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1
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Mohammed HT, Fraser RDJ, Cassata A. Impact of digital wound care solution on healing time: A descriptive study in home health settings. PLOS DIGITAL HEALTH 2025; 4:e0000855. [PMID: 40445955 PMCID: PMC12124507 DOI: 10.1371/journal.pdig.0000855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 04/10/2025] [Indexed: 06/02/2025]
Abstract
BACKGROUND Chronic wounds pose significant challenges in home healthcare (HH) due to prolonged healing times and high costs. Digital wound care solutions (DWCS) have shown potential for improving healing efficiency. This study evaluated the impact of continuous DWCS use on healing times at HH organizations and explored area reduction in non-healed yet improved pressure injuries (PIs) and diabetic ulcers (DUs). METHODS This descriptive study analyzed 195,915 wound assessments from 59 HH organizations using DWCS in 2022 and 2023. Average healing time was calculated by wound type and compared across the two years, with subgroup analyses for wounds healing within three months versus longer. Improvements in non-healed DUs and PIs were further categorized by initial wound size (≤2 cm², >2 cm² for DUs; ≤4 cm², >4 cm² for PIs). RESULTS Average healing time for all wounds decreased significantly from 62.5 days in 2022 to 38.6 days in 2023, a 38.2% improvement (p < 0.001). DU and PIs showed reductions of 30.8 and 29.3 days, respectively. The proportion of wounds healing within three months rose by 8.9%, with decreased average healing times within this period. For wounds requiring over three months, the average time saved was 57.6 days (8.2 weeks; P = 0.014), representing a 27% improvement. Non-healed but improving PIs showed increase in area reduction from 5.2 cm² to 17.7 cm², with a 25.4% faster time to reduction. Larger PIs (>4 cm²) showed greater reductions, with time to improvement decreasing by 35.5 days (34.7%, p < 0.001). DUs also improved, with area reduction increasing from 4.8 cm² to 15.3 cm² and a 23.8% faster reduction time, while larger DUs (>2 cm²) saw a 32.6-day decrease in time to improvement. CONCLUSION Continuous DWCS use significantly reduces healing times and improves wound area reduction, underscoring its effectiveness in enhancing wound care outcomes in HH settings.
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Affiliation(s)
| | - Robert D. J. Fraser
- Swift Medical Inc., Toronto, Ontario, Canada
- Arthur Labatt School of Nursing, Western University, London, Ontario, Canada
| | - Amy Cassata
- Swift Medical Inc., Toronto, Ontario, Canada
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2
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A Case of Glycogenic Hepatopathy as a Complication of Poorly Controlled Type 1 Diabetes Mellitus. Case Rep Endocrinol 2022; 2022:8939867. [PMID: 36211537 PMCID: PMC9537034 DOI: 10.1155/2022/8939867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 09/17/2022] [Indexed: 11/17/2022] Open
Abstract
A 23-year-old African American male with a medical history significant for poorly controlled type 1 diabetes mellitus (T1DM) presented with abdominal pain and vomiting. His laboratory workup was consistent with diabetic ketoacidosis (DKA). An acute elevation of liver enzymes was noted as the DKA resolved, with the alanine transferase and aspartate transferase levels elevated to more than 50 times the normal limit within the next 24 hours. Because abnormal liver function tests are found frequently in patients with type 1 diabetes mellitus, it is important to have a broad differential diagnosis. Furthermore, a low threshold of suspicion is required to identify a relatively underdiagnosed etiology like glycogenic hepatopathy (GH). This case report describes how patterns and trends of liver function tests provide important clues to the diagnosis of GH; how imaging modalities like ultrasonography, computerized tomography (CT) scan, and magnetic resonance imaging (MRI) scan could be used to differentiate GH from nonalcoholic fatty liver disease (NAFLD); and how the diagnosis of GH can be made without the need for invasive liver biopsy. The knowledge about GH should prevent its delayed diagnosis and improve the outcomes by appropriately managing uncontrolled type 1 DM.
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3
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Singh Y, Gurung S, Gogtay M. Glycogen hepatopathy in type-1 diabetes mellitus: A case report. World J Hepatol 2022; 14:471-478. [PMID: 35317186 PMCID: PMC8891674 DOI: 10.4254/wjh.v14.i2.471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/19/2021] [Accepted: 01/11/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND It has been studied that fluctuating glucose levels may superimpose glycated hemoglobin in determining the risk for diabetes mellitus (DM) complications. While non-alcoholic steatohepatitis (NASH) remains a predominant cause of elevated transaminases in Type 2 DM due to a strong underplay of metabolic syndrome, Type 1 DM can contrastingly affect the liver in a direct, benign, and reversible manner, causing Glycogen hepatopathy (GH) - with a good prognosis. CASE SUMMARY A 50-year-old female with history of poorly controlled type 1 DM, status post cholecystectomy several years ago, and obesity presented with nausea, vomiting, and abdominal pain. Her vitals at the time of admission were stable. On physical examination, she had diffuse abdominal tenderness. Her finger-stick glucose was 612 mg/dL with elevated ketones and low bicarbonate. Her labs revealed abnormal liver studies: AST 1460 U/L, ALP: 682 U/L, ALP: 569 U/L, total bilirubin: 0.3mg/dL, normal total protein, albumin, and prothrombin time/ international normalized ratio (PT/INR). A magnetic resonance cholangiopancreatography (MRCP) demonstrated mild intra and extra-hepatic biliary ductal dilation without evidence of choledocholithiasis. She subsequently underwent a diagnostic ERCP which showed a moderately dilated CBD, for which a stent was placed. Studies for viral hepatitis, Wilson's Disease, alpha-1-antitrypsin, and iron panel came back normal. Due to waxing and waning transaminases during the hospital course, a liver biopsy was eventually done, revealing slightly enlarged hepatocytes that were PAS-positive, suggestive of glycogenic hepatopathy. With treatment of hyperglycemia and ensuing strict glycemic control, her transaminases improved, and she was discharged. CONCLUSION With a negative hepatocellular and cholestatic work-up, our patient likely had GH, a close differential for NASH but a poorly recognized entity. GH, first described in 1930 as a component of Mauriac syndrome, is believed to be due to glucose and insulin levels fluctuation. Dual echo magnetic resonance imaging sequencing and computed tomography scans of the liver are helpful to differentiate GH from NASH. Still, liver biopsy remains the gold standard for diagnosis. Biopsy predominantly shows intra-cellular glycogen deposition, with minimal or no steatosis or inflammation. As GH is reversible with good glycemic control, it should be one of the differentials in patients with brittle diabetes and elevated transaminases. GH, however, can cause a dramatic elevation in transaminases (50-1600 IU/L) alongside hepatomegaly and abdominal pain that would raise concern for acute liver injury leading to exhaustive work-up, as was in our patient above. Fluctuation in transaminases is predominantly seen during hyperglycemic episodes, and proper glycemic control is the mainstay of the treatment.
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Affiliation(s)
- Yuvaraj Singh
- Internal Medicine, Saint Vincent Hospital, Worcester, MA 01604, United States.
| | - Susant Gurung
- Internal Medicine, Saint Vincent Hospital, Worcester, MA 01604, United States
| | - Maya Gogtay
- Internal Medicine, Saint Vincent Hospital, Worcester, MA 01604, United States
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4
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Mertens J, De Block C, Spinhoven M, Driessen A, Francque SM, Kwanten WJ. Hepatopathy Associated With Type 1 Diabetes: Distinguishing Non-alcoholic Fatty Liver Disease From Glycogenic Hepatopathy. Front Pharmacol 2021; 12:768576. [PMID: 34759828 PMCID: PMC8573337 DOI: 10.3389/fphar.2021.768576] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 10/06/2021] [Indexed: 12/14/2022] Open
Abstract
Autoimmune destruction of pancreatic β-cells results in the permanent loss of insulin production in type 1 diabetes (T1D). The daily necessity to inject exogenous insulin to treat hyperglycemia leads to a relative portal vein insulin deficiency and potentiates hypoglycemia which can induce weight gain, while daily fluctuations of blood sugar levels affect the hepatic glycogen storage and overall metabolic control. These, among others, fundamental characteristics of T1D are associated with the development of two distinct, but in part clinically similar hepatopathies, namely non-alcoholic fatty liver disease (NAFLD) and glycogen hepatopathy (GlyH). Recent studies suggest that NAFLD may be increasingly common in T1D because more people with T1D present with overweight and/or obesity, linked to the metabolic syndrome. GlyH is a rare but underdiagnosed complication hallmarked by extremely brittle metabolic control in, often young, individuals with T1D. Both hepatopathies share clinical similarities, troubling both diagnosis and differentiation. Since NAFLD is increasingly associated with cardiovascular and chronic kidney disease, whereas GlyH is considered self-limiting, awareness and differentiation between both condition is important in clinical care. The exact pathogenesis of both hepatopathies remains obscure, hence licensed pharmaceutical therapy is lacking and general awareness amongst physicians is low. This article aims to review the factors potentially contributing to fatty liver disease or glycogen storage disruption in T1D. It ends with a proposal for clinicians to approach patients with T1D and potential hepatopathy.
