Yashpal Gogate

Non-islet cell tumor-induced hypoglycemia: a report of five cases and brief review of the literature

Summary We describe the clinical presentation, diagnostic and management issues in five cases of non-islet cell tumor hypoglycemia (NICTH), diagnosed at a tertiary care institute over a period of 15 years. The clinical, laboratory, and histopathological findings of these patients along with diagnostic utility of IGF2:IGF1 ratio are discussed. The mean age of presentation was 52 years, with a male predominance (3:2). Three patients presented with recurrent episodes of fasting hypoglycemia and it was detected in other two patients during hospitalization. Two patients had acromegaloid features that regressed following treatment. One patient had hypokalemia. Low levels of insulin, C-peptide, GH, and IGF1 were invariably found in all. The IGF2 level was elevated in only one patient; however, IGF2:IGF1 ratio was more than 10 in four of the five patients. The mean tumor size was 16.4 cm and mean weight was 3.6 kg. Four patients had mesenchymal tumors and one had epithelial tumor. NICTH is a rare cause of hypoglycemia. Hypoinsulinemic hypoglycemia with low IGF1 and IGF2:IGF1 ratio more than 10 is suggestive of this entity. Learning points NICTH should be considered in patients presenting with tumor of mesenchymal origin and hypoglycemia. Hypoinsulinemic hypoglycemia with low IGF1 is a strong biochemical evidence of NICTH. IGF2:IGF1 ratio of more than 10 is a complementary investigation in the absence of an assay facility for IGF2.

Emphysematous cystitis in a patient with type-2 diabetes mellitus

Emphysematous cystitis is a relatively rare clinical entity caused by gas-fermenting bacteria or fungus. Presentation is often nonspecific and imaging is the best diagnostic modality. We report a case of a 45-year-old male who presented with fever, dysuria, and pneumaturia, and was found to have emphysematous cystitis.

