- Email: [email protected]
Skin storage of cystine and premature skin ageing in cystinosis
RESEARCH LETTERS
effusion without signs of tamponade. A dopamine infusion, antibiotics, and intravenous corticosteroid therapy were started. Subsequently, norepinephrine and phenylephrine infusions were also started. The patient remained in refractory shock with oliguria and multiple organ failure. 35 h after admission, the patient had no pulse and died despite full resuscitation measures. Findings on necropsy included massive bilateral serous pleural effusions, a 150 mL serous pericardial effusion with a thickened right ventricle, but minimum artherosclerotic heart disease and renal changes consistent with tubular necrosis. There was no evidence of metastatic melanoma; viral inclusions, or bacterial infection. The lungs showed pulmonary oedema with diffuse alveolar damage. Previous reports of IFN pulmonary and cardiac toxic effects have described a subacute or chronic process occurring after weeks or months of therapy.2 There are anecdotal reports of severe dilated cardiomyopathy with chronic heart-failure occurring within the first few days of IFN treatment;3 our patient had no evidence of cardiomyopathy on echocardiography or at autopsy. Fatal rhabdomyolysis and multiple-organ failure was reported in a patient after receiving four doses of IFN ␣-2b 20 million U/m2 for malignant melanoma.4 Although our patient did not develop rhabdomolysis, there are similarities between the two cases. The two patients were generally healthy men who became acutely hypotensive and acidotic, requiring volume replacement therapy, vasopressors, and ventilatory support after a short course of high-dose IFN ␣-2b. ScheringPlough, the manufacturer of IFN ␣-2b, could find no similar case reports in its adverse effects database (B Cobert, personal communication). The mechanism (or mechanisms) for such a striking reaction is unclear. 1
2 3 4
Kirkwood JM, Strawderman MH, Emstoff MS, et al. Interferon alpha 2b adjuvant therapy of high risk cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996; 14: 7–17. Vial T, Descotes J. Clinical toxicity of the interferons. Drug Safety 1994; 10: 115–50. Cohen MC, Huberman MS, Nesto RW. Recombinant alpha2 interferon related cardiomyopathy. Am J Med 1988; 85: 549–51. Reinhold U, Hartyl C, Hering R, Hoeft A, Kreysel H. Fatal rhabdomyolysis and multiple organ failure associated with adjuvant high-dose interferon alpha in malignant melanoma. Lancet 1997; 349: 540–41.
St Peter’s Hospital Pharmacy, Albany, New York, USA; Pulmonary and Critical Care Associates, 319 South Manning Blvd, Albany, NY 12208, USA (L H Gold)
Skin storage of cystine and premature skin ageing in cystinosis G Guillet, B Sassolas, S Fromentoux, E Gobin, J P Leroy
Cystinosis is caused by a defect in the transport of cystine through the lysosomal membrane to the cytosol. The cystinosis gene locus is on the short arm of chromosome 17.1 In France, cystinosis affects five per million live births, about half the incidence of oxalosis. Toni-Debre-Fanconi syndrome is the most common clinical presentation in children, for which renal biopsy is diagnostic. Prognosis has been improved by treatment with chelators and renal transplantation.2 With a better renal prognosis, extrarenal effects have become apparent, such as photophobia, growth retardation, hypothyroidisim, insulin-dependent diabetes, muscular weakness, and involvement of the central nervous system.
1444
Electron micrograph of a fibroblast The cytoplasm is filled with crystals. Two pathological elastic fibres are seen with increased density because of accumulation of microfibrillar material.
