof 7-dehydrocholesterol to cholesterol resulting in abnor-mally low serum cholesterol and adrenal insufficiency.Subjects with abetalipoproteinaemia (2–4) and thosewith impaired LDL receptor function (5) have also beendescribed with adrenal insufficiency (10–12). Of interestin the mouse adrenal gland, 75% of steroid hormone syn-thesis is derived from plasma LDL-cholesterol uptake (6).There is also evidence to support that ACTH-stimulatedadrenal steroid synthesis increases adrenal cholesteroluptake via LDL receptors (7).

Vitamin and mineral deficiencies are common after BPDand, therefore, all patients should be commenced on imme-diate replacement to avoid long-term (and sometimesirreversible) deficiencies. This case highlights the need forlong-term follow-up post-BPD and, furthermore, nutri-tional or endocrine deficiencies may appear as late sequelaewhich may be missed.

Cholesterol

Liver

Primary bile acids Reabsorption

Ileal bypass results in

Common

Portalvein

loss of bile acid reabsorption

bile duct

Primary bile acids & salts Primary & secondary bile acidsReduction

deconjugation

Small intestine

Excretion

0.3–0.5 g d–1

15–30 g d–1

Conjugation& secretion

15–30 g d–1

0.3–0.5 g d–1

Figure 1 The enterohepatic circulation of bilesalts. Usually only a small amount of hepaticcholesterol is utilized for hepatic bile acidsynthesis with the majority of bile acidsundergoing enterohepatic circulation withreabsorption from the ileum via the portalvein. Following ileal bypass, the reabsorptionof bile acids is markedly reduced andtherefore de novo hepatic synthesis of bileacids is dependent on increased hepaticcholesterol.

obesity reviews Adrenal insufficiency and bariatric surgery J. W. Stephens et al. 561

© 2012 The Authorsobesity reviews © 2012 International Association for the Study of Obesity 13, 560–562, June 2012

Conflict of Interest Statement

None declared.

References

1. Sezer K, Emral R, Corapcioglu D, Gen R, Akbay E. Effect ofvery low LDL-cholesterol on cortisol synthesis. J Endocrinol Invest2008; 31: 1075–1078.2. Illingworth DR, Kenny TA, Connor WE, Orwoll ES. Corticos-teroid production in abetalipoproteinemia: evidence for animpaired response ACTH. J Lab Clin Med 1982; 100: 115–126.3. Illingworth DR, Kenny TA, Orwoll ES. Adrenal function inheterozygous and homozygous hypobetalipoproteinemia. J ClinEndocrinol Metab 1982; 54: 27–33.

4. Illingworth DR, Orwoll ES, Connor WE. Impaired cortisolsecretion in abetalipoproteinemia. J Clin Endocrinol Metab 1980;50: 977–979.5. Illingworth DR, Lees AM, Lees RS. Adrenal cortical function inhomozygous familial hypercholesterolemia. Metabolism 1983; 32:1045–1052.6. Faust JR, Goldstein JL, Brown MS. Receptor-mediated uptakeof low density lipoprotein and utilization of its cholesterol forsteroid synthesis in cultured mouse adrenal cells. J Biol Chem1977; 252: 4861–4871.7. Kovanen PT, Basu SK, Goldstein JL, Brown MS. Low densitylipoprotein receptors in bovine adrenal cortex. II. Low densitylipoprotein binding to membranes prepared from fresh tissue.Endocrinology 1979; 104: 610–616.

Acyl CoA

7-dehydrocholesterol

Vitamin D3 Cholecalciferol

Cholesterol

25-hydroxyvitamin DCalcidiol

1,25-dihydroxyvitamin DCalcitriol

Adrenal steroid hormones

Bile acids

+

+

-

-Dietary

vitamin D3

Many steps

Figure 2 Synthesis of vitamin D, cholesterol,steroid hormones and bile salts from7-dehyrocholesterol. Following ileal bypass,there is marked malabsorption of bile acidsand therefore an increase in hepatic bile acidsynthesis which requires greater utilization ofhepatic cholesterol and 7-dehydrocholesterol(+). We would hypothesize that this wouldresult in reduced (-) cholesterol and7-dehydrocholesterol availability for steroidhormone and vitamin D synthesis.

562 Adrenal insufficiency and bariatric surgery J. W. Stephens et al. obesity reviews

© 2012 The Authorsobesity reviews © 2012 International Association for the Study of Obesity13, 560–562, June 2012