Multiple Endocrine Neoplasia

A 42-year-old male presented with prominence of both the eyeballs for the last 6 months. He was detected to have hypertension 7 years earlier and for that he was receiving telmisartan, atenolol, and amlodipine. He had history of recurrent pain abdomen and dyspeptic symptoms for the last 5 years, and he frequently used to take proton pump inhibitors to relieve these symptoms. He had no history of headache, vomiting, or visual disturbances. There was no history of anorexia, constipation, bone pains, polyuria, graveluria, or renal stone disease. However, he had history of tightening of rings, palmar sweating, decreased libido and erectile dysfunction, and reduced frequency of shaving. There was history of fatigue and progressive increase in weakness for the last 2–3 years, and he was diagnosed to have iron deficiency anemia. There was no history of symptoms suggestive of thyrotoxicosis, chronic obstructive airway disease, or chronic kidney or liver disease. He was a nonsmoker and nonalcoholic. On examination his height was 169 cm, weight 90 Kg, BMI 31.3 Kg/m2, blood pressure 130/80 mmHg, and pulse rate 96 bpm and had multiple skin tags and grade 3 acanthosis nigricans. He did not have other cutaneous markers like collagenoma, angiofibroma, and lipoma. There was bilateral mild proptosis and he had palmar sweating and seborrhea. He did not have goiter and deep tendon reflexes were normal. His sexual maturation score was A+, P3, testicular volume 20 ml (bilateral), and sparse facial and body hair. He also had bilateral lipomastia. Visual fields, visual acuity, and optic disk were normal. Other systemic examination was unremarkable. On investigations, hemoglobin was 9.8 g/dl with normal leucocytes and platelet counts, and liver and renal function tests were normal. Corrected serum calcium was 11.4 mg/dl, phosphorus 2.4 mg/dl, alkaline phosphatase 104 IU/L, iPTH 1,098 pg/ml (N 15–65), and 25(OH)D 6 ng/ml (N 30–70). 0800-h serum cortisol was 262 nmol/L (N 171–536), prolactin 9,291 ng/ml (N 4–15.2), free T4 0.5 ng /dl (N 0.8–1.8), TSH 2.92 μIU/ml (N 0.27–4.2), LH 0.21 mIU/ml (N 1.7–8.6), FSH 0.26 mIU/ml (N 1.5–12.4), and testosterone 0.206 nmol/L (N 9.9–27). Serum IGF1 was 363 ng/ml (N 101–267, age matched), basal serum GH 15 ng/ml, and nadir serum GH after glucose load 5.6 ng/ml. Serum gastrin level was 284 pg/ml (N 13–115), basal acid output 40 mEq/L (N 550 nmol/l). Twenty-four-hour urinary metanephrine was 93 μg (N <350) and normetanephrine 161 μg (N <600). CEMRI sella showed a 5 × 4.6 × 3.2 cm sellar–suprasellar mass with right parasellar extension. The CECT abdomen showed small enhancing focal lesion in the head of the pancreas, circumferential wall thickening in D1 and D2 segment of the duodenum, and bilateral adrenal gland enlargement. Endoscopic ultrasonography showed two lesions in the pancreas (8 × 8 mm in the body and 6 × 4 mm in the tail of the pancreas). DOTANOC–PET CT showed somatostatin receptor expressing lesions in the sella turcica, thyroid gland, and posterior to the thyroid gland (parathyroid gland); however, focal non-avid hypodense lesions were identified in the pancreas and in the adrenal gland. Upper gastrointestinal endoscopy showed multiple superficial ulcers in D1 and D2 segment of the duodenum. Ultrasonography of the neck showed 1 × 0.9 cm size heterogeneous lesion with central vascularity in antero-inferior aspect of left lobe of the thyroid gland. Sestamibi parathyroid scan showed uptake in the right superior and the left superior and inferior parathyroid glands. SPECT–CT fusion image showed increased tracer uptake in the left superior parathyroid gland. The patient was initiated with L-thyroxine and cabergoline. Patient underwent transsphenoidal surgery (TSS) and resection of the pituitary tumor was carried out. Postoperatively, patient was continued with L-thyroxine supplementation and hydrocortisone was added. Cabergoline was also continued as there was large residual tumor postoperatively. After 3 months of pituitary surgery, he underwent bilateral neck exploration, and three enlarged parathyroid glands were identified (left superior and inferior parathyroid, and right inferior parathyroid gland) and were excised. Simultaneously, open laparotomy was also performed; intraoperative ultrasonography confirmed the lesions in the head and body of the pancreas, and these were excised accordingly. Postoperatively 3 months after TSS, serum prolactin was 23 ng/ml (on cabergoline) and GH was non-suppressible (nadir GH 1.3 ng/ml) after glucose load, however, IGF 1 was normalized (226 ng/ml; N 101–267, age matched). Repeat CEMRI sella revealed 1.5 × 2.8 × 2.8-cm sellar–suprasellar mass with parasellar extension. After parathyroid surgery with one gland in situ, serum calcium and phosphorus was normalized (9.3 mg/dl and 3.3 mg/dl, respectively), serum iPTH was 46.6 pg/ml, and serum gastrin was undetectable (<10 pg/ml). Histopathology of the sellar mass confirmed pituitary adenoma and showed diffuse positivity for GH and prolactin on immunohistochemistry (IHC). Parathyroid gland histology showed parathyroid adenoma in all three resected glands. Pancreatic tumor histology was consistent with neuroendocrine tumor. Genetic analysis for MEN1 gene demonstrated duplication of C1546 gene in exon 10 and frame-shift mutation at P-Arg 516 consistent with MEN1 syndrome. The pedigree of the index patient is shown in the figure given below. The patient was continued with cabergoline and received external beam radiotherapy (EBRT) for residual pituitary lesion. However, serum GH still remained non-suppressible after glucose load with elevated IGF1; therefore, he was initiated with octreotide LAR (20 mg once a month). He did not have features of hungry bone syndrome postoperatively. He was continued with proton pump inhibitor along with calcium carbonate and calcitriol (Fig. 11.1).

Petrified ears with idiopathic adult-onset pituitary insufficiency.