We followed up four patients (three men) aged 25–32 years (mean 27 years) in the second decade after renal transplantation, They were all receiving immunosuppression with corticosteroids, azathioprine, and/or cyclosporine. Clinical features were coarse facial features with subcutaneous infiltration of a palpable amorphous material and variable degrees of skin atrophy and telangiectasia mimicking premature ageing. Photoexposed areas were most involved. All patients had fair complexions and hair; one had numerous naevi, which could be related to immunosuppression. 3 Histological analysis, after informed consent, showed abnormalities of the dermal elastic network with broken fibres in a reticular dermis. Epidermis was normal or slightly atrophic. At ultrastructural level, elastic fibres contained microfibrillar amorphous material, as seen in ageing. The most striking feature in all samples was the presence of quadrangular crystalline intracytoplasmic cystine deposits in fibroblasts or macrophages (figure). To our knowledge, such deposits in the skin have never been described before. We did not confirm the absence of cystine crystals in the skin, as claimed by Charnas and colleagues,4 but our follow-up after graft was longer (14·5 vs 11·2 years). Long-term survival of patients after renal transplantation has allowed the development of previously unknown or non-studied complications of cystinosis.5 It is impossible for us to know when skin deposition of cystine crystals starts, but the involvement of elastic fibres may give a clue about alterations on other elastic tissues of these patients and could be a useful index of treatment.
THE LANCET • Vol 352 • October 31, 1998
RESEARCH LETTERS 1
2 3
4 5
Jean G, Fuchshuber A, Town MM, et al. High-resolution mapping of the gene of cystinosis using combined biochemical and linkage analysis. Am J Hum Genet 1996; 58: 535–43. Broyer M, Tete MJ, Gubler MC. Late symptoms of infantile cystinosis. Pediatr Nephrol 1987; 1: 519–24. Grob JJ, Bastuji-Garin S, Vaillant L, et al. Excess of nevi related to immunodeficiency: a study in HIV infected patients and renal transplant recipients. J Invest Dermatol 1996; 107: 694–97. Charnas LR, Luciano CA, Dalakas M, et al. Distal vacuolar myopathy in nephropathic cystinosis. Ann Neurol 1994; 35: 181–88. Almond PS, Matas AJ, Nakhleh RE, et al. Renal transplantation for infantile cystinosis: long term follow-up. J Pediatr Surg 1993; 28: 232–38.
correlation calls into question the use of conservative treatment without histological confirmation of diagnosis. In the presence of histological samples, thorough histological examination is highly recommended, even if all clinical data support the presence of an endocrine-inactive macroadenoma. We thank Kalman Kovacs, Pathology, St Michael’s Hospital, Toronto, Canada for reviewing the histology of the patient with a salivary gland-like tumour. Presented in part at the 5th International Pituitary Congress, Naples, Florida, June 28–30, 1998. Departments of Neurosurgery (T Mindermann; e-mail [email protected]), Endocrinology, and Neuropathology, University Hospitals Basel, 4031 Basel, Switzerland
Departments of Dermatology ( B Sassolas) and Pathology, University of Brest, 29609 Brest, France
High rate of unexpected histology in presumed pituitary adenomas
Refeeding of anorexics: wasteful not wilful Janice Russell, Louise Baur, Peter Beumont, Suzy Byrnes, Stephan Zipfel
Thomas Mindermann, Jean-Jacques Staub, Alphonse Probst
With improvements in radiotherapy and medical treatment, more patients with pituitary adenoma (PA) are treated without histological confirmation of diagnosis. Conservative treatment is based on the assumption that the tumour’s clinical phenotype is identical to its histological diagnosis. Conservative treatment is justified only if there is a high correlation between the preoperative diagnosis based on a tumour’s clinical phenotype and its postoperative histological diagnosis. However, there are no data correlating the preoperative with the postoperative diagnosis in PAs. To assess the occurrence of unexpected histological findings, we retrospectively reviewed the records of 50 patients who were operated on trans-sphenoidally for PA (by TM) between 1995 and 1997. We compared the preoperative diagnoses based on endocrine testing, MRIs, and cranialnerve deficits with postoperative histological diagnoses. Unexpected histology was defined as histological findings that were not compatible with the preoperative diagnosis of PA. Four (8%) patients had unexpected