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A rare but endocrine cause of chronic diarrhea
AJG – January, 2003
Letters to the Editor
consequences on the health of the entire population. However, when facing the individual patient diagnosed with a screening test, it would be desirable to identify those who will never note a negative effect on their health. The development of tools to identify these subjects may avoid the long medical process that follows the diagnosis and its negative effects on quality of life. Juan Co´ rdoba, M.D. Josep Reyes, M.D. Juan Ignacio Esteban, M.D. Liver Unit Hospital Universitari Vall D’Hebron Barcelona, Spain Jose´ Manuel Herna´ ndez, M.D. Centre de Transfusio´ i Banc de Teixits Barcelona, Spain
REFERENCES 1. Koff RS. Impaired health-related quality of life in chronic hepatitis C: The how but not the why. Hepatology 1999;29: 277–9. 2. Forton DM, Taylor-Robinson SD, Thomas HC. Reduced quality of life in hepatitis C—Is it all in the head? J Hepatol 2002;36:435–8. 3. Rodger AJ, Jolley D, Thompson SC, et al. The impact of diagnosis of hepatitis C virus on quality of life. Hepatology 1999;30:1299 –301. 4. Fontana RJ, Hussain KB, Schwartz SM, et al. Emotional distress in chronic hepatitis C patients not receiving antiviral therapy. J Hepatol 2002;36:401–7. 5. Wenger NK. Quality of life issues in hypertension: Consequences of diagnosis and considerations in management. Am Heart J 1988;116:628 –32. Reprint requests and correspondence: Juan Co´ rdoba, M.D., Liver Unit, Hospital Universitari Vall d’Hebron, Pg, Vall d’Hebron 119, Barcelona, Spain 08035. Received Aug. 15, 2002; accepted Aug. 19, 2002.
A Rare But Endocrine Cause of Chronic Diarrhea TO THE EDITOR: A 41-yr-old man was referred for evaluation of chronic diarrhea, which lasted since early infanthood. He complained about frequent (15 of 24 h) watery stools, which persisted during fasting, slight abdominal pain, and bloating. The patient denied significant weight loss, fever, or night sweats. Nine yr ago, he was treated for presumptive Crohn’s disease with steroids (30 –50 mg prednisolone/day) over a period of several wk without any improvement. The past medical history comprised unclassified hypothyroidism, recurrent muscle cramps attributed to hypocalcemia of unknown cause, and a congenital lym-
227
phatic edema on the left leg. The current medication consisted of levothyroxine (150 g/day), recently calcitriol (1.5 g in three divided doses daily), oral supplementation of calcium (2–3 g/day, divided in several doses a day, unregular intake), magnesium (40 mval/day), and potassium (40 mmol/day). Additionally, the patient used loperamide and simethicon as needed. The round-faced patient had a short stature and a body mass index of 24.5 kg/m2 with normal vital signs. Apart from the lymphatic edema of the left leg and two cafe´ -au-lait spots on his arm, the physical examination was normal. However, his intelligence was below average. The laboratory results were remarkable with respect to calcium 1.3–1.86 mmol/L (normal range 2.15–2.60), serum albumin 1.8 g/dl (3.8 –5.1), total serum protein 3.5 g/dl (6 – 8.5), parathyroid hormone 118.2 pg/ml (5– 65), folliclestimulating hormone 24.1 U/L (1–10), luteinizing hormone 14.3 U/L (1–10), normal testosterone (574 ng/dl), insulinlike growth factor-1 83 ng/ml (93–302), human growth hormone 1.0 ng/ml (0.5–5), colecalciferol 35 nmol/L (50 – 300), vitamin B12 113 pg/ml (250 –1100), thyroid-stimulating hormone 10.85 E/ml (0.4 – 4) with unbound T3 and T4 in the normal range under substitution with levothyroxine 150 g/day. During previous yr, the patient had already underwent an extensive evaluation comprising repeat upper and lower GI tract endoscopies with multiple biopsy specimens, abdominal magnetic resonance imaging and CT scan, albumin scintigraphy, lactose and glucose breath tests, and repeated stool cultures, which did not reveal any abnormalities. The clue to the diagnosis in the present case was the fact that the patient displayed consistently decreased systemic calcium paralleled by normal phosphate values (2.4 –3.3 mg/dl) and elevated parathyroid hormone. Hypocalcemia resulting from malabsorption may lead to secondary hyperparathyroidism, which in turn causes increased urinary output of phosphate. Thus, normal phosphate concentrations