- Email: [email protected]
Chylomicron retention disease: A rare cause of chronic diarrhea
ARCPED-4217; No of Pages 3
Received: 1st September 2015 Accepted: 9 April 2016
Available online at
ScienceDirect www.sciencedirect.com
Clinical case
Chylomicron retention disease: A rare cause of chronic diarrhea Maladie de re´tention des chylomicrons : une cause rare de diarrhe´e chronique S. Ben Ameura,b,*, H. Alouloua,b, N. Jlidia,b, F. Kamouna,b, I. Chabchouba,b, M. Di Filippoc, L. Sfaihia,b, M. Hachichaa,b a
Hedi Chaker Hospital, Department of pediatrics, 3029 Sfax, Tunisia Faculty of medicine, Sfax, Tunisia c Centre de Biologie Est, UF Dyslipidemia Laboratory, 69677 Bron cedex, France b
Summary
Re´sume´
Chylomicron retention disease (CRD) is a rare autosomal recessive hereditary hypocholesterolemic disorder. The disease most frequently presents in infants and is characterized by a lipid malabsorption syndrome with steatorrhea, chronic diarrhea, and growth retardation. The disease is characterized by normal fasting serum triglyceride levels combined with the absence of apolipoprotein (apo) B48 and chylomicrons after a fat load. In this report, we describe the clinical, laboratory, and histological data as well as the molecular DNA analysis of a 12-month-old girl from Tunisia with CRD. The patient was treated with a low-fat diet and fat-soluble vitamin supplementation resulting in significant improvement. ß 2016 Elsevier Masson SAS. All rights reserved.
La maladie de re´tention des chylomicrons (MRC) est une malabsorption lipidique de transmission autosomique re´cessive. Elle est due a` une incapacite´ de se´cre´tion des chylomicrons et de l’apolipoprote´ine B48 en pe´riode post-prandiale. Elle re´sulte d’une anomalie du ge`ne codant pour la prote´ine SAR1B. Elle est me´connue et pose le proble`me de diagnostic diffe´rentiel surtout avec la maladie cœliaque. Le diagnostic pre´coce permet d’instaurer un traitement le plus toˆt possible, e´vitant la de´nutrition se´ve`re et les complications neurologiques. Nous rapportons l’observation d’une enfant de 12 mois d’origine tunisienne hospitalise´e pour diarrhe´e chronique. Le diagnostic de MRC a e´te´ e´voque´ devant une hypocholeste´role´mie, un taux normal des triglyce´rides et un aspect lactescent de la muqueuse duode´nale a` la fibroscopie digestive. L’e´tude ge´ne´tique a confirme´ le diagnostic. Le re´gime pauvre en graisses avec supple´mentation en vitamines liposolubles a permis une e´volution favorable. ß 2016 Elsevier Masson SAS. Tous droits re´serve´s.
1. Introduction
complicated by pre-eclampsia. He birth weight was 1500 g and Apgar scores were 9 and 10 at 1 and 5 minutes, respectively. Her parents were second-degree cousins and they had another 5-year-old healthy son. The family history was noncontributory. She presented with feeding intolerance, nonbloody, nonbilious emesis, diarrhea, and failure to thrive since birth. The patient was both breast- and bottle-fed and her symptoms persisted despite changing her feeds to hydrolyzed formula. On physical examination, her weight was 5.8 kg ( 4 SD), and her height was 63 cm ( 4 SD). Pallor, dyschromic dents, and distended abdomen were noted. Otherwise the physical examination was unremarkable with a normal neurological examination. Complete blood count showed a low hemoglobin
Chylomicron retention disease (CDR) is a rare autosomal recessive hereditary hypocholesterolemic disorder. We report the case of a 12-month-old girl who presented with chronic diarrhea and failure to thrive.
2. Case report A 12-month-old girl was referred to our hospital because of chronic diarrhea. She was born after a term pregnancy * Corresponding author at: Hedi Chaker Hospital, Department of pediatrics, 3029 Sfax, Tunisia. e-mail: [email protected] (S. Ben Ameur). http://dx.doi.org/10.1016/j.arcped.2016.04.010 Archives de Pe´diatrie 2016;xxx:1-3 0929-693X/ß 2016 Elsevier Masson SAS. All rights reserved.