histological findings that were not compatible with the preoperative diagnosis of PA (table). All four patients were from a subgroup of the 22 patients with the preoperative diagnosis of endocrineinactive PA. The four patients’ mean age at surgery was 67 (SD 16) years and female/male ratio was 1:1. Histological examination showed granular cell tumour in one, metastasis of a pulmonary carcinoma to the pituitary in one, salivarygland-like tumour in one, and pituitary adenocarcinoma in another patient. We found a high rate of unexpected histological findings (18%) among patients with probable endocrine-inactive macroadenomas of the pituitary. Accordingly, the correlation between the preoperative diagnosis of endocrine inactive macroadenomas of the pituitary was low based on their clinical phenotype and the same tumours’ postoperative diagnosis based on their histological assessment. This low Number of patients 22 17 6 4 1
Women/ men 6/16 9/8 1/5 3/1 0/1
Total (n=50) 19/31
Mean (SD) age (years)
Preoperative diagnosis
Incompatible histology
63 36 52 38 74
Endocrine inactive PA Prolactinoma Acromegaly Cushing’s disease Endocrine inactive PA or metastasis PA (PA or metastasis in one case)
4*/22 (18%) 0/17 0/6 0/4 0†/1
(17) (13) (6) (14)
50 (19)
4*/50 (8%)
PA=pituitary adenoma. *One granular cell tumour, one metastasis of pulmonary carcinoma to pituitary, one salivary gland-like tumour, one pituitary adenocarcinoma with remote metastasis. †Metastasis, accordingly not counted as incompatible or unexpected histology.
Characteristics of patients and presumed pituitary adenomas
THE LANCET • Vol 352 • October 31, 1998
Anorexia nervosa is estimated to be the third most common chronic medical illness in girls aged 15–19 years. 1 Motivation to be treated is commonly ambivalent and the inducement of patients to eat, gain weight, and maintain in the normal range is difficult. Relapse rates and recidivism are so high that the cost of treatment aimed at weight gain has been questioned. Yet, anorexia nervosa has major morbidity and mortality.2 Without weight restoration, which may be achievable only in hospital, the patient’s physiology and thinking remain so disordered as to perpetuate the problem and preclude a normal life. Even during active nutritional rehabilitation, as with established emaciation, energy intake may not be reflected in weight gain. It is tempting to blame poor compliance, and patient-staff conflicts ensue. When weight approaches a minimum healthy level, which is often substantially less than the patient’s weight when they started dieting,2 energy needs can reach a point where it is almost impossible for her to ingest enough to gain weight. Food records of recovered patients have shown that increased energy requirements persist for about 6 months. 3 As part of a larger controlled study of energy expenditure in treatment of anorexia nervosa, we used anthropometry then indirect calorimetry to measure basal metabolic rate and respiratory quotient at baseline and for 4 h after a 100 g glucose load. Patients were tested at low weight and after a mean weight gain of 9·0 kg and compared with controls who were women of normal weight and comparable ages. The mean basal metabolic rate was 245·52 (SD 28·70) kJ per day before and 290·62 (35·90) kJ per day after weight gain. Mean change after glucose in basal metabolic rate area under curve per unit lean body mass (area under curve) was initially 0·12 (0·06) kJ per day and 0·08 (0·06) kJ per day after weight gain, and mean thermogenesis after glucose fell from 13·1% (5·8) of basal metabolic weight at baseline to 8·4% (5·3) after refeeding. Since the mean lean body mass determined by skinfold thickness, increased from 35·6 (3·9) kg to 39·7 (3·5) kg after weight gain and patients in the refeeding programme ate six times a day, we estimated energy loss by area under curve⫻lean body mass⫻6. Energy loss was 27·71 kJ per day before and 20 ·61 kJ per day after refeeding. Therefore, the increase in metabolic weight after glucose was paradoxically high at baseline and was persistently raised throughout the period of testing. When ingestion of a high-fat nutritional supplement was compared with that of a high-carbohydrate supplement in two weight-stable emaciated patients, the basal metabolic rate increase was highest in those given carbohydrate, which suggests that the increased diet-induced thermogenesis is an effect of carbohydrate as a substrate. Anorexic patients tend to avoid fats and proteins, preferring a relatively high carbohydrate diet.
