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Can parathyroid carcinoma (PTC) patients have normocalcaemia (NC)?.
Most patients with PTC present with profound hypercalcaemia with or without kidney stones , osteitis fibrosa cystica , pancreatitis and non specific symptoms such as fatigue, depression , musculoskeletal aches and pains and weakness. NC is due to a non functioning PTC, which is diagnosed in the absence of symptoms of hypercalcaemia by the presence of locally advanced disease, a palpable neck mass, dysphagia, vocal cord paralysis or hoarseness. Chest pain, dyspnoea and pleural effusion are less common. The diagnosis is established immunohistochemically. These cases are often misdiagnosed as thyroid or thymic carcinoma, as in the absence of hypercalcaemia, the presentation is similar and the histological appearance similar.The presence of intracellular immunoreactive PTH with the absence of thyroglobulin and Calcitonin is used to diagnose PTC in the absence of hyperparathyroidism. Ref: Fernandez- Ranvier G.G. et al Endocrine practice 2007 Nov/Dec; 13 (7): 750 -757.
What are the endocrine syndromes associated with Lithium therapy?.
1) Thyroid disorders. 2) Parathyroid disorders. 3) Nephrogenic diabetes insipidus. Thyroid disorders:
Li increases intrathyroidal iodine content, inhibits coupling of Iodotyrosine residues to form iodothyronines, and to inhibit the secretion of T4 and T3. It also increases the release of TSH from the pituitary gland by releasing TRH from the hypothalamus. The combined effects result in decreased serum T4 and T3 and elevated TSH. Hyperplasia of the thyroid gland follows resulting in a non tender goiter with hypothyroidism. Thyrotoxicosis from Li therapy could be due to 1) Autoimmune thyroid disease triggered by Li. 2) Disturbed Iodine kinetics with escape phenomenon and overflow of thyroid hormone after expansion of the intrathyroidal iodine pool. 4) Direct damage of thyroid follicular cells with subsequent release of preformed thyroid hormone into the circulation. 5) Coincident Graves’ disease or other coincidental causes of hyperthyroidism. Ref: Dalan R. et al Endocrine Practice 2007 Nov/Dec; 13 (7): 758 – 763.
Lithium and the Parathyroid glands.
Hyperparathyroidism (HPT) associated with Li therapy seems to be unrelated to Li concentration, duration of treatment or cumulative dose. The PTH levels are usually only mildly elevated, and the PTH level is inappropriately high for the concomitant serum Ca levels. As opposed to primary HPT, where the urinary Ca and Phosphorus excretion is increased, in HPT associated with Li-hypocalciuria is the norm. The serum Phosphorus levels tend to be normal rather than low as in primary HPT. There is a high prevalence of multiglandular disease with Li. The hypocalciuria is most likely a direct effect of Li on the renal tubules, inhibiting the formation of cyclic AMP. Li also inhibits phosphate excretion, so that serum levels may be in the upper limit of normal. Li withdrawal does not usually normalize the hypercalcaemia. If this does not normalize- removal of 3 1/2 parathyroid glands or parathyroidectomy with reimplantation of the remaining half portion of the parathyroid gland into the forearm is advocated. Ref: Dalan R. et al Endocrine Practice 2007 Nov/ Dec; 13 (7): 758 – 763.
Lithium and nephrogenic diabetes insipidus (NDI).
The risk of NDI correlates with the duration of Li therapy. Elderly patients are especially prone. Patients on Li for more than 15 years have been found to have a concentrating defect in the kidney in 44% and overt NDI in 12%. Increased thirst is found in 53%. The possible mechanisms for NDI are 1. Down regulation in aquaporin – 2 expression. 2. Reduction in the fraction of principal cells in the collecting ducts. 3. Impairment of the AVP stimulatory effect on adenylate cyclase. The Li induced defect in the renal tubules is generally reversible but sometimes may be permanent after prolonged therapy. If stopping the Li does not result in improvement of NDI, then amiloride is advocated. This drug decreases extracellular fluid and promotes proximal tubular resorption, which is independent of AVP, resulting in less free water transmitted to the collecting tubules, (where the urine concentrating defect is located), thereby reducing polyuria. Other drugs which may be used include carbamazepine, NSAIDs , Bendroflumethiazide or a combination of these agents. Ref: Dalan R. et al Endocrine Practice 2007 Nov/Dec; 13 (7): 758 – 763.