“Petrified ears” or calcification of auricular cartilage is an uncommonly reported condition. The most common causes of this phenomenon are local trauma, frost bite, and inflammation. Adrenal insufficiency is the most frequent systemic disease associated with auricular calcification. We present a case of idiopathic adult-onset pituitary insufficiency with hypocortisolism and bilateral auricular calcification. Recognition of the association between auricular calcification and adrenal insufficiency can be an important step toward the identification of a life-threatening cortisol deficiency.

Disorders of Growth and Development: Diagnosis and Treatment

Although a height >2SD below the mean for age and gender is used to define short stature, evaluation of short children based on this criteria yields organic etiology only in 14 % of these children. However, when a height SD <−3 is considered for the evaluation of short stature, the proportion of children with organic causes increases to 58 %. Nevertheless, children with height between −2SD and −3SD need careful monitoring for growth velocity, and if they show faltering, they need further evaluation.

Disorders of Growth and Development: Clinical Perspectives

A 9-year-old boy presented with complaint of growth failure since 2 years of age. He was a product of non-consanguineous marriage and was delivered at full-term by normal vaginal delivery. His birth weight was 3.3 kg and he had normal Apgar score. However, data of his birth length was not available. He had history of prolonged physiological jaundice, that lasted for 3 weeks and required phototherapy for its resolution. There was no history of any episode of hypoglycemia. His developmental milestones were normal, except delay in walking which was due to congenital dislocation of his left hip. The growth velocity data available, showed his height at 1 year of age was 65 cm, at second year 75 cm, and later at the age of 9 year it was 96 cm with annual growth velocity of approximately 3 cm/year from third year of age onward. He has good scholastic performance and now is studying in fourth standard. There was no history of any systemic illness, chronic diarrhea, drug intake (e.g., steroid), head injury, meningitis/encephalitis, headache, and visual defects. He had no history of fatigue, lethargy, irritability, somnolence, or constipation. His both parents were short and were 95th percentile). He had cherubic face with frontal bossing, depressed nasal bridge, midfacial hypoplasia, low-set ears, and poor dentition with crowded teeth. He had no goiter. His blood pressure was 90/60 mmHg. He had bilateral palpable testes with testicular volume of 1 ml and stretch penile length of 2 cm with Tanner staging of A-, P1. He had bilateral palpable testes with testicular volume of 1 ml and stretched penile length of 2 cm, and he had bilateral lipomastia. Systemic examination was unremarkable except shortening of his left lower limb with restriction of movement at the left hip joint. On investigations, his hemoglobin was 10 g/dl with normal total and differential leukocyte counts. Renal and liver function tests, electrolytes (K+ and HCO3−), calcium profile, and IgA tTG were normal. Hormonal profile showed serum T4 6.7 μg/dl (N 4.8–12.7), TSH 4.6 μIU/ml (N 0.27–4.2), 0800 h cortisol 140 nmol/L (N 171–536), LH <0.1 mIU/ml (N 1.7–8.6), FSH 0.52 mIU/ml (N 1.5–12.4), testosterone <0.08 nmol/L (N 9.9–27.8), prolactin 5.07 ng/ml (N 4–15.2), and IGF1 50 ng/ml (N 58–401). GH response to insulin-induced hypoglycemia and clonidine stimulation test, after priming with estrogen, were performed and showed subnormal peak GH response to both these stimuli (<0.03 ng/ml for both). Peak cortisol response to insulin-induced hypoglycemia was also suboptimal (150 nmol/L). His bone age was 7 years. CEMRI sella showed small pituitary with normal midline stalk and eutopic posterior pituitary bright spot. X-ray pelvis showed dislocation of left hip joint. With this profile, a diagnosis of multiple pituitary hormone deficiency (GH and ACTH) was considered, and patient was initiated with rhGH at doses of 0.3 mg/kg/week and hydrocortisone 2.5 mg twice a day. With this treatment, the growth velocity during first year was 11 cm and during second year was 14 cm, and after 2 years of initiation of rhGH therapy, the height increased from 96 to 121 cm. His weight increased from 21 to 41 kg, possibly due to immobilization during his surgery for hip dislocation. After 3 months of initiation of rhGH, the serum T4 level declined to 5.2 μg/dl and he was initiated with 50 μg/day of L-thyroxine. Serum IGF1 levels were 378 ng/ml (N 70–458) and 251 ng/ml (N 82–516) after first and second years of therapy, respectively. No adverse event was noted during the course of therapy (Fig. 1.1).