1445
effusion without signs of tamponade. A dopamine infusion, antibiotics, and intravenous corticosteroid therapy were started. Subsequently, norepinephrine and phenylephrine infusions were also started. The patient remained in refractory shock with oliguria and multiple organ failure. 35 h after admission, the patient had no pulse and died despite full resuscitation measures. Findings on necropsy included massive bilateral serous pleural effusions, a 150 mL serous pericardial effusion with a thickened right ventricle, but minimum artherosclerotic heart disease and renal changes consistent with tubular necrosis. There was no evidence of metastatic melanoma; viral inclusions, or bacterial infection. The lungs showed pulmonary oedema with diffuse alveolar damage. Previous reports of IFN pulmonary and cardiac toxic effects have described a subacute or chronic process occurring after weeks or months of therapy.2 There are anecdotal reports of severe dilated cardiomyopathy with chronic heart-failure occurring within the first few days of IFN treatment;3 our patient had no evidence of cardiomyopathy on echocardiography or at autopsy. Fatal rhabdomyolysis and multiple-organ failure was reported in a patient after receiving four doses of IFN ␣-2b 20 million U/m2 for malignant melanoma.4 Although our patient did not develop rhabdomolysis, there are similarities between the two cases. The two patients were generally healthy men who became acutely hypotensive and acidotic, requiring volume replacement therapy, vasopressors, and ventilatory support after a short course of high-dose IFN ␣-2b. ScheringPlough, the manufacturer of IFN ␣-2b, could find no similar case reports in its adverse effects database (B Cobert, personal communication). The mechanism (or mechanisms) for such a striking reaction is unclear. 1
2 3 4
Kirkwood JM, Strawderman MH, Emstoff MS, et al. Interferon alpha 2b adjuvant therapy of high risk cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996; 14: 7–17. Vial T, Descotes J. Clinical toxicity of the interferons. Drug Safety 1994; 10: 115–50. Cohen MC, Huberman MS, Nesto RW. Recombinant alpha2 interferon related cardiomyopathy. Am J Med 1988; 85: 549–51. Reinhold U, Hartyl C, Hering R, Hoeft A, Kreysel H. Fatal rhabdomyolysis and multiple organ failure associated with adjuvant high-dose interferon alpha in malignant melanoma. Lancet 1997; 349: 540–41.
St Peter’s Hospital Pharmacy, Albany, New York, USA; Pulmonary and Critical Care Associates, 319 South Manning Blvd, Albany, NY 12208, USA (L H Gold)
Skin storage of cystine and premature skin ageing in cystinosis G Guillet, B Sassolas, S Fromentoux, E Gobin, J P Leroy
Cystinosis is caused by a defect in the transport of cystine through the lysosomal membrane to the cytosol. The cystinosis gene locus is on the short arm of chromosome 17.1 In France, cystinosis affects five per million live births, about half the incidence of oxalosis. Toni-Debre-Fanconi syndrome is the most common clinical presentation in children, for which renal biopsy is diagnostic. Prognosis has been improved by treatment with chelators and renal transplantation.2 With a better renal prognosis, extrarenal effects have become apparent, such as photophobia, growth retardation, hypothyroidisim, insulin-dependent diabetes, muscular weakness, and involvement of the central nervous system.
1444
Electron micrograph of a fibroblast The cytoplasm is filled with crystals. Two pathological elastic fibres are seen with increased density because of accumulation of microfibrillar material.