A new cause for increased bone mass – Type 1 Lipodystrophy (Berardinelli- Seip syndrome
- BSS).
BSS is a congenital generalized lipodystrophy inherited as an autosomal recessive. There is absent adipose tissue, emphasizing the muscle contours from birth. Accelerated linear growth with advanced bone age , acromegalic features, acanthosis nigricans, hyperinsulinaemia with insulin resistance are often seen. Ketosis resistant diabetes mellitus generally develops during adolescence. Hypertriglyceridaemia, low levels of leptin, hepatomegaly due to a fatty liver, prominent umbilicus or umbilical hernia are other features. In the bone osteopaenia has been reported. Increased bone mineral density may occur due to low levels of leptin ( Leptin inhibits bone formation) or increased levels of Insulin which increases osteoblast proliferation directly. Hyperinsulinaemia may also suppress the level of sex hormone binding globulins thereby increasing the free sex hormone levels which stimulate bone formation. Hyperinsulinaemia may also depress insulin like growth factor binding proteins there by increasing the free IGF1 levels which augment bone mass. One such case has been reported. Ref: Bandeira F.F. et al Endocrine Practice 2007 Nov/Dec; 13 (7): 764 – 769.
A new cause for PCOS – 13 – cis Retinoic acid
( isotretinoin).
Isotretinoin is a highly effective treatment for severe recalcitrant nodulo cystic acne, particularly in the adolescent population. It has many adverse effects including psychiatric disturbances such as depression, psychosis or suicidal ideation. Elevated TG, TC, FPG and reduced HDLC are biochemical adverse events. It can induce insulin resistance and the metabolic syndrome. It is now known to cause or worsen PCOS. Because of the teratogenic effects of the drug, female patients in their fertile years have to take an oral contraceptive. This masks the menstrual irregularities and other clinical features that accompany PCOS making the diagnosis more difficult. Ref: Pham T et al Endocrine Practice 2007 Nov/Dec; 13 (7): 776 – 779.
What are the features of a glucagonoma?.
This is a neuro endocrine tumor arising from the Alpha cells of the pancreas. It is slow growing and can manifest many signs and symptoms that are disseminated in time viz necrolytic migratory erythema, stomatitis, hyperglycaemia, weight loss, DVT and neuropsychiatric symptoms. Early detection is important because at least 50% of malignant glucagonomas are metastatic at the time of diagnosis. 2. Lack of suppression of glucagon levels by a standard OGTT (autonomy). 3. Elevated ALT and AST. 4. Octreotide scintigraphy which reveals abnormal uptake in the pancreas, usually in the tail. 5. Immunohistochemical staining on biopsy specimen revealing glucagon. 6. Neoplastic cells reacting strongly to chromogranin and glucagon. Glucagon levels do not always correlate with the symptoms and signs but there is a positive correlation between tumour size and metastatic potential. Metastases occur most commonly to the liver. They can secrete other hormones such as gastrin. They may present as recent impaired fasting glucose or a chronic diarrhea. Rarely the glucagons levels may be suppressed by an OGTT. Sometimes there is a paradoxical increase in glucagon levels with an OGTT. Secondary causes of hyperglucagonaemia are 1. Cirrhosis. 2. Renal failure. 3. Cushings syndrome. 4. Bacteraemia. 5. Acute trauma. 6. Burn injury. The prognosis is good after surgical resection in patients without metastatic lesions. Ref: Mai V.Q. et al Endocrine Practice 2007 Nov/Dec; 13 (7): 780 – 784.
Can patients with primary hyperparathyroidism (PHPT) have low serum Ca levels?.