are usually not found in patients with severe enteropathy with hypocalcemia. Hence, the elevated values for parathyroid hormone seen herein are not caused by a malabsorption. Taking into account the elevated thyroid-stimulating hormone levels despite normal values for T3 and T4 (which were attributed to the comparable high substitution dose of levothyroxine), the elevated follicle-stimulating hormone and luteinizing hormone concentrations with normal testosterone and the impaired insulin-like growth factor-1 values, the diagnosis was compatible with a distinct form of pseudohypoparathyroidism (Albright syndrome type I). In his original description, Albright characterized this form of pseudohypoparathyroidism by a failure to respond to administration of exogenous parathyroid hormone by a rise in the urinary excretion of phosphate and of serum calcium levels (1). Characteristic clinical features in some, but not all the patients with pseudohypoparathyroidism comprise short stature, brachymetacarpia, and brachymetatarsia, a round face, obesity, and reduced intelligence. Autosomal-domi-
228
Letters to the Editor
AJG – Vol. 98, No. 1, 2003
nant inheritance is most frequently encountered, often accompanied by signs of Albright osteodystrophy, but recessive and multifactorial inheritance are also described. Albright syndrome type I leads to the clinical picture of hypoparathyroidism with severely impaired enteral calcium absorption because of decreased 1-␣ hydroxylation of vitamin D3. Absence of the respective gene mutation of protein G (Gs ␣) in our patient as demonstrated by sequencing of exons 7–13 of the gene encoding Gs ␣ (GNAS-1) is still compatible with presence of subtype Ia, as most, but not all patients with the more common form, type Ia, have detectable mutation in the GNAS-1 (2– 4). Hypoparathyroidism is considered a comparably rare cause of diarrhea in which correction of hypocalcemia may lead to normalized stool frequency. However, the exact pathophysiological mechanisms remain to be elucidated. Apart from impaired secretion of enteropancreatic peptides after a caloric stimulus (5), an increased permeability of the intestinal epithelium because of cytosceletal alterations has been suggested (6). After establishing the diagnosis, the patient received i.v. calcium (20 ml/10% thrice weekly) in addition to the oral calcium supplementation. Additionally, we switched the previously insufficient vitamin D supplementation from calcitriol to alfacalcidol (3 g/day in divided doses). This therapy resulted in prompt cessation of the diarrhea within a few days. Meanwhile, the treatment was switched to oral calcium supplementation (1 g/day). Currently, the patient reports three formed stools a day, and the muscle cramps have subsided. Most interestingly, in our patient, the diagnosis of pseudohypoparathyroidism was already suggested in 1977, which turned out after the patient showed his former medical record that he had stored away at home. Probably because of the reduced intelligence, this information was lost for more than 25 years. Nikola Landauer, M.D. Roland Ga¨ rtner, M.D. Christian Folwaczny, M.D. Medizinische Poliklinik Medizinische Klinik-Innenstadt Ludwig-Maximilians Universita¨ t Mu¨ nchen, Germany
ACKNOWLEDGMENT The authors gratefully acknowledge sequencing of the GNAS gene by E. Kaminsky and W. Ho¨ ppner (Private Office, Hamburg, Germany).
REFERENCES 1. Albright F, Burnett C, Smith PH, et al. Pseudo-hypoparathyroidism—An example of “Seabright-Bantam” syndrome. Endocrinology 1942;30:922–32. 2. Ahmed SF, Dixon PH, Bonthron DT, et al. GNAS 1 mutational
3.
4.
5. 6.
analysis in pseudohypoparathyroidism. Clin Endocrinol (Oxf) 1998;49:525. Shapira H, Mouallem M, Shapiro MS, et al. Pseudohypoparathyroidism type 1a: Two new heterozygous frameshift mutations in exons 5 and 10 of the Gs alpha gene. Hum Genet 1996;97:73. Spiegel AM, Weinstein LS, Shenker A. Abnormalities in Gcoupled signal transduction pathways in human disease. J Clin Invest 1993;92:1119. Heubi JE, Partin JC, Schubert WK. Hypocalcemia and steatorrhea—Clues to etiology. Dig Dis Sci 1983;28:124 –8. Ma Ty, Tran D, Hoa N, et al. Mechanism of extracellular calcium regulation of intestinal epithelial tight junction permeability: A role of cytoskeletal involvement. Micros Res Tech 2000;51:156 –68.