1
ARCPED-4217; No of Pages 3
Archives de Pe´diatrie 2016;xxx:1-3
S. Ben Ameur et al.
concentration (9 g/dL) with low mean corpuscular volume (77 fl), microcytosis, no acanthocytosis, and normal profiles of white blood cells and platelets. In the liver function tests, we noted elevated aspartate aminotransferase (774 IU/L), alanine aminotransferase (360 IU/L), and alkaline phosphatase (671 IU/L) with normal bilirubin and gamma-glutamyl transpeptidase values. Anti-transglutaminase antibodies were negative. Total-, low-density-lipoprotein (LDLC), and high-density-lipoprotein cholesterol (HDL-C) levels were low (1.35 mmol/L, 0.57 mmol/L, and 0.39 mmol/L, respectively), whereas the triglycerides level was normal (1.09 mmol/L). The plasma total cholesterol levels of her father and mother and their LDL cholesterol levels were in the normal range. Lipoprotein electrophoresis of postprandial plasma did not show the presence of chylomicrons. Immunoblot testing to identify apoB and apoA fractions and abnormal apoB forms was unavailable in the country. Liver ultrasonography did not reveal any hepatic abnormalities. Esophagogastroduodenoscopy showed a whitish aspect of the duodenal mucosa. At light microscopy examination of the biopsies, enterocytes presented fat-laden vacuolization without villous atrophy (fig. 1A and B). Therefore, the clinical picture, the laboratory profile, and the pathological features indicated an inherited disorder of fat malabsorption, especially CRD. Fat-soluble vitamin (FSV) levels were low: (25-hydroxy vitamin D = 60 nmol/L – normal = 70–250; vitamin E = 2 mmol/L – normal = 5–14). A blood sample for genetic analysis was obtained after written informed consent was given. Genotyping identified a homozygous SAR1B gene mutation: deletion of exon 2 (c. 1–4482_58 + 1406 del 5946 ins15 bp). Her parents were heterozygous for the same mutation. Treatment included restriction of dietary fats, orally administered medical formula high in medium-chain triglycerides, fatsoluble vitamin supplementation, and monthly intravenous fat [(Figure_1)TD$IG]emulsion. During follow-up, the child showed catch-up growth
in weight–height and a clinical examination did not show muscle weakness or areflexia. Liver function tests normalized after 10 months of treatment. Currently the child is 4 years and 10 months old, has normal psychomotor development, but a moderate failure to thrive [weight = 13 kg ( 2 SD) and height = 97 cm ( 2.5 SD)]. Hematochemical parameters show normal levels of hemoglobin (12 g/dL), aspartate aminotransferase (43 IU/L), alanine aminotransferase (40 IU/L), and creatine-kinase (114 IUI/L). Despite administration of fat-soluble vitamins, the vitamin E serum level is persistently low: 2.4 mmol/L (normal, 5–14).
3. Discussion CRD was described for the first time by Anderson et al. in 1961 [1], and this disorder was called Anderson’s disease for many years. However, the term ‘‘chylomicron retention disease’’ is preferred as it is more indicative of the underlying defect. Additional reports further characterized this disorder, which appears to result from a specific defect involving the failure to secrete apoB-48-containing lipoproteins from the gut. It manifests in the complete absence of postprandial chylomicrons in the sera. Chylomicrons are large heterogeneous lipidrich spheric particles synthesized exclusively by the enterocytes, transporting dietary fats and fat-soluble vitamins. The enterocytes of these patients fail to secrete chylomicrons in lymph and are consequently overloaded with small lipid droplets [2,3]. Most infants present with an unremarkable birth history. Consanguinity is frequent. Similar to our patient, the diagnosis is often delayed because symptoms are nonspecific. Malabsorptive diarrhea is constant and begins in infants shortly after birth. Other digestive symptoms, such as vomiting or abdominal swelling, are often present. Hepatomegaly is
Figure 1. Duodenal biopsies: diffuse enterocyte vacuolization with large cytosolic lipid droplets. (A. H&E stain, 200. B. Periodic acid Schiff stain, 200)
2
ARCPED-4217; No of Pages 3
Chylomicron retention disease