Since the introduction of immunometric PTH (1-84) assays, distinguishing PHPT from hypercalcaemia due to non PTH mediated causes is generally easy. Hypercalcaemia of malignancy and other non PTH mediated hypercalcaemic processes manifest with a low serum PTH concentration. When serum PTH levels are inappropriately normal in the setting of hypercalcaemia, levels in the upper one half to 1/3rd of the reference range have been used as a cut off for the diagnosis of PHPT. Factors contributing to hypercalcaemia leading to suppression of PTH are 7. Measurement of PTH during the trough stage of intermittent PTH secretion. 9. The “hook” effect where very high levels of PTH cause antibodies to mop up PTH. This can be unmasked by a 1/100 dilution sample estimation. 10. Atypical but bioactive form of PTH that is not measured by the current PTH assays. 11. Raised pancreatic enzymes as in pancreatitis which may increase degradation of PTH. In these settings high endogenous serum Ca and 1,25-dihydroxy Vit D levels may negatively regulate PTH secretion. Collection of PTH is important. Blood is drawn in a red top or serum gel tube, the contents are spun down, and 0.8ml of serum is sent on ice to the automated immunoassay lab. The serum is analysed for PTH on the same day and analysis begins less than 4 hours after the blood specimen is obtained. Clinicians should consider repeating PTH testing when the cause is unclear. If a repeated PTH measurement remains inappropriately in the lower half of the reference range despite continued hypercalcaemia and if other causes of hypercalcaemia are not present, then serial sample dilution may be considered. Ref: Khoo T.K. et al Endocrine Practice 2007 Nov/Dec;13 (7): 785 – 789.
What are the endocrine effects of Leflunomide?.
Leflunomide is a disease modifying antirheumatic drug used in the treatment of rheumatoid arthritis, autoimmune diseases like SLE, solid organ transplants and in cytomegalo virus disease. The commonest side effect is diarrhea. The adverse endocrine effects include 6. Hypocalcaemia – parasthesiae of finger tips, toes and perioral region. Carpal spasm, tetani, bronchospasm, laryngospasm and muscle weakness when severe. Prolongation of QT interval, abnormal T waves, congestive heart failure or reversible cardiomyopathy may occur. Ref: Young M.G. et al Endocrine Practice 2007 Nov/Dec; 13 (7) : 805 – 807.
Type 1 diabetes - some aspects.
* The incidence of Type 1 DM varies from country to country and is increasing all over the world. The incidence in Finland is 500 times that in India. * Antibodies can be produced in children even when the child is only 18 months old. * By the time Type 1 DM manifests at least 50% of the Beta cells are lost. The balance 50% are gradually lost over many years or even decades. Thus residual Beta cells may still be available for regeneration even 25 years after Type 1 DM onset. * Type 1 DM can develop at any age viz early childhood, juvenile, adult or as late onset autoimmune diabetes in adults (LADA). * The development of Type 1 DM goes through different phases. a) The period of genetic susceptibility. * Prediction of future Type 1 DM will depend on the prescence of multiple antibodies, the loss of immediate release of insulin on a GTT, family history of Type 1 DM and genetic susceptibility. * Potential therapeutic targets include targeting the autoimmune process, protecting whatever residual Beta cell mass that exists and helping regeneration of residual Beta cells. * The infant diet may play a role in preventing the autoimmune process. Cereal and gluten consumption have the highest association with Type 1 DM. * Hydrolysed casein is better than cow's milk in preventing antibody production. * High n-3 fatty acids in the diet has anti inflamatory, anti thrombotic, hypolipidaemic and vasodilatory actions, while n-6 fatty acids in the diet have the opposite effect. Higher the n-3 FA content the better. * In the Trial Net study, oral insulin was tried in IAA positive individuals. Initial results suggested that there was no beneficial effect of oral insulin in preventing Type1 DM. However secondary analysis suggested that in those who had an IAA antibody concentration > 80, there is a delay in onset compared to placebo treated patients. Higher the titre of IAA, the greater the protective effect. * Other preventive methods viz an anti CD3 monoclonal antibody, rituximab (anti CD 20 monoclonal antibody) and exenatide are being studied. Ref: Atkinson M. AACE 2008 syllabus Annual Sessions ; 77-100.
