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Original article
Hepatopathy of Mauriac syndrome: a retrospective review from a tertiary liver centre
  1. E Fitzpatrick1,2,
  2. C Cotoi2,
  3. A Quaglia2,
  4. S Sakellariou2,
  5. M E Ford-Adams3,4,
  6. N Hadzic1,2
  1. 1Paediatric Liver, GI and Nutrition Centre, King's College London School of Medicine at King's College Hospital, London, UK
  2. 2Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
  3. 3Department of General Paediatrics, King's College London School of Medicine at King's College Hospital, London, UK
  4. 4Department of Diabetes, King's College London School of Medicine at King's College Hospital, London, UK
  1. Correspondence to Dr Emer Fitzpatrick, Paediatric Liver, GI and Nutrition Centre, King's College London School of Medicine at King's College Hospital, Denmark Hill, London SE5 9PJ, UK; emer.fitzpatrick{at}kcl.ac.uk

Abstract

Background Mauriac syndrome is characterised by growth failure, cushingoid appearance and hepatomegaly which occurs in patients with insulin dependent diabetes and was first described shortly after the introduction of insulin as a treatment for the condition.

Objective To describe the clinical features, histological findings and outcome of young people with glycogenic hepatopathy, the hepatic manifestation of Mauriac syndrome (MS).

Design Retrospective cohort study.

Patients Young people with glycogenic hepatopathy.

Setting Tertiary paediatric hepatology unit.

Results Thirty-one young people (16 M), median age of 15.1 years (IQR 14–16.2) presented within the study period. Median age of diagnosis of diabetes was 10 years (IQR 8–11). Median insulin requirement was 1.33 units/kg/day; median HbA1c was 96.7 mmol/mol (IQR 84.7–112.0). Growth was impaired: median height z-score was −1.01 (−1.73 to 0.4) and median body mass index (BMI) z-score was 0.28 (−0.12 to 0.67). Hepatomegaly was universal with splenomegaly in 16%. Transaminases were abnormal with a median aspartate aminotransferase (AST) of 76 IU/L and gamma glutamyltransferase of 71 IU/L. Liver biopsy was undertaken in 19 (61%). All showed enlarged hepatocytes with clear cytoplasm with glycogenated nuclei in 17. Steatosis was present in the majority. Inflammation was present in 8 (42%). Fibrosis was seen in 14 (73%) and was generally mild though 2 had bridging fibrosis. Megamitochondria were described in 7. Presence of megamitochondria correlated with AST elevation (p=0.026) and fibrosis on biopsy (p=0.007). At follow-up 17 children had normal or improved transaminases, in 13 there was no change. Transaminases followed the trend of the child's HbA1c.

Conclusions Despite modern insulin regimens and monitoring in children with type 1 diabetes, MS still exists. Significant steatosis, inflammation and fibrosis were all seen in liver biopsies.

  • Hepatology
  • Metabolic
  • Diabetes

https://doi.org/10.1136/archdischild-2013-304426

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    What is already known

    • Mauriac syndrome may occur in patients with poorly controlled insulin-dependent diabetes but the underlying pathophysiology is not fully understood.

    • Typical appearances on liver biopsy are of glycogen accumulation.

    What this study adds

    • Despite modern insulin regimens and monitoring, Mauriac syndrome still exists.

    • In addition to glycogen accumulation, macrovescicular and microvescicular steatosis may be evident on liver biopsy.

    • Liver inflammation and fibrosis may often be present on biopsy.

    Introduction

    The classical description of Mauriac syndrome (MS) includes growth failure, delayed puberty, hepatomegaly and cushingoid features in children with poorly controlled type 1 diabetes mellitus.1 The term glycogenic hepatopathy was coined by Torbenson et al2 in a review of liver histopathology in 14 cases of adults and children with the condition. Children typically present with abdominal pain, possibly mediated by distension of the liver capsule by what is often massive hepatomegaly. Case reports and small case series have been reported,3–10 but as yet the pathophysiology of MS remains incompletely understood. The accumulation of glucose as glycogen in the hepatocyte is in part caused by prolonged periods of hyperglycaemia where glucose passes into the hepatocyte independent of insulin,11 followed by periods of insulin treatment which mediates the conversion of the entrapped glucose to glycogen.12 Why some patients with poorly controlled diabetes develop the condition and others do not is as yet unknown.

    In view of the significant number of children diagnosed with the condition in our unit, we undertook a review of our experience over the last decade.