reported in about 20% of patients with CRD. However, hepatomegaly and steatosis have been detected in a few cases on ultrasonography. No case of cirrhosis has been reported. Nonspecific hepatic cytolysis is very frequent, but moderate (1.5–3 N), and poorly correlates with steatosis or hepatomegaly [2]. Creatine-kinase is usually elevated and may be suggestive of the diagnosis [2]. In the present case, the measurement was not made at diagnosis. Nutritional deficiencies associated with fat malabsorption can lead to: serious complications in late childhood such as ataxia, proprioceptive abnormalities, and sensory neuropathy owing to vitamin E deficiency; ophthalmologic complications secondary to vitamin A deficiency; and osteopenia from vitamin D and K deficiency. Vitamin E is the most affected among the fatsoluble vitamins in CRD, because its transport is highly dependent on apoB-containing lipoproteins [2]. Vitamin E deficiency is constant at diagnosis in young children. Essential fatty acid (EFA) deficiency can also occur. Hypocholesterolemia associated with chronic diarrhea is common but nonspecific. In the present case, CRD was suspected in view of the patient’s lipid profile. First, the more than 50% decrease in total cholesterol, LDL-C, and HDL-C in the presence of normal triglycerides is almost pathognomonic. Endoscopic findings of lipid accumulation in enterocytes supported the diagnosis [2,3]. CRD is a rare recessive disorder that seems to be more frequent in highly inbred ethnic groups or in geographically isolated populations. This may be the case in the Tunisian population, which has a high rate of consanguineous marriages [4]. Mutations of the SAR1B gene were identified in 2003 as the specific molecular defect [5]. The SAR1B gene encodes the Sar1b protein, which is involved in chylomicron transport from the endoplasmic reticulum to the Golgi apparatus [2]. The mutations found in this report had already been described by Charcosset et al., in a French family originating from Algeria [6]. Treatment aims at preventing nutritional deficiencies and optimizing growth. A diet low in long-chain fat should be implemented with the addition of essential fatty acids. Simple counseling to increase oral essential fatty acids with vegetable oils and fish seems appropriate in CRD. Four patients of the French cohort also received intravenous infusion of lipid emulsion (intralipid 20% 2 g/kg/month). Intravenous and oral supplementations were unable to normalize the EFA plasma levels [2]. All patients should receive FSV orally: vitamin E, 50 IU/kg/day; vitamin A, 15,000 IU/day; vitamin D, 800– 1200 IU/day; and vitamin K, 15 mg/week. The doses should
be further adjusted based on subsequent serum levels. Vitamin E levels may never reach normal values because it primarily circulates within chylomicron vesicles [2,3]. Our patient showed catch-up growth on a low-fat diet with the addition of essential fatty acids and FSV. During childhood, standard clinical examination and biological evaluations should be performed twice a year, in order to adjust fatsoluble vitamin supplementation and focus on gastrointestinal, liver, and neurological manifestations and complications. In children over the age of 10 years, neurology and ophthalmology consultations, bone densitometry, and echocardiography should be undertaken every 3 years [2].
4. Conclusion The diagnosis of CMRD should be considered early in children born from consanguineous parents, who present with chronic diarrhea associated with hypocholesterolemia and normal triglycerides blood level.
Disclosure of interest The authors declare that they have no competing interest.
References [1]
[2]
[3]
[4]
[5]
[6]
Anderson C, Townley RRW, Freeman M, et al. Unusual causes of steatorrhoea in infancy and childhood. Med J Aust 1961;11: 617–22. Peretti N, Sassolas A, Roy C, et al. Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers. Orphanet J Rare Dis 2010;5:24. Boldrini R, Biselli R, Bosman C. Chylomicron retention disease: the role of ultrastructural examination in differential diagnosis. Pathol Res Pract 2001;197:753–7. Magnolo L, Najah M, Fancello T, et al. Novel mutations in SAR1B and MTTP genes in Tunisian children with chylomicron retention disease and abetalipoproteinemia. Gene 2013;512:28–34. Jones B, Jones EL, Bonney SA, et al. Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. Nat Genet 2003;34:29–31. Charcosset M, Sassolas A, Peretti N, et al. Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein. Mol Genet Metab 2008;93:74–84.