Reprint requests and correspondence: Christian Folwaczny, M.D., Medizinische Poliklinik und Chirurgische Klinik-Innenstadt, Pettenkoferstr. 8a, 80336 Mu¨ nchen, Germany. Received Aug. 19, 2002; accepted Aug. 26, 2002.
A New Treatment for HCV-Ulcerative Colitis Comorbidity Intolerant to INF-␣ TO THE EDITOR: Treatment of patients with hepatitis C virus (HCV) infection who have inflammatory bowel disease like ulcerative colitis (UC) is very complicated because interferon (INF)-␣, which is the most common treatment for HCV (1) is a proinflammatory cytokine (2) and can provoke UC relapse. Here, we report successful treatment of a patient with HCV and UC by a combination of INF-␣ to eliminate HCV and granulocytapheresis to suppress UC relapse. A 62-yr-old man with chronic HCV and left-sided UC was admitted to our hospital while his UC had relapsed. His medical history showed that a diagnosis of UC was made in 1978 and had responded to conventional medications. This patient had received blood transfusions on several occasions for anemia associated with his UC and subsequently had contracted HCV, possibly during transfusion. Although his UC had continued to respond to medication, any time INF-␣ was given to clear HCV, it had provoked a relapse. After repeated failures to clear his HCV in a general hospital, he was sent to our hospital as a complicated case. He had bloody diarrhea about eight times/day, body temperature 38°C, tachycardia, and a Hb of 10 g/dl. Liver biopsy together with blood biochemistry revealed chronic active HCV F1/A2, genotype 1b, liver injury associated with HCV, ALT 105 IU/ml, AST 80 IU/ml, and HCV RNA 140 kIU/ml (by reverse transcription nested polymerase chain reaction). For treating HCV, we were aware that his UC was intolerant to INF-␣. Based on our understanding that relapse of UC is associated with activated and elevated circulating levels of neutrophils (3, 4) and reducing the level of activated neutrophils by granulocytapheresis improves active UC (4), we
Letters to the Editor
consequences on the health of the entire population. However, when facing the individual patient diagnosed with a screening test, it would be desirable to identify those who will never note a negative effect on their health. The development of tools to identify these subjects may avoid the long medical process that follows the diagnosis and its negative effects on quality of life. Juan Co´ rdoba, M.D. Josep Reyes, M.D. Juan Ignacio Esteban, M.D. Liver Unit Hospital Universitari Vall D’Hebron Barcelona, Spain Jose´ Manuel Herna´ ndez, M.D. Centre de Transfusio´ i Banc de Teixits Barcelona, Spain
REFERENCES 1. Koff RS. Impaired health-related quality of life in chronic hepatitis C: The how but not the why. Hepatology 1999;29: 277–9. 2. Forton DM, Taylor-Robinson SD, Thomas HC. Reduced quality of life in hepatitis C—Is it all in the head? J Hepatol 2002;36:435–8. 3. Rodger AJ, Jolley D, Thompson SC, et al. The impact of diagnosis of hepatitis C virus on quality of life. Hepatology 1999;30:1299 –301. 4. Fontana RJ, Hussain KB, Schwartz SM, et al. Emotional distress in chronic hepatitis C patients not receiving antiviral therapy. J Hepatol 2002;36:401–7. 5. Wenger NK. Quality of life issues in hypertension: Consequences of diagnosis and considerations in management. Am Heart J 1988;116:628 –32. Reprint requests and correspondence: Juan Co´ rdoba, M.D., Liver Unit, Hospital Universitari Vall d’Hebron, Pg, Vall d’Hebron 119, Barcelona, Spain 08035. Received Aug. 15, 2002; accepted Aug. 19, 2002.