Disorders of Sex Development

A 20-year-old individual presented with poor development of secondary sexual characteristics and primary amenorrhea. She was born of a non-consanguineous marriage at term by vaginal delivery at home without any perinatal complications and was assigned female gender. There was no history of maternal virilization or any drug intake by the mother during pregnancy. The child did not have history of salt crisis or failure to thrive. The index patient identified self as a female, used to play with girls, and had preference for girl’s toys. The developmental milestones and growth were normal and the child had an average scholastic performance. During adolescence, patient had development of axillary and pubic hair and mild phallic enlargement. In addition, patient could also feel the presence of some globular structure in both labioscrotal folds. Patient continued to identify self as a female and had a preference for male partner. She had eight siblings and one elder sibling also had genital ambiguity and was reared as a male. There was no family history of primary infertility, gynecomastia, salt-crisis, precocious puberty, and neonatal deaths. The patient did not receive any medical treatment or surgical intervention till presentation. On examination, she had height of 161 cm (upper segment 77 cm, lower segment 84 cm, and arm span 167 cm), weight 55 kg, and blood pressure 100/60 mmHg. Tanner staging was A+, P4, B2. External genitalia revealed phallus of 4.5 cm with presence of chordee and ventral–urethral groove. There were two distinct openings with presence of posterior labial fusion. Both the gonads were palpable in the inguinal region (measuring 10 ml and 8 ml on the left and right side, respectively) which could be brought down to labioscrotal folds. Labioscrotal folds were partially rugosed and pigmented. The external masculinization score was 2. The patient did not have temporal recession, facial hair, acne, male torso, body hairs, and deepening of voice. Systemic examination was unremarkable. On investigations, hormonal profile showed LH 32.5 mIU/ml (N 1.7–8.6), FSH 48.5 mIU/ml (N 1.5–12.4), T 6.4 nmol/L (N 9.9– 27.8), DHT 281 pg/ml (N 240–650), E2 39.7 pg/ml (N 7.63–42.6), 0800 h cortisol 371.5 nmol/L (N 171–536), prolactin 11.4 ng/ml (N 4–15), T4 8.7 μg/dl (N 4.8–12.7), and TSH 1.53 μIU/ml (N 0.27–4.2). Ultrasound and MRI abdomen confirmed the absence of Mullerian structure and showed the presence of homogeneous solid structure in both inguinal canal with right one measuring 3.2 × 2.7 × 1 cm and left measuring 3.8 × 2.2 × 1 cm. Karyotype from mononuclear cell was 46,XY. Patient underwent hCG stimulation test and the results are summarized in the table given below.