We followed up four patients (three men) aged 25–32 years (mean 27 years) in the second decade after renal transplantation, They were all receiving immunosuppression with corticosteroids, azathioprine, and/or cyclosporine. Clinical features were coarse facial features with subcutaneous infiltration of a palpable amorphous material and variable degrees of skin atrophy and telangiectasia mimicking premature ageing. Photoexposed areas were most involved. All patients had fair complexions and hair; one had numerous naevi, which could be related to immunosuppression. 3 Histological analysis, after informed consent, showed abnormalities of the dermal elastic network with broken fibres in a reticular dermis. Epidermis was normal or slightly atrophic. At ultrastructural level, elastic fibres contained microfibrillar amorphous material, as seen in ageing. The most striking feature in all samples was the presence of quadrangular crystalline intracytoplasmic cystine deposits in fibroblasts or macrophages (figure). To our knowledge, such deposits in the skin have never been described before. We did not confirm the absence of cystine crystals in the skin, as claimed by Charnas and colleagues,4 but our follow-up after graft was longer (14·5 vs 11·2 years). Long-term survival of patients after renal transplantation has allowed the development of previously unknown or non-studied complications of cystinosis.5 It is impossible for us to know when skin deposition of cystine crystals starts, but the involvement of elastic fibres may give a clue about alterations on other elastic tissues of these patients and could be a useful index of treatment.
THE LANCET • Vol 352 • October 31, 1998
RESEARCH LETTERS 1
2 3
4 5
Jean G, Fuchshuber A, Town MM, et al. High-resolution mapping of the gene of cystinosis using combined biochemical and linkage analysis. Am J Hum Genet 1996; 58: 535–43. Broyer M, Tete MJ, Gubler MC. Late symptoms of infantile cystinosis. Pediatr Nephrol 1987; 1: 519–24. Grob JJ, Bastuji-Garin S, Vaillant L, et al. Excess of nevi related to immunodeficiency: a study in HIV infected patients and renal transplant recipients. J Invest Dermatol 1996; 107: 694–97. Charnas LR, Luciano CA, Dalakas M, et al. Distal vacuolar myopathy in nephropathic cystinosis. Ann Neurol 1994; 35: 181–88. Almond PS, Matas AJ, Nakhleh RE, et al. Renal transplantation for infantile cystinosis: long term follow-up. J Pediatr Surg 1993; 28: 232–38.
correlation calls into question the use of conservative treatment without histological confirmation of diagnosis. In the presence of histological samples, thorough histological examination is highly recommended, even if all clinical data support the presence of an endocrine-inactive macroadenoma. We thank Kalman Kovacs, Pathology, St Michael’s Hospital, Toronto, Canada for reviewing the histology of the patient with a salivary gland-like tumour. Presented in part at the 5th International Pituitary Congress, Naples, Florida, June 28–30, 1998. Departments of Neurosurgery (T Mindermann; e-mail [email protected]), Endocrinology, and Neuropathology, University Hospitals Basel, 4031 Basel, Switzerland
Departments of Dermatology ( B Sassolas) and Pathology, University of Brest, 29609 Brest, France
High rate of unexpected histology in presumed pituitary adenomas
Refeeding of anorexics: wasteful not wilful Janice Russell, Louise Baur, Peter Beumont, Suzy Byrnes, Stephan Zipfel
Thomas Mindermann, Jean-Jacques Staub, Alphonse Probst
With improvements in radiotherapy and medical treatment, more patients with pituitary adenoma (PA) are treated without histological confirmation of diagnosis. Conservative treatment is based on the assumption that the tumour’s clinical phenotype is identical to its histological diagnosis. Conservative treatment is justified only if there is a high correlation between the preoperative diagnosis based on a tumour’s clinical phenotype and its postoperative histological diagnosis. However, there are no data correlating the preoperative with the postoperative diagnosis in PAs. To assess the occurrence of unexpected histological findings, we retrospectively reviewed the records of 50 patients who were operated on trans-sphenoidally for PA (by TM) between 1995 and 1997. We compared the preoperative diagnoses based on endocrine testing, MRIs, and cranialnerve deficits with postoperative histological diagnoses. Unexpected histology was defined as histological findings that were not compatible with the preoperative diagnosis of PA. Four (8%) patients had unexpected