A Rare But Endocrine Cause of Chronic Diarrhea TO THE EDITOR: A 41-yr-old man was referred for evaluation of chronic diarrhea, which lasted since early infanthood. He complained about frequent (15 of 24 h) watery stools, which persisted during fasting, slight abdominal pain, and bloating. The patient denied significant weight loss, fever, or night sweats. Nine yr ago, he was treated for presumptive Crohn’s disease with steroids (30 –50 mg prednisolone/day) over a period of several wk without any improvement. The past medical history comprised unclassified hypothyroidism, recurrent muscle cramps attributed to hypocalcemia of unknown cause, and a congenital lym-
227
phatic edema on the left leg. The current medication consisted of levothyroxine (150 g/day), recently calcitriol (1.5 g in three divided doses daily), oral supplementation of calcium (2–3 g/day, divided in several doses a day, unregular intake), magnesium (40 mval/day), and potassium (40 mmol/day). Additionally, the patient used loperamide and simethicon as needed. The round-faced patient had a short stature and a body mass index of 24.5 kg/m2 with normal vital signs. Apart from the lymphatic edema of the left leg and two cafe´ -au-lait spots on his arm, the physical examination was normal. However, his intelligence was below average. The laboratory results were remarkable with respect to calcium 1.3–1.86 mmol/L (normal range 2.15–2.60), serum albumin 1.8 g/dl (3.8 –5.1), total serum protein 3.5 g/dl (6 – 8.5), parathyroid hormone 118.2 pg/ml (5– 65), folliclestimulating hormone 24.1 U/L (1–10), luteinizing hormone 14.3 U/L (1–10), normal testosterone (574 ng/dl), insulinlike growth factor-1 83 ng/ml (93–302), human growth hormone 1.0 ng/ml (0.5–5), colecalciferol 35 nmol/L (50 – 300), vitamin B12 113 pg/ml (250 –1100), thyroid-stimulating hormone 10.85 E/ml (0.4 – 4) with unbound T3 and T4 in the normal range under substitution with levothyroxine 150 g/day. During previous yr, the patient had already underwent an extensive evaluation comprising repeat upper and lower GI tract endoscopies with multiple biopsy specimens, abdominal magnetic resonance imaging and CT scan, albumin scintigraphy, lactose and glucose breath tests, and repeated stool cultures, which did not reveal any abnormalities. The clue to the diagnosis in the present case was the fact that the patient displayed consistently decreased systemic calcium paralleled by normal phosphate values (2.4 –3.3 mg/dl) and elevated parathyroid hormone. Hypocalcemia resulting from malabsorption may lead to secondary hyperparathyroidism, which in turn causes increased urinary output of phosphate. Thus, normal phosphate concentrations are usually not found in patients with severe enteropathy with hypocalcemia. Hence, the elevated values for parathyroid hormone seen herein are not caused by a malabsorption. Taking into account the elevated thyroid-stimulating hormone levels despite normal values for T3 and T4 (which were attributed to the comparable high substitution dose of levothyroxine), the elevated follicle-stimulating hormone and luteinizing hormone concentrations with normal testosterone and the impaired insulin-like growth factor-1 values, the diagnosis was compatible with a distinct form of pseudohypoparathyroidism (Albright syndrome type I). In his original description, Albright characterized this form of pseudohypoparathyroidism by a failure to respond to administration of exogenous parathyroid hormone by a rise in the urinary excretion of phosphate and of serum calcium levels (1). Characteristic clinical features in some, but not all the patients with pseudohypoparathyroidism comprise short stature, brachymetacarpia, and brachymetatarsia, a round face, obesity, and reduced intelligence. Autosomal-domi-
228
Letters to the Editor
AJG – Vol. 98, No. 1, 2003
nant inheritance is most frequently encountered, often accompanied by signs of Albright osteodystrophy, but recessive and multifactorial inheritance are also described. Albright syndrome type I leads to the clinical picture of hypoparathyroidism with severely impaired enteral calcium absorption because of decreased 1-␣ hydroxylation of vitamin D3. Absence of the respective gene mutation of protein G (Gs ␣) in our patient as demonstrated by sequencing of exons 7–13 of the gene encoding Gs ␣ (GNAS-1) is still compatible with presence of subtype Ia, as most, but not all patients with the more common form, type Ia, have detectable mutation in the GNAS-1 (2– 4). Hypoparathyroidism is considered a comparably rare cause of diarrhea in which correction of hypocalcemia may lead to normalized stool frequency. However, the exact pathophysiological mechanisms remain to be elucidated. Apart from impaired secretion of enteropancreatic peptides after a caloric stimulus (5), an increased permeability of the intestinal epithelium because of cytosceletal alterations has been suggested (6). After establishing the diagnosis, the patient received i.v. calcium (20 ml/10% thrice weekly) in addition to the oral calcium supplementation. Additionally, we switched the previously insufficient vitamin D supplementation from calcitriol to alfacalcidol (3 g/day in divided doses). This therapy resulted in prompt cessation of the diarrhea within a few days. Meanwhile, the treatment was switched to oral calcium supplementation (1 g/day). Currently, the patient reports three formed stools a day, and the muscle cramps have subsided. Most interestingly, in our patient, the diagnosis of pseudohypoparathyroidism was already suggested in 1977, which turned out after the patient showed his former medical record that he had stored away at home. Probably because of the reduced intelligence, this information was lost for more than 25 years. Nikola Landauer, M.D. Roland Ga¨ rtner, M.D. Christian Folwaczny, M.D. Medizinische Poliklinik Medizinische Klinik-Innenstadt Ludwig-Maximilians Universita¨ t Mu¨ nchen, Germany
ACKNOWLEDGMENT The authors gratefully acknowledge sequencing of the GNAS gene by E. Kaminsky and W. Ho¨ ppner (Private Office, Hamburg, Germany).