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Affiliation(s)
- Jonathan Mertens
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium.,Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Wilrijk, Belgium
| | - Christophe De Block
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Wilrijk, Belgium
| | - Maarten Spinhoven
- Department of Radiology, Antwerp University Hospital, Edegem, Belgium
| | - Ann Driessen
- Department of Pathology, Antwerp University Hospital, Antwerp, Belgium.,CORE, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Sven M Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Wilrijk, Belgium
| | - Wilhelmus J Kwanten
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Wilrijk, Belgium
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5
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Hitt TA, Eisenberg J, Surrey LF, Gokli A, Semeao E, De Leon DD. Clinical case conundrum: Hyperlactataemia in a case of type 1 diabetes with chronic hyperglycaemia. Diabet Med 2021; 38:e14629. [PMID: 34153120 PMCID: PMC8429068 DOI: 10.1111/dme.14629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 06/20/2021] [Indexed: 11/28/2022]
Affiliation(s)
- Talia A. Hitt
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Corresponding Author: Talia Alyssa Savic Hitt, M.D./M.P.H., Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, 3500 Civic Center Boulevard, Philadelphia, Pennsylvania, 19104, USA, Tel: 267-760-7657,
| | - Joshua Eisenberg
- Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Lea F. Surrey
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Ami Gokli
- Department of Radiology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Edisio Semeao
- Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Diva D. De Leon
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Paediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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6
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Abu NA, Lim CB, Nor NSM. Glycogenic hepatopathy in children with poorly controlled type 1 diabetes mellitus. Clin Pediatr Endocrinol 2021; 30:93-97. [PMID: 33867669 PMCID: PMC8022034 DOI: 10.1297/cpe.30.93] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 12/22/2020] [Indexed: 12/11/2022] Open
Abstract
Mauriac syndrome is a rare and underdiagnosed complication of type 1 diabetes mellitus
(T1DM). It is characterized by growth retardation, delayed puberty, Cushingoid features,
hepatomegaly, and increased transaminase levels. The term glycogenic hepatopathy has been
used to describe patients with poorly controlled T1DM and glycogen overload in the
hepatocytes but without all the features of Mauriac syndrome. Although rare, glycogenic
hepatopathy is reported to be the main cause of hepatomegaly in young patients with T1DM.
We report two cases of glycogenic hepatopathy in children with poorly controlled T1DM.
Both children had hepatomegaly, elevated liver enzyme levels, and elevated lactate levels.
A liver biopsy confirmed the diagnosis of glycogenic hepatopathy in both patients. In
conclusion, hepatomegaly with elevated liver enzymes, negative infective and metabolic
screenings and persistently elevated plasma lactate levels should raise the suspicion of
glycogenic hepatopathy in poorly controlled T1DM. Early diagnosis and improvement in
glycemic control are the mainstays of treatment, which can prevent long-term
complications.
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Affiliation(s)
- Nor Azizah Abu
- Department of Pediatric, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Selangor, Malaysia
| | - Chooi Bee Lim
- Department of Pediatric, Selayang Hospital, Ministry of Health, Lebuhraya Kepong Selayang, Selangor, Malaysia
| | - Noor Shafina Mohd Nor
- Department of Pediatric, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Selangor, Malaysia.,Institute for Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA (UiTM), Selangor, Malaysia
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7
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Subedi A, Kumar VCS, Sharma A, Hoilat G, John S. Persistent lactic acidosis in the Mauriac syndrome in type 1 diabetes mellitus. Proc AMIA Symp 2021; 34:382-383. [PMID: 33953469 PMCID: PMC8059912 DOI: 10.1080/08998280.2020.1866936] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 12/09/2020] [Accepted: 12/14/2020] [Indexed: 01/23/2023] Open
Abstract
Mauriac syndrome is an uncommon clinical condition arising in the setting of poorly controlled type 1 diabetes mellitus. Clinical features include hepatomegaly and liver abnormalities indistinguishable from nonalcoholic fatty liver disease. Early diagnosis and management are essential, as Mauriac syndrome is reversible.
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Affiliation(s)
- Abinash Subedi
- Department of Internal Medicine, State University of New York Upstate Medical University, Syracuse, New York
| | - Vishnu Charan Suresh Kumar
- Department of Internal Medicine, State University of New York Upstate Medical University, Syracuse, New York
| | - Anuj Sharma
- Department of Internal Medicine, State University of New York Upstate Medical University, Syracuse, New York
- Division of Gastroenterology, State University of New York Upstate Medical University, Syracuse, New York
| | - Gilles Hoilat
- Department of Internal Medicine, State University of New York Upstate Medical University, Syracuse, New York
| | - Savio John
- Department of Internal Medicine, State University of New York Upstate Medical University, Syracuse, New York
- Division of Gastroenterology, State University of New York Upstate Medical University, Syracuse, New York
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8
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IfedibaluChukwu EI, Aparoop D, Kamaruz Z. Antidiabetic, anthelmintic and antioxidation properties of novel and new phytocompounds isolated from the methanolic stem-bark of Vernonia amygdalina Delile (Asteraceae). SCIENTIFIC AFRICAN 2020. [DOI: 10.1016/j.sciaf.2020.e00578] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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9
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Glycogenic Hepatopathy: A Rare Hepatic Complication of Poorly Controlled Type 1 DM. Case Rep Med 2020; 2020:1294074. [PMID: 32328105 PMCID: PMC7174941 DOI: 10.1155/2020/1294074] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 03/25/2020] [Indexed: 01/08/2023] Open
Abstract
Glycogen hepatopathy (GH) is a rare complication of type 1 diabetes mellitus that leads to an abnormal accumulation of glycogen in the hepatocytes. The exact mechanism of GH remains unknown, but fluctuations in blood glucose and insulin levels play important roles in promoting glycogen accumulation. We report a case of a 16-year-old female diagnosed with poorly controlled type 1 diabetes mellitus with hepatomegaly and elevated liver enzymes. The patient experienced multiple admissions for diabetic ketoacidosis, and she also had celiac disease diagnosed 2 years previously based on serology and a duodenal biopsy. The laboratory analyses results were compatible with acute hepatitis, and the celiac serology was positive. Other investigations ruled out viral hepatitis and autoimmune and metabolic liver diseases. Ultrasound and computerized tomography (CT) scans of the abdomen revealed liver enlargement with diffuse fatty infiltration. A liver biopsy revealed the presence of abundant glycogen in the cytoplasm of the hepatocytes. PAS staining was strongly positive, which confirmed the diagnosis of GH. There were no features of autoimmune hepatitis or significant fibrosis. Duodenal biopsy results were consistent with celiac disease. Despite our efforts, which are supported by a multidisciplinary team approach that included a hepatologist, a diabetic educator, a dietitian, and an endocrinologist, we have encountered difficulties in controlling the patient's diabetes, and she persistently maintains symptomatic hepatomegaly and abnormal liver biochemistry. Given the patient's age, we assumed that these abnormalities were related to patient noncompliance. In conclusion, GH remains an under-recognized complication of type 1 DM that is potentially reversible with adequate glycemic control. The awareness of GH should prevent diagnostic delay and its implications for management and the outcome.