3
Received: 1st September 2015 Accepted: 9 April 2016
Available online at
ScienceDirect www.sciencedirect.com
Clinical case
Chylomicron retention disease: A rare cause of chronic diarrhea Maladie de re´tention des chylomicrons : une cause rare de diarrhe´e chronique S. Ben Ameura,b,*, H. Alouloua,b, N. Jlidia,b, F. Kamouna,b, I. Chabchouba,b, M. Di Filippoc, L. Sfaihia,b, M. Hachichaa,b a
Hedi Chaker Hospital, Department of pediatrics, 3029 Sfax, Tunisia Faculty of medicine, Sfax, Tunisia c Centre de Biologie Est, UF Dyslipidemia Laboratory, 69677 Bron cedex, France b
Summary
Re´sume´
Chylomicron retention disease (CRD) is a rare autosomal recessive hereditary hypocholesterolemic disorder. The disease most frequently presents in infants and is characterized by a lipid malabsorption syndrome with steatorrhea, chronic diarrhea, and growth retardation. The disease is characterized by normal fasting serum triglyceride levels combined with the absence of apolipoprotein (apo) B48 and chylomicrons after a fat load. In this report, we describe the clinical, laboratory, and histological data as well as the molecular DNA analysis of a 12-month-old girl from Tunisia with CRD. The patient was treated with a low-fat diet and fat-soluble vitamin supplementation resulting in significant improvement. ß 2016 Elsevier Masson SAS. All rights reserved.
La maladie de re´tention des chylomicrons (MRC) est une malabsorption lipidique de transmission autosomique re´cessive. Elle est due a` une incapacite´ de se´cre´tion des chylomicrons et de l’apolipoprote´ine B48 en pe´riode post-prandiale. Elle re´sulte d’une anomalie du ge`ne codant pour la prote´ine SAR1B. Elle est me´connue et pose le proble`me de diagnostic diffe´rentiel surtout avec la maladie cœliaque. Le diagnostic pre´coce permet d’instaurer un traitement le plus toˆt possible, e´vitant la de´nutrition se´ve`re et les complications neurologiques. Nous rapportons l’observation d’une enfant de 12 mois d’origine tunisienne hospitalise´e pour diarrhe´e chronique. Le diagnostic de MRC a e´te´ e´voque´ devant une hypocholeste´role´mie, un taux normal des triglyce´rides et un aspect lactescent de la muqueuse duode´nale a` la fibroscopie digestive. L’e´tude ge´ne´tique a confirme´ le diagnostic. Le re´gime pauvre en graisses avec supple´mentation en vitamines liposolubles a permis une e´volution favorable. ß 2016 Elsevier Masson SAS. Tous droits re´serve´s.
1. Introduction
complicated by pre-eclampsia. He birth weight was 1500 g and Apgar scores were 9 and 10 at 1 and 5 minutes, respectively. Her parents were second-degree cousins and they had another 5-year-old healthy son. The family history was noncontributory. She presented with feeding intolerance, nonbloody, nonbilious emesis, diarrhea, and failure to thrive since birth. The patient was both breast- and bottle-fed and her symptoms persisted despite changing her feeds to hydrolyzed formula. On physical examination, her weight was 5.8 kg ( 4 SD), and her height was 63 cm ( 4 SD). Pallor, dyschromic dents, and distended abdomen were noted. Otherwise the physical examination was unremarkable with a normal neurological examination. Complete blood count showed a low hemoglobin
Chylomicron retention disease (CDR) is a rare autosomal recessive hereditary hypocholesterolemic disorder. We report the case of a 12-month-old girl who presented with chronic diarrhea and failure to thrive.
2. Case report A 12-month-old girl was referred to our hospital because of chronic diarrhea. She was born after a term pregnancy * Corresponding author at: Hedi Chaker Hospital, Department of pediatrics, 3029 Sfax, Tunisia. e-mail: [email protected] (S. Ben Ameur). http://dx.doi.org/10.1016/j.arcped.2016.04.010 Archives de Pe´diatrie 2016;xxx:1-3 0929-693X/ß 2016 Elsevier Masson SAS. All rights reserved.