    Patients and methods

    The Paediatric Liver, GI and Nutrition Centre at King's College Hospital in London is one of the three supraregional paediatric liver centres in the UK. Using a departmental database, 31 children (16 boys) with the condition were identified over a period of 10 years (2003–2012). All children underwent a workup for chronic liver disease including autoimmune screen and evaluation for Wilson disease with a urinary penicillamine challenge. As autoimmune hepatitis can be associated with type 1 diabetes, liver biopsy was undertaken when this or an alternate diagnosis to MS was suspected (19 children). This was particularly in children with significantly abnormal transaminases (>twice the upper limit of normal), autoantibody positivity or splenomegaly. Biopsy was undertaken percutaneously using the Menghini technique. Tissue was fixed in formalin and then processed in paraffin as routine. Sections were stained with haematoxylin and eosin (H&E), reticulin, Perls and orcein. In five children, a small part of the sample was fixed in glutaraldehyde and resin embedded for electron microscopy. Clinical, biochemical, radiological and histological data were analysed. The liver biopsies were reviewed by three histopathologists (CC, SS and AQ). Fibrosis was assessed as follows: no fibrosis, portal fibrosis, periportal fibrosis, bridging fibrosis and cirrhotic transformation. Reticulin staining was used to evaluate fibrosis. Statistical analysis was undertaken using SPSS V.19.0, (IBM, Stanford, California, USA) and included medians and IQR or means and SDs where appropriate. The Student t test or χ2 test were used to compare groups. p values <0.05 were considered significant. As this was an audit of practice, it was registered as such and formal ethical committee approval was not necessary.

    Results

    The median age at diagnosis of glycogenic hepatopathy was 15.1 years (IQR 14–16.2). Children with type 1 diabetes were referred with hepatomegaly, raised transaminases or both. In 12 children who had originally presented with abdominal pain, hepatomegaly was detected in 8 and the remainder were found to have abnormal liver function tests (LFTs) on investigation. In the remaining 19 children, hepatomegaly10 or raised transaminases9 were found incidentally either at annual diabetes review or during an admission with diabetic ketoacidosis. All were referred by the paediatrician who managed their diabetes. Median age at diagnosis of diabetes was 10 years of age (IQR 8–11). All children were insulin dependent: the majority (84%) were on standard multiple dose injection (MDI) regimen using the long-acting analogues Insulin Detemir (NovoNordisk) or Glargine (Sanofi-Aventis) with rapid-acting analogues Novorapid or Lispro. Two children were on short-acting insulin only with another two on the human isophane insulin (Insulatard). One child had recently been commenced on an insulin pump. The reported median units of insulin per kilogram used per day was 1.33 (1.05–1.61). The median glycosylated haemoglobin (HbA1c) at presentation to our unit was 96.7 mmol/mol (IQR 84.7–112.0) (aim for good glycaemic control <58.5 mmol/mol).

    Children were shorter and lighter than UK reference data with a median height z-score of −1.01 (IQR −1.73 to 0.4), a median weight z-score of −0.11 (−0.8 to 0.17) and a median body mass index (BMI) z-score of 0.28 (−0.12 to 0.67). Hepatomegaly was present in all, a soft liver palpable at an average of 4 cm (range 1–12 cm) below the costal margin. Abdominal ultrasound revealed an echogenic liver in all with 5 of 31 children having splenomegaly. LFTs are reported in table 1. No child had synthetic liver dysfunction. Serum lipids were abnormal in 24/31 (77%); 16 children had an elevated lactate (no child was ketoacidotic or clinically unwell when the blood sample was taken).

    View this table:
    Table 1

    Clinical and biochemical features of children with Mauriac syndrome

    A liver biopsy was undertaken in 19 of the 31 children. Diffusely enlarged hepatocytes with a clear cytoplasm were noted in all cases and glycogenated nuclei were also present in 17 out of 19 biopsies (89%). Microscopic examination also revealed different degrees of steatosis, ranging from none to marked. This was mostly in the form of a single large cytoplasmic droplet pushing the nucleus peripherally. Eight biopsies (42.1%) had non-specific inflammation, and mostly mild fibrosis was present in 14 biopsies (73.7%), ranging from portal to early bridging in 2 cases (6%). Cytoplasmic eosinophilic bodies regarded as megamitochondria were described in seven biopsies (22.5%) (figure 1) on light microscopy. Figure 2 demonstrates enlarged mitochondria on EM in one biopsy. EM also confirmed the findings of light microscopy examination in regard to glycogen accumulation and did not demonstrate any alteration in other cellular organelles apart from mitochondria. The presence of fibrosis correlated to elevations in aspartate aminotransferase (AST) (p=0.022), and gamma glutamyltransferase (GGT) (p=0.007) but not to serum levels of alanine aminotransferase (ALT), cholesterol, lactate, HbA1c, age or daily intake of insulin. Fibrosis was also related to the presence of megamitochondria (p=0.007) and to inflammation in the biopsy (p=0.004), but not to splenomegaly or the presence of fat on biopsy. The presence of megamitochondria was also related to higher AST values (p=0.026) and higher GGT values (p=0.014).

    Figure 1
    Figure 1

    Percutaneous liver biopsy section of child with Mauriac syndrome. Section is stained with H&E showing glycogen accumulation (arrow), glycogenated nuclei (open arrow) and megamitochondria (closed arrow).

    Figure 2
    Figure 2

    Electron microscopy from liver biopsy of a child with Mauriac syndrome demonstrating megamitochondria (white star), glycogen accumulation (white arrow) and steatosis (black arrow).