histological findings that were not compatible with the preoperative diagnosis of PA (table). All four patients were from a subgroup of the 22 patients with the preoperative diagnosis of endocrineinactive PA. The four patients’ mean age at surgery was 67 (SD 16) years and female/male ratio was 1:1. Histological examination showed granular cell tumour in one, metastasis of a pulmonary carcinoma to the pituitary in one, salivarygland-like tumour in one, and pituitary adenocarcinoma in another patient. We found a high rate of unexpected histological findings (18%) among patients with probable endocrine-inactive macroadenomas of the pituitary. Accordingly, the correlation between the preoperative diagnosis of endocrine inactive macroadenomas of the pituitary was low based on their clinical phenotype and the same tumours’ postoperative diagnosis based on their histological assessment. This low Number of patients 22 17 6 4 1
Women/ men 6/16 9/8 1/5 3/1 0/1
Total (n=50) 19/31
Mean (SD) age (years)
Preoperative diagnosis
Incompatible histology
63 36 52 38 74
Endocrine inactive PA Prolactinoma Acromegaly Cushing’s disease Endocrine inactive PA or metastasis PA (PA or metastasis in one case)
4*/22 (18%) 0/17 0/6 0/4 0†/1
(17) (13) (6) (14)
50 (19)
4*/50 (8%)
PA=pituitary adenoma. *One granular cell tumour, one metastasis of pulmonary carcinoma to pituitary, one salivary gland-like tumour, one pituitary adenocarcinoma with remote metastasis. †Metastasis, accordingly not counted as incompatible or unexpected histology.
Characteristics of patients and presumed pituitary adenomas
THE LANCET • Vol 352 • October 31, 1998
Anorexia nervosa is estimated to be the third most common chronic medical illness in girls aged 15–19 years. 1 Motivation to be treated is commonly ambivalent and the inducement of patients to eat, gain weight, and maintain in the normal range is difficult. Relapse rates and recidivism are so high that the cost of treatment aimed at weight gain has been questioned. Yet, anorexia nervosa has major morbidity and mortality.2 Without weight restoration, which may be achievable only in hospital, the patient’s physiology and thinking remain so disordered as to perpetuate the problem and preclude a normal life. Even during active nutritional rehabilitation, as with established emaciation, energy intake may not be reflected in weight gain. It is tempting to blame poor compliance, and patient-staff conflicts ensue. When weight approaches a minimum healthy level, which is often substantially less than the patient’s weight when they started dieting,2 energy needs can reach a point where it is almost impossible for her to ingest enough to gain weight. Food records of recovered patients have shown that increased energy requirements persist for about 6 months. 3 As part of a larger controlled study of energy expenditure in treatment of anorexia nervosa, we used anthropometry then indirect calorimetry to measure basal metabolic rate and respiratory quotient at baseline and for 4 h after a 100 g glucose load. Patients were tested at low weight and after a mean weight gain of 9·0 kg and compared with controls who were women of normal weight and comparable ages. The mean basal metabolic rate was 245·52 (SD 28·70) kJ per day before and 290·62 (35·90) kJ per day after weight gain. Mean change after glucose in basal metabolic rate area under curve per unit lean body mass (area under curve) was initially 0·12 (0·06) kJ per day and 0·08 (0·06) kJ per day after weight gain, and mean thermogenesis after glucose fell from 13·1% (5·8) of basal metabolic weight at baseline to 8·4% (5·3) after refeeding. Since the mean lean body mass determined by skinfold thickness, increased from 35·6 (3·9) kg to 39·7 (3·5) kg after weight gain and patients in the refeeding programme ate six times a day, we estimated energy loss by area under curve⫻lean body mass⫻6. Energy loss was 27·71 kJ per day before and 20 ·61 kJ per day after refeeding. Therefore, the increase in metabolic weight after glucose was paradoxically high at baseline and was persistently raised throughout the period of testing. When ingestion of a high-fat nutritional supplement was compared with that of a high-carbohydrate supplement in two weight-stable emaciated patients, the basal metabolic rate increase was highest in those given carbohydrate, which suggests that the increased diet-induced thermogenesis is an effect of carbohydrate as a substrate. Anorexic patients tend to avoid fats and proteins, preferring a relatively high carbohydrate diet.
1445