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10
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Medhioub M, Ayedi H, Chelbi E, Khsiba A, Hamzaoui L, Azzouz MM. Mauriac syndrome: An unusual presentation with portal fibrosis. Presse Med 2019; 48:718-720. [PMID: 31133337 DOI: 10.1016/j.lpm.2019.05.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Revised: 03/18/2019] [Accepted: 05/07/2019] [Indexed: 12/01/2022] Open
Affiliation(s)
- Mouna Medhioub
- Mohamed Taher Maamouri Hospital, gastro-enterology department, 8000 Nabeul, Tunisia.
| | - Hend Ayedi
- Mohamed Taher Maamouri Hospital, gastro-enterology department, 8000 Nabeul, Tunisia
| | - Emna Chelbi
- Mohamed Taher Maamouri Hospital, pathology department, 8000 Nabeul, Tunisia
| | - Amal Khsiba
- Mohamed Taher Maamouri Hospital, gastro-enterology department, 8000 Nabeul, Tunisia
| | - Lamine Hamzaoui
- Mohamed Taher Maamouri Hospital, gastro-enterology department, 8000 Nabeul, Tunisia
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11
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Lui DTW, Woo YC, Chow WS, Lee CH, Lee ACH, Leung EKH, Tan KCB, Lam KSL, Lam JKY. Glycogenic hepatopathy as an unusual etiology of deranged liver function in a patient with type 1 diabetes: A case report. Medicine (Baltimore) 2019; 98:e15296. [PMID: 31027093 PMCID: PMC6831370 DOI: 10.1097/md.0000000000015296] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
RATIONALE Deranged liver function is a common finding among patients with diabetes mellitus. We report a case of liver biopsy-proven glycogenic hepatopathy (GH) in a patient with long-standing poorly controlled type 1 diabetes (DM1), presented with recurrent transaminitis. PATIENT CONCERNS A 28-year-old Chinese woman was noted to have deranged liver function with transaminases elevated to more than 15 times the upper limit of normal. DIAGNOSIS She had underlying long-standing poorly controlled DM1. Blood tests including hepatitis serology and autoimmune panel were negative. Liver biopsy confirmed the diagnosis of GH, showing an increase in glycogen deposition with intact liver parenchymal architecture, and no inflammation or significant fibrosis. INTERVENTIONS Her glycemic control was optimized. OUTCOMES Her transaminase levels normalized upon subsequent follow-up with improved glycemic control. LESSONS GH is suspected when transaminase flare occurs in patients with poorly controlled DM1, usually with exaggerated hemoglobin A1c levels, especially after drug-induced, viral, autoimmune and metabolic liver diseases are excluded. The gold standard of diagnosis is liver biopsy. When diagnosis of GH is ascertained, the mainstay of treatment is to optimize glycemic control. Typically, the transaminases may become normal within days to months after improvement of glycemic control. Compared to non-alcoholic fatty liver disease, GH is associated with favorable prognosis and runs a benign course, making this differentiation clinically important.
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12
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Lombardo F, Passanisi S, Gasbarro A, Tuccari G, Ieni A, Salzano G. Hepatomegaly and type 1 diabetes: a clinical case of Mauriac's syndrome. Ital J Pediatr 2019; 45:3. [PMID: 30616577 PMCID: PMC6322227 DOI: 10.1186/s13052-018-0598-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 12/19/2018] [Indexed: 02/08/2023] Open
Abstract
Background Hepatic glycogenosis is characterized by excessive glycogen accumulation in hepatocytes and represents a complication of poor controlled type 1 diabetes. It can be caused by excessive insulin doses or recurrent ketoacidosis episodes. Mauriac’s syndrome is a rare disease, which includes short stature, growth maturation delay, dyslipidemia, moon facies, protuberant abdomen, hepatomegaly with transaminase elevation. It has become even less common after the emergence of advances on diabetes treatment, but still exists. Recent reports described glycogenosis without the full spectrum of Mauriac’s syndrome in both adults and children with brittle diabetes. Clinical, laboratory and histological abnormalities are reversible with appropriate glycemic control. Case presentation We hereby report a case of 11-year-old male who presented with hepatic glycogenosis mimicking Mauriac’s syndrome. The patient was admitted at our Pediatric Diabetes Clinic for marked hepatomegaly, short stature and for the poor metabolic control. Blood investigations and liver tests excluded most of major causes of hepatopathy. A liver biopsy allowed us to make diagnosis of hepatic glycogenosis. To control hyperglycaemia, initially we titrated daily insulin dosage, and then intravenous insulin treatment was practiced with the consequent normalization of liver enzymes. Conclusion Mauriac’s syndrome should be considered in subjects with brittle type 1 diabetes and hepatomegaly.
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Affiliation(s)
- Fortunato Lombardo
- Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", University of Messina, Via Consolare Valeria 1, 98125, Messina, Italy
| | - Stefano Passanisi
- Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", University of Messina, Via Consolare Valeria 1, 98125, Messina, Italy
| | - Albino Gasbarro
- Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", University of Messina, Via Consolare Valeria 1, 98125, Messina, Italy
| | - Giovanni Tuccari
- Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", Section of Anatomic Pathology, University of Messina, Via Consolare Valeria 1, 98125, Messina, Italy
| | - Antonio Ieni
- Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", Section of Anatomic Pathology, University of Messina, Via Consolare Valeria 1, 98125, Messina, Italy
| | - Giuseppina Salzano
- Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", University of Messina, Via Consolare Valeria 1, 98125, Messina, Italy.
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13
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Asada S, Kawaratani H, Mashitani T, Kaya D, Nishigori M, Kubo T, Sawada Y, Fujinaga Y, Kaji K, Kitade M, Namisaki T, Moriya K, Mitoro A, Yoshiji H. Glycogenic Hepatopathy in Type 1 Diabetes Mellitus. Intern Med 2018; 57:1087-1092. [PMID: 29279489 PMCID: PMC5938497 DOI: 10.2169/internalmedicine.9490-17] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 07/31/2017] [Indexed: 12/29/2022] Open
Abstract
Glycogenic hepatopathy (GH) is a rare complication of poorly controlled type 1 diabetes mellitus (T1DM), and is characterized by elevated liver enzymes, hepatomegaly, and glycogen accumulation. We herein present the case of a 23-year-old man with poorly controlled T1DM who had liver dysfunction. Imaging studies showed severe hepatomegaly and fatty liver. The examination of a liver biopsy specimen revealed fatty droplets, ballooning, inflammation, and mild fibrosis. Subsequent periodic acid-Schiff (PAS) staining after diastase digestion confirmed GH. In this case, the improvement of hyperglycemia, not HbA1c, resulted in the improvement of the patient's liver function. This is the first report on the use of continuous glucose monitoring in patients with GH to show that continuous hyperglycemia may worsen GH.
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Affiliation(s)
- Shohei Asada
- Third Department of Internal Medicine, Nara Medical University, Japan
| | - Hideto Kawaratani
- Third Department of Internal Medicine, Nara Medical University, Japan
| | | | - Daisuke Kaya
- Third Department of Internal Medicine, Nara Medical University, Japan
| | - Maiko Nishigori
- Third Department of Internal Medicine, Nara Medical University, Japan
| | - Takuya Kubo
- Third Department of Internal Medicine, Nara Medical University, Japan
| | - Yasuhiko Sawada
- Third Department of Internal Medicine, Nara Medical University, Japan
| | - Yukihisa Fujinaga
- Third Department of Internal Medicine, Nara Medical University, Japan
| | - Kosuke Kaji
- Third Department of Internal Medicine, Nara Medical University, Japan
| | - Mitsuteru Kitade
- Third Department of Internal Medicine, Nara Medical University, Japan
| | - Tadashi Namisaki
- Third Department of Internal Medicine, Nara Medical University, Japan
| | - Kei Moriya
- Third Department of Internal Medicine, Nara Medical University, Japan
| | - Akira Mitoro
- Third Department of Internal Medicine, Nara Medical University, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Japan
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14
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Young Man with Hepatomegaly: A Case of Glycogenic Hepatopathy. Case Reports Hepatol 2018; 2018:6037530. [PMID: 29850300 PMCID: PMC5925151 DOI: 10.1155/2018/6037530] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 03/03/2018] [Indexed: 02/06/2023] Open
Abstract
Glycogenic hepatopathy is a rare but potentially reversible condition characterized by hepatomegaly and elevated liver enzymes occurring in poorly controlled type 1 diabetes mellitus patients and often requires a liver biopsy to confirm the diagnosis. We present the case of a young man who was admitted with diabetic ketoacidosis in the setting of poorly controlled diabetes mellitus type 1 and was noted to have significantly elevated transaminases that continued to worsen despite appropriate treatment of the diabetic ketoacidosis. A liver biopsy confirmed the diagnosis of glycogenic hepatopathy and the patient improved with diabetes control. The aim of this report is to shed light on possible causes of significant elevation of liver enzymes in patients presenting with diabetic ketoacidosis. In addition, we would like to raise awareness about the diagnosis, management, and prognosis of glycogenic hepatopathy and how to differentiate it from other hepatic conditions that have a similar presentation.