Thyroid cancer - some aspects.
* There is an increased incidence of second primary malignancies after treatment for differentiated thyroid cancer (DTC). These include salivary gland, breast, prostate, kidney, CNS and stomach cancers. Lymphoma, multiple myeloma and leukaemia have been reported. The risk is greatest in those who have been treated with radioactive iodine (20% for RAI vs 5%for those without RAI). The greatest risk is in younger patients, within the first five years of RAI and those on the higher dosage of RAI. However the benefit of RAI far outweighs any negative effects due to these second primary malignancies. * Differentiating benign folicular neoplasms from malignant ones - FNAs cannot differentiate benign from malignant formations. Thus they are reported as “folicular neoplasms”. Improving diagnostic accuracy of thyroid biopsies and FNA is now possible using two stains for DPP-4 (Dipeptidyl-Peptidase 4) and TPO (Thyroid peroxidase). The TPO sensitivity for follicular thyroid carcinoma is almost 100% sensitive and for DP4 100% specific. A combination of these two will be useful in deciding whether a tumour is benign or malignant. Ref: Rodbard H.W. - Hot to[pics in thyroid disease AACE Annual sessions 2008.
Thyroid disease and pregnancy - an update.
* There is an increased clearance of Iodide from the kidneys which decreases the serum iodide level and precipitates hypothyroidism on those with marginal intake or reserves and increases the size of any goitre present. * The TSH levels vary from trimester to trimester and ranges from 2.5 to 3.2 miu /ml. * The TSH level in those who are thyroid peroxidase antibody positive is higher during pregnancy than those who are antibody negative. * The foetal thyroid tissue is only present after 11 weeks and the foetal hypothalamic unit begins to function only at about 20 weeks. Therefore exogenous thyroxine is mandatory in hypothyroid and subclinical hypothyroid patients pre pregnancy or at the earliest opportunity during pregnancy. * The placenta is permeable to iodine, TSH receptor antibodies and antithyroid drugs. These will therefore have an effect on the foetus. Small amounts of T4 may also pass across the placenta. * Autoimmune thyroiditis is a common cause of thyroid dysfunction during pregnancy. TPAb positive patients may be euthyroid, hypothyroid or hyperthyroid. * The miscarriage rate in TPAb positive pregnancies is higher than TPAb negative pregnancies. * Will T4 therapy prevent miscarriage in pregnant euthyroid TPAb positive women?. In a randomized study, thyroxine in doses of 30, 50, and 70 mcg/d was compared with placebo. Those treated with thyroxine had less miscarriages than controls (Negro J.C.E.M.2006). * Pregnancy complications of overt and subclinical hypothyroidism are spontaneous abortion (60 and 40%), PIH/ pre eclampsia (22 and 9%), abruption (10% and 0%), still birth (6 and 1.5%) anaemia (16 and 1%), postpartum haemorrhage (10 and 9%), pre term birth (25 and 5%). * The foetal outcomes depend on the TSH levels. It is best to keep the TSH below 2.5 miu/ml during all trimesters. * Drugs that delay the absorption or interfere with its action, should be given at least 4 hours after the thyroxine is taken. * The dose of thyroxine for replacement is higher in those with athyreosis than those with autoimmune hypothyroidism. The required dose increases by about 45% in athyreotics, by 25% in Hashimotos and usually no change in subclinical hypothyroidism during pregnancy. * Screening for thyroid disease in pregnancy is recommended in History of hyperthyroid or hypothyroid disease, postpartum thyroiditis or thyroidectomy. Symptoms and signs suggestive of thyroid dysfunction. Those with prior therapeutic head or neck irradiation. Women in whom the last delivery was pre term. In spite of this screening procedure, 30% of women with overt or subclinical hypothyroidism would be missed in the first Trimester. Ref: Mandel S.J. AACE Annual sessions 2008 - Thyroid -Pregnancy update.