REFERENCES 1. Albright F, Burnett C, Smith PH, et al. Pseudo-hypoparathyroidism—An example of “Seabright-Bantam” syndrome. Endocrinology 1942;30:922–32. 2. Ahmed SF, Dixon PH, Bonthron DT, et al. GNAS 1 mutational
3.
4.
5. 6.
analysis in pseudohypoparathyroidism. Clin Endocrinol (Oxf) 1998;49:525. Shapira H, Mouallem M, Shapiro MS, et al. Pseudohypoparathyroidism type 1a: Two new heterozygous frameshift mutations in exons 5 and 10 of the Gs alpha gene. Hum Genet 1996;97:73. Spiegel AM, Weinstein LS, Shenker A. Abnormalities in Gcoupled signal transduction pathways in human disease. J Clin Invest 1993;92:1119. Heubi JE, Partin JC, Schubert WK. Hypocalcemia and steatorrhea—Clues to etiology. Dig Dis Sci 1983;28:124 –8. Ma Ty, Tran D, Hoa N, et al. Mechanism of extracellular calcium regulation of intestinal epithelial tight junction permeability: A role of cytoskeletal involvement. Micros Res Tech 2000;51:156 –68.
Reprint requests and correspondence: Christian Folwaczny, M.D., Medizinische Poliklinik und Chirurgische Klinik-Innenstadt, Pettenkoferstr. 8a, 80336 Mu¨ nchen, Germany. Received Aug. 19, 2002; accepted Aug. 26, 2002.
A New Treatment for HCV-Ulcerative Colitis Comorbidity Intolerant to INF-␣ TO THE EDITOR: Treatment of patients with hepatitis C virus (HCV) infection who have inflammatory bowel disease like ulcerative colitis (UC) is very complicated because interferon (INF)-␣, which is the most common treatment for HCV (1) is a proinflammatory cytokine (2) and can provoke UC relapse. Here, we report successful treatment of a patient with HCV and UC by a combination of INF-␣ to eliminate HCV and granulocytapheresis to suppress UC relapse. A 62-yr-old man with chronic HCV and left-sided UC was admitted to our hospital while his UC had relapsed. His medical history showed that a diagnosis of UC was made in 1978 and had responded to conventional medications. This patient had received blood transfusions on several occasions for anemia associated with his UC and subsequently had contracted HCV, possibly during transfusion. Although his UC had continued to respond to medication, any time INF-␣ was given to clear HCV, it had provoked a relapse. After repeated failures to clear his HCV in a general hospital, he was sent to our hospital as a complicated case. He had bloody diarrhea about eight times/day, body temperature 38°C, tachycardia, and a Hb of 10 g/dl. Liver biopsy together with blood biochemistry revealed chronic active HCV F1/A2, genotype 1b, liver injury associated with HCV, ALT 105 IU/ml, AST 80 IU/ml, and HCV RNA 140 kIU/ml (by reverse transcription nested polymerase chain reaction). For treating HCV, we were aware that his UC was intolerant to INF-␣. Based on our understanding that relapse of UC is associated with activated and elevated circulating levels of neutrophils (3, 4) and reducing the level of activated neutrophils by granulocytapheresis improves active UC (4), we