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15
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Khoury J, Zohar Y, Shehadeh N, Saadi T. Glycogenic hepatopathy. Hepatobiliary Pancreat Dis Int 2018; 17:113-118. [PMID: 29709217 DOI: 10.1016/j.hbpd.2018.02.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2017] [Accepted: 11/24/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Glycogenic hepatopathy (GH) is a disorder associated with uncontrolled diabetes mellitus, most commonly type 1, expressed as right upper quadrant abdominal pain, hepatomegaly and increased liver enzymes. The diagnosis may be difficult, because laboratory and imaging tests are not pathognomonic. Although GH may be suggested based on clinical presentation and imaging studies, the gold standard for diagnosis is a liver biopsy, showing a significant accumulation of glycogen within the hepatocytes. GH may be diagnosed also after elevated liver enzymes in routine blood tests. GH usually regresses after tight glycemic control. Progression to end-stage liver disease has never been reported. This review aims to increase the awareness to this disease, to suggest a pathway for investigation that may reduce the use of unnecessary tests, especially invasive ones. DATA SOURCES A PubMed database search (up to July 1, 2017) was done with the words "glycogenic hepatopathy", "hepatic glycogenosis", "liver glycogenosis" and "diabetes mellitus-associated glycogen storage hepatopathy". Articles in which diabetes mellitus-associated liver glycogen accumulation was described were included in this review. RESULTS A total of 47 articles were found, describing 126 patients with GH. Hepatocellular disturbance was more profound than cholestatic disturbance. No synthetic failure was reported. CONCLUSIONS GH may be diagnosed conservatively, based on corroborating medical history, physical examination, laboratory tests, imaging studies and response to treatment, even without liver biopsy. In case of doubt about the diagnosis or lack of clinical response to treatment, a liver biopsy may be considered. There is no role for noninvasive tests like fibroscan or fibrotest for the diagnosis of GH or for differentiation of this situation from nonalcoholic fatty liver disease.
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Affiliation(s)
- Johad Khoury
- Internal Medicine B, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Liver Unit, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Yaniv Zohar
- Department of Pathology, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Naim Shehadeh
- Meyer Children's Hospital of Haifa, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Institute of Diabetes, Endocrinology and Metabolism, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Tarek Saadi
- Liver Unit, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Department of Gastroenterology, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
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16
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Sherigar JM, Castro JD, Yin YM, Guss D, Mohanty SR. Glycogenic hepatopathy: A narrative review. World J Hepatol 2018; 10:172-185. [PMID: 29527255 PMCID: PMC5838438 DOI: 10.4254/wjh.v10.i2.172] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Revised: 12/22/2017] [Accepted: 01/24/2018] [Indexed: 02/06/2023] Open
Abstract
Glycogenic hepatopathy (GH) is a rare complication of the poorly controlled diabetes mellitus characterized by the transient liver dysfunction with elevated liver enzymes and associated hepatomegaly caused by the reversible accumulation of excess glycogen in the hepatocytes. It is predominantly seen in patients with longstanding type 1 diabetes mellitus and rarely reported in association with type 2 diabetes mellitus. Although it was first observed in the pediatric population, since then, it has been reported in adolescents and adults with or without ketoacidosis. The association of GH with hyperglycemia in diabetes has not been well established. One of the essential elements in the pathophysiology of development of GH is the wide fluctuation in both glucose and insulin levels. GH and non-alcoholic fatty liver disease (NAFLD) are clinically indistinguishable, and latter is more prevalent in diabetic patients and can progress to advanced liver disease and cirrhosis. Gradient dual-echo MRI can distinguish GH from NAFLD; however, GH can reliably be diagnosed only by liver biopsy. Adequate glycemic control can result in complete remission of clinical, laboratory and histological abnormalities. There has been a recent report of varying degree of liver fibrosis identified in patients with GH. Future studies are required to understand the biochemical defects underlying GH, noninvasive, rapid diagnostic tests for GH, and to assess the consequence of the fibrosis identified as severe fibrosis may progress to cirrhosis. Awareness of this entity in the medical community including specialists is low. Here we briefly reviewed the English literature on pathogenesis involved, recent progress in the evaluation, differential diagnosis, and management.
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Affiliation(s)
- Jagannath M Sherigar
- Department of Gastroenterology and Hepatology, NYP-Brooklyn Methodist Hospital, Brooklyn, NY 11215, United States
| | - Joline De Castro
- Department of Gastroenterology and Hepatology, NYP-Brooklyn Methodist Hospital, Brooklyn, NY 11215, United States
| | - Yong Mei Yin
- NYP-Brooklyn Methodist Hospital, Brooklyn, NY 11215, United States
| | - Debra Guss
- Department of Gastroenterology and Hepatology, NYP-Brooklyn Methodist Hospital, Brooklyn, NY 11215, United States
| | - Smruti R Mohanty
- Department of Gastroenterology and Hepatology, NYP-Brooklyn Methodist Hospital, Brooklyn, NY 11215, United States
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17
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Silva M, Marques M, Cardoso H, Rodrigues S, Andrade P, Peixoto A, Pardal J, Lopes J, Carneiro F, Macedo G. Glycogenic hepatopathy in young adults: a case series. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2017; 108:673-676. [PMID: 26900767 DOI: 10.17235/reed.2016.3934/2015] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Glycogenic hepatopathy is a rare and under-recognized complication in long-standing poorly controlled type 1 diabetes mellitus patients. This is a distinct entity from other causes of hepatomegaly and elevated liver enzymes in diabetics, such as nonalcoholic fatty liver disease. Glycogenic hepatopathy is characterized by the combination of poorly controlled diabetes, acute liver injury with marked elevation in serum aminotransferases, and the characteristic histological features on liver biopsy. It is important to distinguish this entity as it has the potential for resolution following improved glycemic control. In this report, we describe four cases of adult patients presenting elevated serum transaminases and hepatomegaly with a history of poorly controlled type I diabetes mellitus. One of the patients had also elevated amylase and lipase in the serum, without clinical or imagiologic evidence of acute pancreatitis (AP). Liver biopsy was performed in all patients and revealed glycogenic hepatopathy. Clinician's awareness of glycogenic hepatopathy should prevent diagnostic delay or misdiagnosis and will provide better insight and management for this condition.
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Affiliation(s)
- Marco Silva
- Gastroenterology, Centro Hospitalar São João, Portugal
| | | | | | | | - Patrícia Andrade
- Gastroenterology department, Centro Hospitalar São João, Portugal
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18
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Focal Hepatic Glycogenosis in a Patient With Uncontrolled Diabetes Mellitus Type 1. J Comput Assist Tomogr 2017; 42:230-235. [PMID: 28937487 DOI: 10.1097/rct.0000000000000673] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Hepatomegaly and elevated liver enzymes in patients with diabetes are commonly associated with fatty liver disease. However, physicians often forget about another intrinsic substance that can cause a similar clinical picture-glycogen. Liver stores approximately one third of the total body glycogen and is responsible for blood glucose homeostasis. Excessive hepatocellular glycogen accumulation occurs not only in congenital glycogen storage diseases, but also in acquired conditions associated with hyperglycemic-hyperinsulinemic states such as uncontrolled diabetes mellitus, high-dose corticosteroid use, and dumping syndrome. All reported cases of acquired abnormal glycogen deposition described a diffuse form of hepatic glycogenosis with the entire liver involved in the accumulating process. To our knowledge, this is the first reported case of abnormal focal glycogen deposition in a patient with diabetes mellitus type 1 with imaging and pathologic correlation. Awareness of the imaging appearance of focal glycogen deposition can help to distinguish it from other pathologic conditions.