Childhood Cushing’s Syndrome

A 16-year-old girl presented with weight gain, secondary amenorrhea, and increased facial hair for the past 2 years; however, her appetite was normal and there was no change in her lifestyle. She also complained of weakness and appearance of striae over the abdomen for the last 1 year. She had a history of poor gain in height during the last 4 years. Patient also had difficulty in climbing the stairs. However, there was no history of easy bruisibility, back pain, or pathological fracture. She had menarche at the age of 12 years and later oligomenorrhea, followed by secondary amenorrhea for the last 2 years. There was no history of any drug intake, or use of alternative medications, or steroid preparations, either inhalational or ointments. On examination, her height was 157 cm ( 75th percentile, weight age >20 years), BMI 24.1 Kg/m2, and blood pressure 112/74 mmHg. She had florid features of Cushing’s syndrome including moon facies, facial plethora, acne, dorso-cervical fat pad, and wide violaceous striae over lower abdomen and thighs. She also had cuticular atrophy, knuckle hyperpigmentation, and proximal muscle weakness. She had generalized obesity with waist circumference of 90 cm. However, she did not have bruise and pulp atrophy. Patient had hirsutism with Ferriman–Gallwey score of 15/36 and did not have features of virilization. There was no cafe-au-lait macule, lentigines, bony deformity, spine tenderness, or cutaneous fungal infection. Biochemical evaluation revealed serum potassium 4.2 mEq/L, liver, and renal function tests were normal. Fasting blood glucose was 92 mg/dl and 2 h plasma glucose after glucose load was 112 mg/dl with HbA1c of 5.0 %. Lipid profile showed serum cholesterol 159 mg/dl, LDL-C 99.6 mg/dl, triglyceride 198 mg/dl, and HDL-C 32.2 mg/dl. Cortisol dynamics showed 0800 h cortisol 567 nmol/L; awake 2300 h cortisol 520 nmol/L; 0800 h ACTH 16.8 pg/ml; awake 2300 h ACTH 63.7 pg/ml; late-night salivary cortisol 12.5 nmol/L and 28.7 nmol/L on two consecutive days, respectively; and 24 h urinary free cortisol on three consecutive days was 448 μg, 469 μg, and 532.8 μg, respectively. Serum cortisol after overnight dexamethasone suppression test (ONDST) was 464 nmol/L, low-dose dexamethasone suppression test (LDDST) 408 nmol/L, and after high-dose dexamethasone suppression test (HDDST) was 157 nmol/L. Serum prolactin was 8.63 ng/ml (N 4.7–23.3), T4 7.02 μg/dl (N 4.8–12.7), TSH 0.894 μIU/ml (N 0.27–4.2), testosterone 0.32 nmol/L (N 0.2–2.9), LH 0.24 mIU/ml (N 2.4–12.6), and FSH 0.32 mIU/ml (N 3.5–12.5). Ultrasound pelvis showed normal ovaries and uterus. Dynamic contrast-enhanced MRI sella revealed differentially enhancing 4.8 × 4.0 mm lesion which was hypointense on T1W and hyperintense on T2W images in the left half of the pituitary gland. She underwent bilateral inferior petrosal sinus sampling (IPSS) with 100 μg (IV bolus) human CRH. IPSS localized the source of ACTH excess to the pituitary and lateralized to right side of the pituitary gland. Serum ACTH and cortisol profile during IPSS are summarized in the table given below. She underwent transsphenoidal surgery, intraoperatively tumor was localized to the left side of the pituitary, and excision of the tumor was accomplished. Patient developed left lateral rectal palsy postoperatively, which recovered within 2 weeks. She was documented to have hypocortisolemia (83.5 nmol/l) on day 1 postoperatively and was started on hydrocortisone supplementation. Histopathology of the tumor tissue showed pituitary adenoma, while immunostaining for ACTH was negative. At 6 weeks, she had weight loss of 5 kg, resolution of plethora, disappearance of acne, and violaceous striae started fading. A 0800 h serum cortisol after the omission of hydrocortisone for 24 h was 4.6 nmol/L, and serum T4 was 10.5 μg/dl. She is continued with hydrocortisone supplementation and advised to follow up every three monthly (Fig. 4.1).

Congenital Adrenal Hyperplasia

A 15-day-old child was brought by her parents for repeated vomiting, excessive crying and jitteriness, and poor feeding. She was a product of non-consanguineous marriage and was delivered by induced labor at 33 weeks of gestation due to maternal complications (pregnancy-induced hypertension). Her birth weight was 1.9 kg and she was assigned female gender. She was investigated and found to have hyponatremia and hyperkalemia (Na+ 119 mEq/L, K+ 8.1 mEq/L) and was diagnosed to have hypoaldosteronism. She was initiated with fludrocortisone 50 μg/day. With this treatment, her symptoms subsided but she failed to thrive and progressively became darker; however, serum electrolyte abnormalities were resolved. She was taken to an endocrinologist at 5 months of age, and she was suspected to have congenital adrenal hyperplasia (CAH) and was investigated accordingly. Her unstimulated serum 17α-hydroxyprogesterone [17(OH)P] was 120 ng/ml and was diagnosed to have CAH due to 21α-hydroxylase deficiency, and dexamethasone was added to fludrocortisone. This therapy resulted in weight gain and decrease in pigmentation, and patient became more active. At 2 years of age, she was referred to our institute. Her height was 81 cm (10th percentile, target height 158 cm), weight 12 kg (25th percentile), and she had a Tanner staging of A-, P1, B1. She did not have Cushing’s stigmata. Examination of the external genitalia showed posterior labial fusion, hyperpigmented labioscrotal folds, isolated clitoromegaly, and the gonads were not palpable. Two distinct openings were seen at perineum. The karyotype was 46,XX. Serum 17(OH)P was 26.8 ng/ml. Dexamethasone was replaced with hydrocortisone (7.5 mg/day) and fludrocortisone (100 μg/day) was continued. The annual follow-up of the patient with clinical and biochemical parameters is depicted in the table given below.