1
ARCPED-4217; No of Pages 3
Archives de Pe´diatrie 2016;xxx:1-3
S. Ben Ameur et al.
concentration (9 g/dL) with low mean corpuscular volume (77 fl), microcytosis, no acanthocytosis, and normal profiles of white blood cells and platelets. In the liver function tests, we noted elevated aspartate aminotransferase (774 IU/L), alanine aminotransferase (360 IU/L), and alkaline phosphatase (671 IU/L) with normal bilirubin and gamma-glutamyl transpeptidase values. Anti-transglutaminase antibodies were negative. Total-, low-density-lipoprotein (LDLC), and high-density-lipoprotein cholesterol (HDL-C) levels were low (1.35 mmol/L, 0.57 mmol/L, and 0.39 mmol/L, respectively), whereas the triglycerides level was normal (1.09 mmol/L). The plasma total cholesterol levels of her father and mother and their LDL cholesterol levels were in the normal range. Lipoprotein electrophoresis of postprandial plasma did not show the presence of chylomicrons. Immunoblot testing to identify apoB and apoA fractions and abnormal apoB forms was unavailable in the country. Liver ultrasonography did not reveal any hepatic abnormalities. Esophagogastroduodenoscopy showed a whitish aspect of the duodenal mucosa. At light microscopy examination of the biopsies, enterocytes presented fat-laden vacuolization without villous atrophy (fig. 1A and B). Therefore, the clinical picture, the laboratory profile, and the pathological features indicated an inherited disorder of fat malabsorption, especially CRD. Fat-soluble vitamin (FSV) levels were low: (25-hydroxy vitamin D = 60 nmol/L – normal = 70–250; vitamin E = 2 mmol/L – normal = 5–14). A blood sample for genetic analysis was obtained after written informed consent was given. Genotyping identified a homozygous SAR1B gene mutation: deletion of exon 2 (c. 1–4482_58 + 1406 del 5946 ins15 bp). Her parents were heterozygous for the same mutation. Treatment included restriction of dietary fats, orally administered medical formula high in medium-chain triglycerides, fatsoluble vitamin supplementation, and monthly intravenous fat [(Figure_1)TD$IG]emulsion. During follow-up, the child showed catch-up growth
in weight–height and a clinical examination did not show muscle weakness or areflexia. Liver function tests normalized after 10 months of treatment. Currently the child is 4 years and 10 months old, has normal psychomotor development, but a moderate failure to thrive [weight = 13 kg ( 2 SD) and height = 97 cm ( 2.5 SD)]. Hematochemical parameters show normal levels of hemoglobin (12 g/dL), aspartate aminotransferase (43 IU/L), alanine aminotransferase (40 IU/L), and creatine-kinase (114 IUI/L). Despite administration of fat-soluble vitamins, the vitamin E serum level is persistently low: 2.4 mmol/L (normal, 5–14).
3. Discussion CRD was described for the first time by Anderson et al. in 1961 [1], and this disorder was called Anderson’s disease for many years. However, the term ‘‘chylomicron retention disease’’ is preferred as it is more indicative of the underlying defect. Additional reports further characterized this disorder, which appears to result from a specific defect involving the failure to secrete apoB-48-containing lipoproteins from the gut. It manifests in the complete absence of postprandial chylomicrons in the sera. Chylomicrons are large heterogeneous lipidrich spheric particles synthesized exclusively by the enterocytes, transporting dietary fats and fat-soluble vitamins. The enterocytes of these patients fail to secrete chylomicrons in lymph and are consequently overloaded with small lipid droplets [2,3]. Most infants present with an unremarkable birth history. Consanguinity is frequent. Similar to our patient, the diagnosis is often delayed because symptoms are nonspecific. Malabsorptive diarrhea is constant and begins in infants shortly after birth. Other digestive symptoms, such as vomiting or abdominal swelling, are often present. Hepatomegaly is
Figure 1. Duodenal biopsies: diffuse enterocyte vacuolization with large cytosolic lipid droplets. (A. H&E stain, 200. B. Periodic acid Schiff stain, 200)
2
ARCPED-4217; No of Pages 3
Chylomicron retention disease