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19
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Shah ND, Sasatomi E, Baron TH. Acute and Relapsing Hepatitis Caused by Glycogenic Hepatopathy. Clin Gastroenterol Hepatol 2017; 15:A23-A24. [PMID: 28189697 DOI: 10.1016/j.cgh.2017.02.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 02/01/2017] [Accepted: 02/03/2017] [Indexed: 02/07/2023]
Affiliation(s)
- Neil D Shah
- Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Eizaburo Sasatomi
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Todd H Baron
- Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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20
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Ikarashi Y, Kogiso T, Hashimoto E, Yamamoto K, Kodama K, Taniai M, Torii N, Takaike H, Uchigata Y, Tokushige K. Four cases of type 1 diabetes mellitus showing sharp serum transaminase increases and hepatomegaly due to glycogenic hepatopathy. Hepatol Res 2017; 47:E201-E209. [PMID: 27027269 DOI: 10.1111/hepr.12713] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Revised: 03/18/2016] [Accepted: 03/22/2016] [Indexed: 02/06/2023]
Abstract
Poorly controlled diabetes mellitus (DM) patients sometimes show serum transaminase elevations due to steatohepatitis. However, we experienced four cases with type 1 DM with sharp elevations in serum transaminases that could not be explained by steatohepatitis alone and showed bright liver. They were diagnosed with glycogenic hepatopathy (GH) clinicopathologically. The four patients had a median age of 22.5 years (range, 19-29 years) and 12.5 (4-15)-year histories of type 1 DM and showed marked increases in serum transaminases (aspartate aminotransferase, 698 U/L [469-2763 U/L]; alanine transaminase, 255 U/L [216-956 U/L]). Diabetes mellitus control was poor and hemoglobin A1c was 12.7% (11-16.5%). Three cases had a past history of diabetic ketoacidosis. Hepatomegaly and hyperdense liver were seen on computed tomography scans. Magnetic resonance imaging showed low intensity in T2-weighted images. The pathological findings revealed pale and swollen hepatocytes and glycogenated nuclei. The architecture of the liver was preserved, and steatosis and fibrosis were mild. The cytoplasm of hepatocytes stained densely positive with periodic acid-Schiff, and the positive staining disappeared after diastase digestion, suggesting glycogen deposition. No other cause of hepatitis was evident, and the diagnosis was GH. Elevated transaminases improved within 1 month with good glycemic control. Transaminase elevations were observed several times in three cases with poor glycemic control. Glycogenic hepatopathy is rare, but extremely high serum elevations of transaminases are important to identify clinically. Despite showing a good clinical course in general, GH sometimes recurs and requires strict glycemic control. Clinicians should be aware of and recognize GH when dealing with uncontrolled DM patients.
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Affiliation(s)
- Yuichi Ikarashi
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Tomomi Kogiso
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Etsuko Hashimoto
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Kuniko Yamamoto
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Kazuhisa Kodama
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Makiko Taniai
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Nobuyuki Torii
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Hiroko Takaike
- Diabetes Center, Tokyo Women's Medical University, Tokyo, Japan
| | - Yasuko Uchigata
- Diabetes Center, Tokyo Women's Medical University, Tokyo, Japan
| | - Katsutoshi Tokushige
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
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21
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MacDonald MJ, Hasan NM, Ansari IUH, Longacre MJ, Kendrick MA, Stoker SW. Discovery of a Genetic Metabolic Cause for Mauriac Syndrome in Type 1 Diabetes. Diabetes 2016; 65:2051-9. [PMID: 27207549 DOI: 10.2337/db16-0099] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 03/28/2016] [Indexed: 12/13/2022]
Abstract
A mechanistic cause for Mauriac syndrome, a syndrome of growth failure and delayed puberty associated with massive liver enlargement from glycogen deposition in children with poorly controlled type 1 diabetes, is unknown. We discovered a mutation in the catalytic subunit of liver glycogen phosphorylase kinase in a patient with Mauriac syndrome whose liver extended into his pelvis. Glycogen phosphorylase kinase activates glycogen phosphorylase, the enzyme that catalyzes the first step in glycogen breakdown. We show that the mutant subunit acts in a dominant manner to completely inhibit glycogen phosphorylase kinase enzyme activity and that this interferes with glycogenolysis causing increased levels of glycogen in human liver cells. It is known that even normal blood glucose levels physiologically inhibit glycogen phosphorylase to diminish glucose release from the liver when glycogenolysis is not needed. The patient's mother possessed the same mutant glycogen phosphorylase kinase subunit, but did not have diabetes or hepatomegaly. His father had childhood type 1 diabetes in poor glycemic control, but lacked the mutation and had neither hepatomegaly nor growth failure. This case proves that the effect of a mutant enzyme of glycogen metabolism can combine with hyperglycemia to directly hyperinhibit glycogen phosphorylase, in turn blocking glycogenolysis causing the massive liver in Mauriac disease.
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Affiliation(s)
- Michael J MacDonald
- Childrens Diabetes Center, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Noaman M Hasan
- Childrens Diabetes Center, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Israr-Ul H Ansari
- Childrens Diabetes Center, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Melissa J Longacre
- Childrens Diabetes Center, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Mindy A Kendrick
- Childrens Diabetes Center, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Scott W Stoker
- Childrens Diabetes Center, University of Wisconsin School of Medicine and Public Health, Madison, WI
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22
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Irani NR, Venugopal K, Kontorinis N, Lee M, Sinniah R, Bates TR. Glycogenic hepatopathy is an under-recognised cause of hepatomegaly and elevated liver transaminases in type 1 diabetes mellitus. Intern Med J 2016; 45:777-9. [PMID: 26134697 DOI: 10.1111/imj.12807] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Accepted: 04/29/2015] [Indexed: 12/16/2022]
Abstract
Glycogenic hepatopathy (GH) is an under-recognised complication of type 1 diabetes mellitus (T1DM) not controlled to target resulting in hepatomegaly and elevated liver transaminases. We report the case of a 19-year-old man with T1DM not controlled to target who presented with abdominal pain, hepatomegaly and deranged liver transaminases. He was subsequently diagnosed with GH on liver biopsy, with the mainstay of treatment being reduction in caloric intake and insulin.
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Affiliation(s)
- N R Irani
- Department of Gastroenterology and Hepatology, Royal Perth Hospital, Perth, Western Australia, Australia
| | - K Venugopal
- Department of Gastroenterology and Hepatology, Royal Perth Hospital, Perth, Western Australia, Australia
| | - N Kontorinis
- Department of Gastroenterology and Hepatology, Royal Perth Hospital, Perth, Western Australia, Australia
| | - M Lee
- Department of General Medicine, Swan District Hospital, Perth, Western Australia, Australia
| | - R Sinniah
- Department of Pathology, Royal Perth Hospital, Perth, Western Australia, Australia
| | - T R Bates
- Department of General Medicine, Swan District Hospital, Perth, Western Australia, Australia.,School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia
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23
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Abstract
Liver involvement in diabetes is well recognized in the form of steatohepatitis and glycogenic hepatopathy. More recently, sinusoidal fibrosis, even in the absence of steatosis, has also been suggested to be associated with diabetes (diabetic hepatosclerosis); however, case-control studies are lacking. In addition, microangiopathy (hyaline arteriolosclerosis), a well-known complication of diabetes, has not been well studied in liver. Therefore, we undertook a cross-sectional blinded study with the specific aim of evaluating the association between hepatic sinusoidal fibrosis and hepatic arteriolosclerosis (HA) with diabetes. Liver biopsy findings from 89 diabetic patients obtained between January 2006 and December 2009 were compared with those of 89 nondiabetic patients matched by age and hepatitis C virus infection status. Patients with cirrhosis, liver mass, right heart failure, significant alcohol use, or insufficient available clinical information were excluded. Medical records were reviewed for the presence of diabetes, body mass index, diabetes treatment, and comorbidities at the time of biopsy (eg, underlying liver disease, hypertension, dyslipidemia). Liver biopsies were evaluated blinded to all clinical data (including presence or absence of diabetes) for a variety of histologic features, especially patterns of fibrosis and HA. Diabetic patients had a higher average body mass index (33 vs. 30 m/kg, P=0.0039), prevalence of hypertension (78% vs. 33%, P<0.0001), and dyslipidemia (52% vs. 20%, P<0.0001). Among diabetic patients, 87% had type 2 diabetes, and 57% used insulin. Whereas sinusoidal fibrosis, with or without steatosis, was not significantly associated with the presence of diabetes, HA was significantly more prevalent among diabetic patients compared with controls: 45% versus 29% (P=0.0298). The presence of both diabetes and hypertension had a significant odds for HA: with an adjusted odds ratio of 2.632 (95% confidence interval, 1.178-5.878; P=0.0183). Biliary changes were associated with HA in some cases (10.6%).In this study, we describe the histopathologic entity of HA for the first time. It is a small-vessel complication (microangiopathy) of the liver observed mainly in patients with diabetes who also have arterial hypertension. The clinical and prognostic implications of this finding, particularly regarding liver injury, remain to be further investigated.
