states associated with low plasma cholesterol levels its transport t - PDF document

states associated with low plasma cholesterol lev-els, its transport to various steroid-producing tis-sues may be impaired. A subsequent reduction ofcholesterol conversion to steroid hormones mayaffect their production and release and lead to thedevelopment of some endocrine deficiencies.Therefore, very low LDL cholesterol levels ob-served in the index patient may have disturbedthe production of both adrenocortical and go-nadal hormones by limiting the amount of cho-lesterol for steroidogenesis. In line with this hy-pothesis, patients with low LDL cholesterol lev-els were found to have an impaired initial gluco-corticoid and dehydroepiandrosterone responseto ACTH stimulation, as well as lower free andtotal testosterone levelsBecause the reported patient is the first subjectwith abetalipoproteinemia who developed clini-cally overt hormonal deficiencies, it seems thatonly in selected individuals with either a suscep-tible genetic profile or exposed to particular envi-ronmental factors. In agreement with this hypoth-esis our patient developed hypogonadism andAddison’s disease several months after he startedthe treatment with carbamazepine, which is adrug known to enhance hepatic hydrocortisonemetabolism. Moreover, the pa-tient poorly complied with treatment of the un-derlying disease. Probably in this case, adrenalglands and testes we unable to increase steroidhormone production in response to their en-hanced metabolism in the liver.Summing up, we have reported for the firsttime endocrine manifestations of abetalipopro-teinemia, which resulted from the abnormal pro-duction of adrenal and testicular hormones.Treatment with hydrocortisone, fludrocortisone,dehydroepiandrosterone and testosterone com-bined with a reduction in carbamazepine dosemade it possible to effectively control these clini-cal entities in the index patient.ReferencesVANgenic hypocholesterolaemic lipid disorders andapolipoprotein B metabolism. Crit Rev Clin LabSci 2005; 42: 515-545.LP, SM, WThe role of the microso-mal triglygeride transfer protein in abetalipopro-teinemia. Annu Rev Nutr 2000; 20: 663-697.LLINGWORTHTA, CRWOLLCorticosteroid production in abetalipopro-teinemia: evidence for an impaired responseACTH. J Lab Clin Med 1982; 100: 115-126.LLINGWORTHTA, ORWOLL. Adrenalfunction in heterozygous and homozygous hypo-betalipoproteinemia. J Clin Endocrinol Metab1982; 54: 27-33.R, GH, EJ, CJP.Effectof decreased plasma low-density lipoprotein lev-els on adrenal and testicular function in man. ClinBiochem 1997; 30: 419-424.P, KALTSASGA, SATTAThe effects of anti-convulsant drugs on adrenalfunction. Horm Metab Res 1998; 30: 389-397.Metabolic consequences of antiepilep-tic drugs. Curr Opin Neurol 2010; 23: 164-169. Abetalipoproteinemia and endocrine disorders Grunwald-Giemsa-stained erythrocytes. Stere-omicroscopy revealed diffuse microvesicularclinical picture and laboratory findings were sug-gestive of abetalipoproteinemia, the patient wasadvised to follow dietary recommendations, andwas prescribed high-doses of vitamin E (1000mg daily), calcitriol (0.25 g daily), vitamin A(10,000 IU daily) and vitamin K (10 mg twice aweek), as well as calcium and magnesium salts.However, after discharge from hospital theseagents were taken irregularly, and after six yearsthe patient on his own terminated this treatment. At the age of 25, there appeared symptoms ofpolyneuropathy (glove and stocking numbnessand tingling) and the patient started treatmentwith carbamazepine at the daily dose of 600 mg.Two months later, he started to experience somesexual probl