Thyroid Disorders in Children

A 14-year-old girl presented with complaints of growth failure and poor development of secondary sexual characteristics. She also complained of occasional headache and for that a brain imaging was performed. The MRI of the brain showed a sellar–suprasellar mass and she was referred to the department of neurosurgery for surgical intervention. An endocrine consultation was sought prior to subjecting the patient to surgery. A detailed history was elucidated, which revealed that she had linear growth failure for the last 7–8 years. She also complained of lethargy, weakness, constipation, cold intolerance, dry skin, and decreased appetite. She studied till class seventh; however, later she dropped out because of progressive decline in her scholastic performance. There was history of poor development of secondary sexual characteristics; however the mother gave a history that the patient had a single episode of vaginal bleed at the age of 12 years. She had no history of visual field defect or diminution of visual acuity. She was residing in iodine-sufficient area and had no family history of autoimmune disorders. On examination, her height was 116 cm (−7 SDS, height age 6 years and target height 164 cm), weight 35 kg (weight age 10.5 years), pulse rate 64/min, regular and blood pressure 90/60 mmHg. Her facial features revealed pallor with yellowish hue, periorbital puffiness, and depressed nasal bridge. She did not have goiter. Her skin was dry and coarse with papillomatous projections (toad’s skin) and scalp hair was dry, thin, and brittle. Deep tendon reflexes were grossly delayed particularly the relaxation phase. She also had myoedema which was elicitable on flicking the biceps belly with thumb and index finger and showed a post-flicker mounding phase. She did not have a pseudohypertrophy of calf muscle. Other systemic examination was unremarkable. On investigations, hemoglobin was 8 g/dl with microcytic hypochromic anemia. Liver and renal function tests were normal. Serum cholesterol was 220 mg/dl, LDL-C 160 mg/dl, HDL-C 30 mg/dl, and triglyceride 220 mg/dl. Hormonal profile revealed, serum T3 0.3 ng/ml (N 0.8–2), T4 0.3 μg/dl (N 4.8–12.7), TSH 1024 μIU/ml (0.27–4.2), TPO >1200 IU/ml (N < 34), prolactin 50 ng/ml (N 4.7–23.3), LH 0.8 mIU/ml (N 2.4–12.6), FSH 8.6 mIU/ml (N 3.5–12.5), estradiol 15 pg/ml (N 12.5–166), and 0800h cortisol 170 nmol/L (N 171–536). Bone age was 6 years and there was no epiphyseal dysgenesis. CEMRI sella revealed a 1.5 × 1.8 cm homogeneously enhancing sellar–suprasellar mass, while the rest of the brain parenchyma was unremarkable. Ultrasound pelvis showed bilateral enlarged multicystic ovaries with small uterus and endometrial thickness of 1 mm. With this clinical and biochemical profile, she was diagnosed as a case of long-standing, untreated juvenile primary hypothyroidism of autoimmune origin (Hashimoto’s thyroiditis) with thyro-lactotrope hyperplasia and multicystic ovaries. She was initiated with L-thyroxine at a dose of 25 μg/day, with a weekly increase by 25 μg till a dose of 100 μg/day was attained. In addition, hydrocortisone was also added at a dose of 10 mg/day in divided doses. At 6 weeks of follow-up, serum T4 was 6.6 μg/dl and TSH 15 μIU/ml. With initiation of treatment, she had polyuria which abated later. The dose of L-thyroxine was increased to 125 μg/day and hydrocortisone was withdrawn, and the repeat serum 0800h cortisol after 24h of omission of hydrocortisone was 390 nmol/L (Figs. 3.1 and 3.2).