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24
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Glycogenic Hepatopathy in Type 1 Diabetes Mellitus. Case Reports Hepatol 2015; 2015:236143. [PMID: 26347835 PMCID: PMC4546963 DOI: 10.1155/2015/236143] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Accepted: 07/28/2015] [Indexed: 12/16/2022] Open
Abstract
Glycogenic hepatopathy is a rare cause of high transaminase levels in type 1 diabetes mellitus. This condition, characterized by elevated liver enzymes and hepatomegaly, is caused by irreversible and excessive accumulation of glycogen in hepatocytes. This is a case report on a 19-year-old male case, diagnosed with glycogenic hepatopathy. After the diagnosis was documented by liver biopsy, the case was put on glycemic control which led to significant decline in hepatomegaly and liver enzymes. It was emphasized that, in type 1 diabetes mellitus cases, hepatopathy should also be considered in the differential diagnoses of elevated liver enzyme and hepatomegaly.
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25
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Parmar N, Atiq M, Austin L, Miller RA, Smyrk T, Ahmed K. Glycogenic Hepatopathy: Thinking Outside the Box. Case Rep Gastroenterol 2015; 9:221-6. [PMID: 26269698 PMCID: PMC4520193 DOI: 10.1159/000437048] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Glycogenic hepatopathy (GH) remains underrecognized in adults as most clinicians mistake it for the more common hepatic abnormality associated with uncontrolled diabetes mellitus in this age group, non-alcoholic fatty liver disease. This is also complicated by the fact that both entities are indistinguishable on liver ultrasound. We herein describe a similar predicament in which a young adult female presented with bilateral upper quadrant abdominal pain, tender hepatomegaly, lactic acidosis and a >10-fold increase in liver enzymes, which worsened after the administration of high-dose steroids. Despite intravenous normal saline resuscitation, serum transaminitis persisted in a fluctuating manner. Ultimately, a liver biopsy confirmed GH. Biochemically, GH is driven by high amounts of both circulating glucose and insulin or by the administration of high-dose steroids. Improving glycemic control is the mainstay of treatment for GH. However, in our case, improvement in glycated hemoglobin of just 0.6% was enough to achieve symptomatic relief, supporting recent claims of the involvement of other identified factors in disease development.
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Affiliation(s)
- Nishant Parmar
- Department of Internal Medicine, Sanford USD School of Medicine, Sioux Falls, S. Dak., USA
| | - Muslim Atiq
- Sanford Center for Digestive Health, Sanford USD Medical Center, Sioux Falls, S. Dak., USA
| | - Lee Austin
- Sanford Center for Digestive Health, Sanford USD Medical Center, Sioux Falls, S. Dak., USA
| | - Ross A Miller
- Department of Pathology, The Methodist Hospital, Houston, Tex., USA
| | - Thomas Smyrk
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minn., USA
| | - Kabir Ahmed
- Department of Internal Medicine, Sanford USD School of Medicine, Sioux Falls, S. Dak., USA
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26
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Julián MT, Alonso N, Ojanguren I, Pizarro E, Ballestar E, Puig-Domingo M. Hepatic glycogenosis: An underdiagnosed complication of diabetes mellitus? World J Diabetes 2015; 6:321-325. [PMID: 25789113 PMCID: PMC4360425 DOI: 10.4239/wjd.v6.i2.321] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Revised: 10/15/2014] [Accepted: 12/19/2014] [Indexed: 02/05/2023] Open
Abstract
Hepatic glycogenosis (HG) is characterized by excessive glycogen accumulation in hepatocytes and represents a hepatic complication of diabetes that particularly occurs in patients with longstanding poorly controlled type 1 diabetes (T1D). HG has been reported to be a very rare disease, although it is believed to be extremely underdiagnosed because it is not possible to distinguish it from non-alcoholic fatty liver disease (NAFLD) unless a liver biopsy is performed. In contrast to HG, NAFLD is characterized by liver fat accumulation and is the more likely diagnosis for patients with type 2 diabetes and metabolic syndrome. The pathogenesis of HG involves the concomitant presence of insulin and excess glucose, which increases glycogen storage in the liver. HG is characterized by a transient elevation in liver transaminases and hepatomegaly. Differentiating between these two conditions is of the utmost importance because HG is a benign disease that is potentially reversible by improving glycemic control, whereas NAFLD can progress to cirrhosis. Therefore, HG should be suspected when liver dysfunction occurs in patients with poorly controlled T1D. The aim of this article is to review the epidemiology, clinical characteristics, pathogenesis and histology of HG.
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27
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Giordano S, Martocchia A, Toussan L, Stefanelli M, Pastore F, Devito A, Risicato MG, Ruco L, Falaschi P. Diagnosis of hepatic glycogenosis in poorly controlled type 1 diabetes mellitus. World J Diabetes 2014; 5:882-888. [PMID: 25512791 PMCID: PMC4265875 DOI: 10.4239/wjd.v5.i6.882] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Revised: 10/02/2014] [Accepted: 10/27/2014] [Indexed: 02/05/2023] Open
Abstract
Hepatic glycogenosis (HG) in type 1 diabetes is a underrecognized complication. Mauriac firstly described the syndrome characterized by hepatomegaly with altered liver enzymes, growth impairment, delay puberty and Cushingoid features, during childhood. HG in adulthood is characterized by the liver disorder (with circulating aminotransferase increase) in the presence of poor glycemic control (elevation of glycated hemoglobin, HbA1c levels). The advances in the comprehension of the metabolic pathways driving to the hepatic glycogen deposition point out the role of glucose transporters and insulin mediated activations of glucokinase and glycogen synthase, with inhibition of glucose-6-phosphatase. The differential diagnosis of HG consists in the exclusion of causes of liver damage (infectious, metabolic, obstructive and autoimmune disease). The imaging study (ultrasonography and/or radiological examinations) gives information about the liver alterations (hepatomegaly), but the diagnosis needs to be confirmed by the liver biopsy. The main treatment of HG is the amelioration of glycemic control that is usually accompanied by the reversal of the liver disorder. In selected cases, more aggressive treatment options (transplantation) have been successfully reported.
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28
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Jeong HR, Shim YS, Kim YB, Lee HS, Hwang JS. Glycogenic hepatopathy in a Korean girl with poorly controlled type 1 diabetes mellitus. Ann Pediatr Endocrinol Metab 2014; 19:49-52. [PMID: 24926465 PMCID: PMC4049544 DOI: 10.6065/apem.2014.19.1.49] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Revised: 02/20/2014] [Accepted: 03/10/2014] [Indexed: 01/06/2023] Open
Abstract
Glycogenic hepatopathy (GH) is a rare complication of type 1 diabetes mellitus. We report the case of a 13-year-old diabetic female with poorly controlled blood sugar levels who presented with abdominal pain and distention 1 month in duration. She exhibited tender hepatomegaly, an elevated lipid profile, and elevated serum transaminase levels. Her liver histology was consistent with GH. The pathophysiology and/or underlying genetic background of GH remains unclear. The optimum treatment for GH is optimal glycemic control, and the prognosis is favorable. Clinicians should be aware of the possibility of GH and observe the clinical response to optimal glycemic control prior to invasive investigation.