Testosterone deficiency (TD) - some aspects.
TD is defined by the FDA as a total testosterone level < 300ng/dl. It causes a decreased muscle mass, an increased fat mass, anaemia, osteoporosis, limited exercise tolerance, impaired spermatogenesis, decreased sex drive and erectile dysfunction. In the last named – TD decreases cyclic GMP levels in the corpora cavernosa, decreasing cavernosal nitric oxide synthase levels, leading to vasoconstriction and lack of erection. In patients who are sildenafil failures and with low or low normal testosterone levels, added testosterone leads to improved erectile dysfunction. The testosterone may be given as Depot injections once in two weeks or as patches or gels. A new preparation testosterone undecanoate can be given im 4ml once in 3 months. The absolute contraindications to testosterone therapy are Prostate cancer, male breast cancer, erythrocythaemia, malignant hypertension and a relative contraindication is sleep apnoea. Low testosterone is also known to increase mortality as was shown in a study of 794 men, age 50 -91 on a 12 year follow up. Ref: Laughlin G.A. JCEM 2008 ; 93: 68 -75.
Shabsigh et al J.Urol.172: 658 -663.
Spark R.F. AACE 2008 Annual sessions.
Anabolic steroids - some aspects.
These are man made substances related to testosterone and have been used by professional sportsman to enhance their performance over the last few decades. This abuse has now spread even to the adolescent and high school children. The rationale for using them are either the desire to improve appearance or to improve performance. The potential side effects of anabolic steroids include liver tumours and cancer, abnormal LFTs , hypertension, abnormal enlargement of the heart muscles, fluid retention, increase in LDL cholesterol, decrease in HDL cholesterol, renal tumours, severe acne, irreversible stretch marks, trembling, serious psychiatric effects ( mood swings, aggressive behaviour, paranoia,irritability, impaired judgment, delusions), tendon rupture, hepatitis and HIV. In men testicular atrophy, reduced sperm count, infertility, baldness, gynaecomastia and prostate cancer are potential side effects. In women, hirsutism, male pattern baldness, changes in menstrual cycle, clitoromegaly and deepening of the voice may be seen. In adolescents accelerated puberty and premature skeletal maturation may be encountered. Testing for exogenous testosterone derivatives is now possible by various analytical methods. If the ratio
of the total concentration of testosterone to that of epitestosterone in the urine is > 6: 1 then it is deemed
to be positive, unless there is evidence that this ratio is due to a physiological or pathological condition.
Anabolic steroids may also be assayed in 100mg of hair.
Ref: Cunningham G.R. 2008 AACE Annual Sessions.
Metformin in polycystic ovarian syndrome (PCOS).
* Decreases circulating insulin levels. * Decreases ovarian secretion of androgens. * Does not improve clinical signs of androgen excess such as hirsutism, acne, and androgenic alopecia. * Increases the incidence of ovulation. * when combined with clomiphene, it increases the cumulative ovulation rate but does not increase the rate of live birth compared to clomiphene alone. * Metformin is less effective than clomiphene in induction of ovulation. * Prevents progression of normal glucose tolerance to IGT and IGT to Type 2 DM. * May reduce the risk of cardiovascular disease by preventing diabetes and decreasing insulin resistance. * No terotogenic effects have been reported and is therefore safe in the first trimester. * The dose is 500mg/d to start with, increasing to a maximum of 1000mg b.d. * May be considered to be the initial intervention in most women with PCOS particularly those overweight or obese. Ref: Nestler J.E. N.E.J.Med 2008 Jan 3, 358 : 47 - 54.
Iodine deficiency in iodine replete environments.
Iodine deficiency disorders in regions with low iodine levels have generally been eliminated through the
wide spread use of iodized salt. However if iodized salt is not used for a prolonged period, iodine
deficiency may occur. This may result in a goitre which may be euthyroid or hypothyroid. Radioactive
iodine uptake shows an elevated uptake. Urinary 24 hour iodine will be < 100micrograms. Dietary iodine
supplementation has an anti goitrogenic effect and leads to dramatic resolution of iodine deficiency.