reported in about 20% of patients with CRD. However, hepatomegaly and steatosis have been detected in a few cases on ultrasonography. No case of cirrhosis has been reported. Nonspecific hepatic cytolysis is very frequent, but moderate (1.5–3 N), and poorly correlates with steatosis or hepatomegaly [2]. Creatine-kinase is usually elevated and may be suggestive of the diagnosis [2]. In the present case, the measurement was not made at diagnosis. Nutritional deficiencies associated with fat malabsorption can lead to: serious complications in late childhood such as ataxia, proprioceptive abnormalities, and sensory neuropathy owing to vitamin E deficiency; ophthalmologic complications secondary to vitamin A deficiency; and osteopenia from vitamin D and K deficiency. Vitamin E is the most affected among the fatsoluble vitamins in CRD, because its transport is highly dependent on apoB-containing lipoproteins [2]. Vitamin E deficiency is constant at diagnosis in young children. Essential fatty acid (EFA) deficiency can also occur. Hypocholesterolemia associated with chronic diarrhea is common but nonspecific. In the present case, CRD was suspected in view of the patient’s lipid profile. First, the more than 50% decrease in total cholesterol, LDL-C, and HDL-C in the presence of normal triglycerides is almost pathognomonic. Endoscopic findings of lipid accumulation in enterocytes supported the diagnosis [2,3]. CRD is a rare recessive disorder that seems to be more frequent in highly inbred ethnic groups or in geographically isolated populations. This may be the case in the Tunisian population, which has a high rate of consanguineous marriages [4]. Mutations of the SAR1B gene were identified in 2003 as the specific molecular defect [5]. The SAR1B gene encodes the Sar1b protein, which is involved in chylomicron transport from the endoplasmic reticulum to the Golgi apparatus [2]. The mutations found in this report had already been described by Charcosset et al., in a French family originating from Algeria [6]. Treatment aims at preventing nutritional deficiencies and optimizing growth. A diet low in long-chain fat should be implemented with the addition of essential fatty acids. Simple counseling to increase oral essential fatty acids with vegetable oils and fish seems appropriate in CRD. Four patients of the French cohort also received intravenous infusion of lipid emulsion (intralipid 20% 2 g/kg/month). Intravenous and oral supplementations were unable to normalize the EFA plasma levels [2]. All patients should receive FSV orally: vitamin E, 50 IU/kg/day; vitamin A, 15,000 IU/day; vitamin D, 800– 1200 IU/day; and vitamin K, 15 mg/week. The doses should
be further adjusted based on subsequent serum levels. Vitamin E levels may never reach normal values because it primarily circulates within chylomicron vesicles [2,3]. Our patient showed catch-up growth on a low-fat diet with the addition of essential fatty acids and FSV. During childhood, standard clinical examination and biological evaluations should be performed twice a year, in order to adjust fatsoluble vitamin supplementation and focus on gastrointestinal, liver, and neurological manifestations and complications. In children over the age of 10 years, neurology and ophthalmology consultations, bone densitometry, and echocardiography should be undertaken every 3 years [2].
4. Conclusion The diagnosis of CMRD should be considered early in children born from consanguineous parents, who present with chronic diarrhea associated with hypocholesterolemia and normal triglycerides blood level.
Disclosure of interest The authors declare that they have no competing interest.
References [1]
[2]
[3]
[4]
[5]
[6]
Anderson C, Townley RRW, Freeman M, et al. Unusual causes of steatorrhoea in infancy and childhood. Med J Aust 1961;11: 617–22. Peretti N, Sassolas A, Roy C, et al. Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers. Orphanet J Rare Dis 2010;5:24. Boldrini R, Biselli R, Bosman C. Chylomicron retention disease: the role of ultrastructural examination in differential diagnosis. Pathol Res Pract 2001;197:753–7. Magnolo L, Najah M, Fancello T, et al. Novel mutations in SAR1B and MTTP genes in Tunisian children with chylomicron retention disease and abetalipoproteinemia. Gene 2013;512:28–34. Jones B, Jones EL, Bonney SA, et al. Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. Nat Genet 2003;34:29–31. Charcosset M, Sassolas A, Peretti N, et al. Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein. Mol Genet Metab 2008;93:74–84.
3