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Affiliation(s)
- Hwal Rim Jeong
- Department of Pediatrics, Ajou University School of Medicine, Suwon, Korea
| | - Young Seok Shim
- Department of Pediatrics, Ajou University School of Medicine, Suwon, Korea
| | - Young Bae Kim
- Department of Pathology, Ajou University School of Medicine, Suwon, Korea
| | - Hae Sang Lee
- Department of Pediatrics, Ajou University School of Medicine, Suwon, Korea
| | - Jin Soon Hwang
- Department of Pediatrics, Ajou University School of Medicine, Suwon, Korea
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29
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Butts GT, Hairston FJ, Bishop PR, Nowicki MJ. Massive hepatomegaly in poorly controlled insulin-dependent diabetes mellitus. J Pediatr 2014; 164:214-214.e1. [PMID: 24070830 DOI: 10.1016/j.jpeds.2013.08.027] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2013] [Accepted: 08/13/2013] [Indexed: 12/13/2022]
Affiliation(s)
- G Tyler Butts
- School of Medicine, University of Mississippi Medical Center, Jackson, Mississippi
| | - F Jariel Hairston
- Department of Pathology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Phyllis R Bishop
- Division of Pediatric Gastroenterology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Michael J Nowicki
- Division of Pediatric Gastroenterology, University of Mississippi Medical Center, Jackson, Mississippi
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30
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Cha JH, Ra SH, Park YM, Ji YK, Lee JH, Park SY, Baik SK, Kwon SO, Cho MY, Kim MY. Three cases of glycogenic hepatopathy mimicking acute and relapsing hepatitis in type I diabetes mellitus. Clin Mol Hepatol 2013; 19:421-5. [PMID: 24459648 PMCID: PMC3894443 DOI: 10.3350/cmh.2013.19.4.421] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2012] [Revised: 10/10/2012] [Accepted: 10/17/2012] [Indexed: 12/13/2022] Open
Abstract
Glycogenic hepatopathy (GH) is an uncommon cause of serum transaminase elevation in type I diabetes mellitus (DM). The clinical signs and symptoms of GH are nonspecific, and include abdominal discomfort, mild hepatomegaly, and transaminase elevation. In this report we describe three cases of patients presenting serum transaminase elevation and hepatomegaly with a history of poorly controlled type I DM. All of the cases showed sudden elevation of transaminase to more than 30 times the upper normal range (like in acute hepatitis) followed by sustained fluctuation (like in relapsing hepatitis). However, the patients did not show any symptom or sign of acute hepatitis. We therefore performed a liver biopsy to confirm the cause of liver enzyme elevation, which revealed GH. Clinicians should be aware of GH so as to prevent diagnostic delay and misdiagnosis, and have sufficient insight into GH; this will be aided by the present report of three cases along with a literature review.
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Affiliation(s)
- Jae Hwang Cha
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Sang Ho Ra
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Yu Mi Park
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Yong Kwan Ji
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Ji Hyun Lee
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - So Yeon Park
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Soon Koo Baik
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Sang Ok Kwon
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Mee Yon Cho
- Department of Pathology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Moon Young Kim
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
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Doycheva I, Patel N, Peterson M, Loomba R. Prognostic implication of liver histology in patients with nonalcoholic fatty liver disease in diabetes. J Diabetes Complications 2013; 27:293-300. [PMID: 23312215 PMCID: PMC4167586 DOI: 10.1016/j.jdiacomp.2012.10.008] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Revised: 10/06/2012] [Accepted: 10/09/2012] [Indexed: 12/23/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) frequently coexist due to shared risk factors. Their rising prevalence parallels the growing epidemic of obesity and insulin resistance (IR). In patients with T2DM and biopsy-proven NAFLD, a significantly higher prevalence of nonalcoholic steatohepatitis (NASH) (63-87%), any fibrosis (22-60%), and advanced fibrosis (4-9%) is noted. Possible risk factors for more advanced liver disease include concomitant metabolic syndrome with three or more components, visceral obesity, older age, increased duration of diabetes, and family history of diabetes. Liver biopsy is strongly suggested in these patients. Cardiovascular disease (CVD) and malignancy are the leading causes of death in this population, but a growing body of evidence shows liver-related mortality as an important cause of death, including an increased rate of hepatocellular carcinoma (HCC) in diabetes. The presence of NAFLD in T2DM is also associated with increased overall mortality. We aim with this review to summarize the results from studies investigating NAFLD in T2DM and to outline the factors that predict more advanced liver histology as well as the impact of these hepatic changes on CVD, overall and liver-related mortality.
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Affiliation(s)
- Iliana Doycheva
- Department of Medicine, Division of Gastroenterology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Niraj Patel
- Department of Medicine, Division of General Internal Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Michael Peterson
- Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Rohit Loomba
- Department of Medicine, Division of Gastroenterology, University of California, San Diego, La Jolla, CA 92093, USA
- Department of Family and Preventive Medicine, Division of Epidemiology, University of California, San Diego, La Jolla, CA 92093, USA
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Imtiaz KE, Healy C, Sharif S, Drake I, Awan F, Riley J, Karlson F. Glycogenic hepatopathy in type 1 diabetes: an underrecognized condition. Diabetes Care 2013; 36:e6-7. [PMID: 23264308 PMCID: PMC3526232 DOI: 10.2337/dc12-1134] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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Murata F, Horie I, Ando T, Isomoto E, Hayashi H, Akazawa S, Ueki I, Nakamura K, Kobayashi M, Kuwahara H, Abiru N, Kawasaki E, Yamasaki H, Kawakami A. A case of glycogenic hepatopathy developed in a patient with new-onset fulminant type 1 diabetes: the role of image modalities in diagnosing hepatic glycogen deposition including gradient-dual-echo MRI. Endocr J 2012; 59:669-76. [PMID: 22673296 DOI: 10.1507/endocrj.ej12-0081] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Glycogenic hepatopathy (GH) has been reported as a very rare and under recognized complication in long-standing poorly controlled type 1 diabetes (T1D) patients. GH is characterized by transient elevation of liver transaminase and hepatomegaly caused by reversible and excessive glycogen accumulation in hepatocytes. It has been reported that GH is indistinguishable from non-alcoholic fatty liver disease, which is more commonly seen in diabetic patients, even after a history is taken and a physical examination or imaging studies have been performed. GH can only be diagnosed by liver biopsy. We here demonstrate a 21-year-old male patient with new-onset fulminant T1D complicated with diabetic ketoacidosis who subsequently developed GH just after the initiation of insulin treatment. The marked liver dysfunction (serum levels of aspartate aminotransferase 769 IU/L and alanine aminotransferase 1348 IU/L) and hepatomegaly improved spontaneously via glycemic control without any specific treatments thereafter. Moreover, the insulin requirement dramatically decreased from 168 to 80 units per day as GH improved, suggesting a potential role of GH in insulin resistance. GH was diagnosed based on the histological findings of the liver in our case, but we were able to predict GH before the biopsy based on the findings in the gradient-dual-echo magnetic resonance imaging sequence combined with ultrasound and/or computed tomography examinations of the liver.
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Affiliation(s)
- Fumi Murata
- Department of Metabolism/Diabetes and Clinical Nutrition, Nagasaki University Hospital, Japan
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Abstract
A 2-year-old boy, having undergone fundoplication for gastroesophageal reflux disease and fed by gastrostomy, presented with recurrent emesis, syncope with hypoglycemia, and persistently elevated serum liver transaminase levels. Liver biopsy revealed hepatocellular glycogenosis by light and electron microscopy. Further evaluation showed no evidence of diabetes mellitus, glycogen storage disease, or corticosteroid use. Since the hyperglycemic-hyperinsulinemic state of dumping syndrome would provide a mechanism for hepatocellular glycogenosis, the biopsy findings prompted consideration of dumping syndrome. Metabolic evaluation confirmed the diagnosis of dumping syndrome, and appropriate dietary management led to sustained resolution of symptomatology and hypertransaminasemia. Dumping syndrome is proposed to be a cause of hepatocellular glycogenosis, the latter representing a form of acquired glycogenic hepatopathy.