Ref: Nyenwe E.A. and Dagogo- Jack S. N.E.J.Med 2007 Sept 20, 357 (12); 1263 -1264.
A new drug causing hypothyroidism - Sunitinib.
Sunitinib is used in the treatment of renal cell carcinoma or gastrointestinal stromal tumours. Biochemical thyroid dysfunction is seen in 65% and 15% require treatment with L- Thyroxine. Ref: Wolter P. et al N.E.J.Med 2007 Apr 12, 356 (15): 1580 - 1581.
Zoledronic acid (ZA) and secondary prevention of fractures.
ZA is a once yearly iv infusion of 5mg given over 15mts. When initiated within 3 months after repair of hip fracture, it resulted in a 35% reduction in new clinical fractures and a 28% reduction in death from any cause compared with placebo. Importantly it did not delay fracture union. All patients were given adequate supplementation with Ca and Vitamin D. Patients enrolled in the study were those who were unable or unwilling to take an oral bisphosphonate. Ref: Calis K.A. and Pucino F. N.E.J.Med 2007 Nov 1st , 357(18): 1861 - 1862.
Disorders in which serum Ca should be routinely checked.
* Renal calculi.
* Osteoporosis.
* Chondrocalcinosis.
* Hypertension.
* Cardiovascular disease.
* Peptic ulcer.
* Pancreatitis of all types.
* Functional abdominal symptoms.
* Acute or chronic mental disturbances.
* Post menopausal women.
* Pituitary and pancreatic endocrine tumours (MEN 1).
* Medullary carcinoma of thyroid.
* Phaeo (MEN Type 2A).
Ref: Sitges- serra and Bergenfelz Lancet 2007 Aug 11;370: 468-470.
Reversal of idiopathic hypogonadotropic hypogonadism (IHH).
IHH is caused by a congenital defect in the secretion or action of GnRH. Patients have absent or incomplete sexual maturation by the age of 18. Hitherto this condition was thought to require lifelong therapy. When anosmia is present, the condition is called Kallmann’s syndrome. Low levels of gonadotropins and testosterone are found in male patients. Cleft palate and sensory neural hearing loss are known associations. Androgen therapy induces virilization but not fertility. Gonadotropins or pulsatile GnRH therapy usually restores normal pubertal development and fertility. Rare cases of spontaneous reversal of this condition later in life have been reported. The present case series include 15 men who had a sustained reversal after discontinuation of hormonal therapy. 4 of these had anosmia. The serum testosterone level before treatment was less than 100ng/dl which is well below the 300ng/dl required for the diagnosis of hypogonadism. Reversal was assessed 2 weeks or more after pulsatile GnRH, 4 weeks or more for transdermal testosterone and 8 weeks or more after testosterone or human HCG injections were withdrawn. Reversals occured both in men with absent puberty and in men with partial puberty. Testicular growth during androgen therapy is a key factor pointing to possible reversal. After reversal spermatogenesis occured in all patients. Fertility occurred even with sperm counts below one million /ml. Family members of IHH have delayed puberty 12 times as high as normal. Kallmann syndrome is due to defects in the FGFR 1 gene mutation. Even the effect of these can be overcome by an environmental stimulus such as exposure to sex steroids. This phenomenon is called plasticityof the nervous system where the CNS is able to adapt in response to the environment. Neurones in the olfactory epithelium and olfactory bulbs are generated throughout life from multipotent progenitor cells residing in the subcortical white matter, and their generation appears to be modulated by sex steroids leading to reversal of IHH.
Ref: Raivio T. et al N.E.J.Med 2007 Aug 30, 357; (9): 863 -873.
Compiled by :- Dr. Henry N. Rajaratnam
MD, FCCP, FRCP (Lond), (Hon) FRACP, (Hon) FSLCGP, FACE

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