ems (poor libido, fatigue and erectiledysfunctions). Hormone analysis revealed lowplasma testosterone levels (2.9 ng/dL, referencerange: 3.0-9.0), increased plasma levels of bothFSH (12.1 U/L, normal range: 2.8-7.2) and LH(11.9 U/L, reference range: 2.4-6.8) and normalplasma levels of prolactin (10.7 g/L, referencerange: 5-15), which were consistent with hyperg-tions of testosterone enanthate (200 mg everytwo weeks), used at the beginning of the treat-ment, were, on the patient’s request, replacedwith testosterone gel applied to the skin. Thistreatment, providing 6 mg of testosterone daily,improved his sexual performance. However, after the following two years, hewas admitted to our Unit because of increasinglethargy and tiredness, reduced appetite, anepisode of fainting, weight loss as well as diffusepain in the abdomen. On admission, physical ex-amination showed generalized hyperpigmenta-tion of the skin and mucous membranes, whichwas most prominent on the hands, feet, neck andgingival mucosa. His pulse rate was 110 bpm,sound scanning as well as a magnetic resonanceimaging scan of the patient’s abdominal organsdid not reveal any adrenal abnormalities. Be-cause of sig nificant hyperkalemia (5.7 mmol/L,reference range: 3.4-5.3), reduced renal potassi-um loss (22 mmol/L; reference range: 25-100)and low plasma glucose (3.2 mmol/L, referencerange: 3.6-5.6), primary adrenal failure was sus-pected and investigated. Both morning plasmacortisol levels (4.8 droepiandrosterone sulfate levels (75 erence values: 80-450) were abnormally low. Ag cosyntropin stimulation test showed apoor cortisol response with a peak cortisol levelof6.2 g/dL (reference values: above 22.0). Inturn, morning plasma ACTH levels were elevated(162 pg/mL,reference values:10-75). Supineplasma renin activity was markedly enhanced(15.6 ng/mL/hr; reference values: 0.3-2.8),whilesupine plasma aldosterone was decreased (26pg/mL; reference values:30-150)test was negative, excluding the presence of tu-berculosis. The lack of 21-hydroxylase and 17hydroxylase antibodies excluded the autoimmunenature of adrenal insufficiency, while low plasmalevels of very long chain fatty acids ruled out theoccurrence of adrenoleukodystrophy. On the ba-sis of the above findings, the patient was diag-nosed with adrenal failure, and started treatmentwith oral hydrocortisone (10 mg/m/day in twodivided doses), fludrocortisone (0.1 mg daily)and dehydroepiandrosterone (50 mg daily). Clin-ical improvement was observed after a few daysand plasma ACTH levels reached normal values.Hyperpigmentation disappeared after 4 monthsof this treatment. We tried to terminate carba-mazepine treatment, but despite its withdrawal,adrenal cortex hormones and testosterone stillhad to be administered, albeit at lower doses. Be-cause carbamazepine withdrawal worsenedpolyneuropathy, we decided to continue carba-In this article, we report a case of coexistenceof clinically overt primary adrenal failure and hy-pogonadism with abetalipoproteinemia. To thebest of our knowledge no previous study de-scribed a similar association between these disor-were found to have a reduced adrenal gland re-serve after the ACTH stimulation test, baselineplasma cortisol levels in these patients wereLow cortisol, aldosterone, dehydroepiandros-terone and testosterone plasma levels were prob-ably secondary to the low levels of plasma cho-lesterol. Both adrenal cortex hormones andtestosterone are produced from cholesterol, andLDL particles serve as an important source ofcholesterol for adrenal and gonadal steroid syn-

thesis. Because all adrenocortical and gonadalhormones are synthesized from cholesterol, inR. Krysiak, B. Okopie Abetalipopro-teinemia is a rare inherited disorder character-ized by very low plasma levels of cholesterol andtriglycerides, secondary to a dramatic decreasein apolipoprotein B-containing lipoproteins,which is induced by a mutation in the microsomaltriglyceride transfer protein gene. In our paper, we describe an atypicalclinical manifestation of this condition in ayoung man, which included the presence of hy-pogonadism and chronic adrenal failure. Weconnect the development of both endocrinedisorders with very low plasma levels of cho-lesterol, which is uptaken by the gonads andadrenal cortex and used as a substrate forsteroidogenesis, accentuated by carba-mazepine treatment. Testosterone treatmentand administration of hydrocortisone, fludro-cortisone and dehydroepiandrosterone resultedin a significant improvement in a patient’s con-This case shows that untreat-ed or inaccurately managed long-lasting abetal-ipoproteinemia may impair the production ofsteroid hormones and lead to the developmentof some endocrine disorders.Abetalipoproteinemia, Hypogonadism, Adrenal fail- ure, Treatment. IntroductionAbetalipoproteinemia, also known as Bassen-Kornzweig disease, is a rare inherited autosomalrecessive disorder characterized by a marked de-crease in or the absence of plasma apolipoproteincrons, very low density lipoproteins (VLDL) andlow density lipoproteins (LDL)sults from a mutation in the microsomal triglyc-eride transfer protein gene on chromosome 4,Review for Robert Krysiak, MD; e-mail: r.krysiak@interia.pl leading to premature degradation of nascentapolipoprotein Bmanifest for the first time in the first few monthsof life. A dramatic decrease in apolipoprotein B-containing lipoproteins leads to deficiencies ofvarious fat-soluble vitamins (A, D, E and K)Apart from low plasma levels of cholesterol,triglycerides and fat-soluble vitamins, the diseaseis characterized by the presence of acanthocyto-sis, cerebellar ataxia, retinitis pigmentosa, steat-orrheaand fat malabsorptionIn the present paper, we report a young mandiagnosed with abetalipoproteinemia, who withinseveral years developed clinical pictures of hy-pergonadotropic hypogonadism and chronicadrenal failure. We describe diagnostic and treat-ment strategies applied in our patient.Since his early childhood, the patient was in-tolerant to fat-rich meals, which resulted in diar-rhoea, vomiting and abdominal pains. At the ageof 6, he started to experience some deteriorationof night and color vision, which was followed bya worsening of visual acuity and a gradual reduc-tion in the visual field. At the age of 14, he wasadmitted to hospital because of a wide-basedataxic gait and mild intention tremor. Neurologi-cal examination revealed absent ankle and kneejerks and positive Romberg’s sign. Finger-nose-finger and heel-knee-shin tests were impaired.Fundoscopic examination revealed subtle bilater-al pigmentary changes consistent with retinitispigmentosa. Total cholesterol, LDLcholesterol,HDL cholesterol and triglycerides were: 72mg/L, 8 mg/dL, 56 mg/dL and 8 g/dL respective-ly, which was accompanied by very low plasmalevels of apolipoprotein B (8 mg/dL), whilelecithin-cholesterol acyltransferase levels werecytes were found to constitute over 75% of May- 2012; 16(4 Suppl): 95-97Chronic adrenal failure and hypergonadotropicabetalipoproteinemia R. KRYSIAK, B. OKOPIEDepartment of Internal Medicine and Clinical Pharmacology, Medical University of Silesi