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Julián MT, Olaizola I, Riu F, López R. [Hepatic glycogenosis in a patient with type 1 diabetes mellitus]. Rev Clin Esp 2010; 211:65-6. [PMID: 21183166 DOI: 10.1016/j.rce.2010.09.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2010] [Revised: 09/10/2010] [Accepted: 09/19/2010] [Indexed: 12/18/2022]
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El-Karaksy HM, Anwar G, Esmat G, Mansour S, Sabry M, Helmy H, El-Hennawy A, Fouad H. Prevalence of hepatic abnormalities in a cohort of Egyptian children with type 1 diabetes mellitus. Pediatr Diabetes 2010; 11:462-470. [PMID: 20042012 DOI: 10.1111/j.1399-5448.2009.00627.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND AND AIM Children with type 1 diabetes mellitus (T1DM) are frequently investigated for hepatic abnormalities. This study was carried out to report on the prevalence of hepatic abnormalities in diabetic children and adolescents and to highlight the possible etiology and appropriate management. METHODS The study included 692 children (333 were males) with T1DM attending the Diabetes Unit at Cairo University Pediatric Hospital. Their mean age was 9.65 ± 4.18 yr. All children were subjected to clinical examination for hepatomegaly, determination of alanine aminotransferase (ALT) and antibodies to hepatitis C virus (anti-HCV), and abdominal ultrasonography. All children with clinical, laboratory or ultrasound abnormality were counseled about proper glycemic control and followed up. If abnormalities persisted, more detailed investigations were carried out. HCV RNA was done for anti-HCV positive children. RESULTS Sixty (8.7%) were found to have one or more abnormalities: clinical hepatomegaly in 13 (1.9%), elevated ALT in 27 (3.9%), anti-HCV in 25 (3.6%) and abnormal hepatic ultrasound in 31 (4.5%). Forty percent of anti-HCV positive children were HCV-RNA positive. Glycogenic hepatopathy was diagnosed in three cases by liver biopsy. Abnormalities were reversible in 37/60 after proper glycemic control. CONCLUSION Although diabetic children are at risk of acquisition of HCV, poor glycemic control is the key factor that predisposes to hepatomegaly, elevated ALT and abnormal ultrasound findings. A 4 to 8-wk therapeutic trial of proper glycemic control is recommended prior to more invasive diagnostic procedures.
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Floettmann E, Gregory L, Teague J, Myatt J, Hammond C, Poucher SM, Jones HB. Prolonged Inhibition of Glycogen Phosphorylase in Livers of Zucker Diabetic Fatty Rats Models Human Glycogen Storage Diseases. Toxicol Pathol 2010; 38:393-401. [DOI: 10.1177/0192623310362707] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The preclinical efficacy and safety of GPi921, a glycogen phosphorylase inhibitor, was assessed following twenty-eight days of administration to Zucker Diabetic Fatty (ZDF) rats. The ZDF rat is an animal model of type 2 diabetes mellitus (TTDM) which develops severe hyperglycemia. Inhibition of glycogen phosphorylase throughout the duration of the study was demonstrated by reductions in twenty-four-hour glucose profiles and glycated hemoglobin levels. In addition, progression towards hyperglycemia was halted in treated but not control animals, which developed hyperglycemia over the twenty-eight days of the study. Biochemical and histopathological analysis revealed large increases in hepatic glycogen, which closely paralleled the development of hepatomegaly and ultimately resulted in increases in hepatic lipids. Furthermore, prolonged glycogen phosphorylase inhibition resulted in an increased incidence and severity of other adverse pathological findings in the liver, such as inflammation, fibrosis, hemorrhage, and necrosis. The observed biochemical and histopathological phenotype of the liver closely resembled that seen in severe cases of human glycogen storage diseases (GSD) and hepatic glycogenosis in poorly controlled diabetes mellitus. These findings revealed that although glycogen phosphorylase inhibitors are efficacious agents for the control of hyperglycemia, prolonged treatment might have the potential to cause significant clinical hepatic complications that resemble those seen in GSD and hepatic glycogenosis.
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Affiliation(s)
- Eike Floettmann
- Global Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, United Kingdom
| | - Laraine Gregory
- Cardiovascular & Gastrointestinal Research Department, AstraZeneca, Alderley Park, Macclesfield, United Kingdom
| | - Joanne Teague
- Cardiovascular & Gastrointestinal Research Department, AstraZeneca, Alderley Park, Macclesfield, United Kingdom
| | - John Myatt
- Global Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, United Kingdom
| | - Clare Hammond
- Drug Metabolism and Pharmacokinetics, AstraZeneca, Alderley Park, Macclesfield, United Kingdom
| | - Simon M. Poucher
- Cardiovascular & Gastrointestinal Research Department, AstraZeneca, Alderley Park, Macclesfield, United Kingdom
| | - Huw B. Jones
- Global Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, United Kingdom
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Yamasaki K, Hayashi Y, Okamoto S, Osanai M, Lee GH. Insulin-independent promotion of chemically induced hepatocellular tumor development in genetically diabetic mice. Cancer Sci 2010; 101:65-72. [PMID: 19775285 PMCID: PMC11159896 DOI: 10.1111/j.1349-7006.2009.01345.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Diabetes mellitus has been proposed as an epidemiological risk factor for human liver cancer development. One reasonable possibility is that this is attributable to hyperinsulinemia compensatory for obesity-related insulin resistance. However, diabetes mellitus is a complex disease with multiple abnormal conditions essentially caused by hyperglycemia. Therefore, it is not evident whether hyperinsulinemia is prerequisite for the elevated cancer risk. To gain a clue to answer this question, we characterized chemically induced hepatocarcinogenesis in diabetic model mice genetically deficient for insulin. Akita inbred mice originating from the C57BL/6 strain carry a heterozygous germline mutation of the insulin II gene and suffer from inherited insulin deficiency and diabetes in an autosomal dominant manner. They were mated with normal C3H/HeJ mice with high sensitivity to liver carcinogenesis and the resultant F(1) littermates, which were either normal or insulin deficient, were exposed to diethylnitrosamine and induced hepatocellular tumors were evaluated for number, size, proliferative activity, and apoptosis. Unexpectedly, both mean and total volumes of hepatocellular tumors in the insulin-deficient animals were more than twofold larger than those in the normal controls, with no significant difference in tumor number. The tumors in insulin-deficient mice showed a significantly lower frequency of apoptosis but no alteration in cell proliferation. In conclusion, our results indicate that insulin-independent liver tumor promotion occurred in diabetic mice. Clearly, insulin-independent mechanisms for the human case also deserve consideration.
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Affiliation(s)
- Kohtaro Yamasaki
- Department of Pathology, Kochi University School of Medicine, Nankoku, Kochi, Japan
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Hudacko RM, Sciancalepore JP, Fyfe BS. Diabetic microangiopathy in the liver: an autopsy study of incidence and association with other diabetic complications. Am J Clin Pathol 2009; 132:494-9. [PMID: 19762525 DOI: 10.1309/ajcpqbff42zzxxrq] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Diabetic hepatosclerosis (DH) is a recently described form of diabetic microangiopathy with hepatic sinusoidal fibrosis and basement membrane deposition without cirrhosis. The objective was to investigate the frequency of DH and its correlation with other diabetic microangiopathic complications. Complete autopsies from 57 adults with diabetes were reviewed for liver pathology and other diabetic complications. Basement membrane deposition in the liver was highlighted using laminin and type IV collagen immunostains. Only 1 case of DH was identified. Other diabetic end-organ damage in this case included nodular glomerulosclerosis and hepatic hyaline arteriolosclerosis, which were the most severe in the series. DH is an uncommon pattern of liver disease in patients with diabetes and is associated with severe end-organ damage. This study supports the presumed vascular etiology of DH, confirms the rarity of the lesion, and supports the suggestion that it is usually accompanied by other end-organ damage.
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40
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Current literature in diabetes. Diabetes Metab Res Rev 2009; 25:i-viii. [PMID: 19267326 DOI: 10.1002/dmrr.952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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