    As lactate was notably high in one 14-year-old boy (9 mmol/L, HbA1C of 96.7 mmol/mol), liver tissue was sent for additional mitochondrial studies and mitochondrial DNA depletion of 29% was demonstrated (depletion defined as residual mtDNA copies <30% age matched controls),13 though mutational analysis for c.1399G>A, c.1760C.T, c.2243G>C, c.2542G>A and c.2740A>C in the POLG gene was negative as were pathogenic variants in the PEO1 gene. Mean time to follow-up was 18 months (range 1 month to 8.5 years). Most children had undergone some modification in insulin regimen though this was inconsistent. The two children who were on isophane insulin and two that were on short acting only were converted to standard MDI with long-acting and short-acting analogues. Five children were converted to an insulin pump. At last follow-up 17 children had normalised their biochemical markers (AST, ALT, GGT) with the liver reducing to normal size. There was no biochemical difference in 13, while in one child deterioration was noted. LFTs followed the trend of the child's HbA1c in all children. HbA1c decreased by a median of −17.5 mmol/mol in those who had improved, while it decreased by −6.6 mmol/mol in those who made no progress. There was no correlation with outcome (biochemistry/resolution of hepatomegaly) and presence of fibrosis, inflammation, megamitochondria or those with a high serum lactate or initial HbA1c.

    Discussion

    With the introduction of intensive insulin regimens and increased availability of routine near patient maintenance of glucose control, we would have thought the classical description by Pierre Mauriac of this complication of diabetes, shortly after the introduction of insulin in 1922,1 would be only be of historical interest. However, over the last decade we have seen an increasing number of children with the condition which prompted us to review our experience. There are almost 23 000 children and young people with diabetes in England (Diabetes UK National Audit 2012).

    Unfortunately despite modern insulin regimens, poor control mainly associated with poor compliance is common and recent audit data show a persistent percentage of patients with HbA1C >79.2 mmol/mol indicative of poor control.

    Histological features of the hepatopathy secondary to MS are, not surprisingly, similar to glycogen storage disease (GSD). The pathophysiological assumption in MS is that prolonged periods of hyperglycaemia cause glucose accumulation. The administration of insulin then results in glucose conversion to glycogen in the hepatocytes. In this series we have also observed considerable steatosis in 8 of 19 children which makes distinction between non-alcoholic fatty liver disease (NAFLD) and MS more difficult. In MS and NAFLD, there is significant dyslipidemia with similar liver appearance on ultrasonography.14 However, the majority of children with NAFLD have a BMI in the overweight/obese range,15 whereas children in this MS series were relatively thin with a median BMI z-score of 0.28. Fibrosis is not typically described in glycogenic hepatopathy. In this series we have observed mostly mild fibrosis in the majority of the biopsied children, with splenomegaly in five children which otherwise remains unexplained.16 This new finding is potentially significant for the long-term prognosis of children with MS because if the mechanisms of fibrogenesis are shared with NAFLD, by analogy this could lead to significant liver disease in adulthood if poor glycaemic control is not reversed and the process continues.17 Longer-term evaluation of outcome in children with MS is needed.

    Megamitochondria are described in glycogenic hepatopathy but not in GSD. There are reports of megamitochondria in NAFLD, primary mitochondrial cytopathies and alcoholic liver disease.3 ,18 ,19 The formation of megamitochondria may be secondary to mitochondrial swelling or to membrane fusion of adjacent mitochondria as they try to decrease intracellular reactive oxygenation species by decreasing consumption of oxygen.20 ,21 If the process is overwhelmed, and there is continuous exposure to free radicals, apoptosis is induced.20 ,22 We found that there was correlation between the severity of liver disease (fibrosis/transaminases levels) and the presence of megamitochondria (found in 7/19 biopsies) similar to in NAFLD.23

    Our study reports a dramatic elevation of lactate in half of the patients, even when clinically very well. Hyperlactatemia may be expected during ketoacidosis, however lactate should be normal in a well patient. In addition, the presence of megamitochondria strongly suggests that the chronic poor glycaemic control may have significantly affected the hepatocytes at a microanatomical and a functional level. One boy in the series was found to have evidence of mitochondrial DNA depletion in liver biopsy but it is not clear if this could simply be a consequence of poor control of diabetes in MS. Alternatively, an underlying undiagnosed state of primary mitochondrial DNA depletion could predispose diabetic children to glycogenic hepatopathy. Mutations of POLG can cause a number of overlapping syndromes and have emerged as one of the most common causes of inherited mitochondrial disease in children and adults. In particular the phenotypes of Alpert disease and myocerebrohepatopathy spectrum disorders encompass liver disease. In one child with mtDNA depletion on liver biopsy, POLG sequencing was felt appropriate, however we could not document the standard POLG mutations in this neurologically normal child. It may be interesting to prospectively investigate children with MS who have very elevated serum lactate and possible clinical features of primary mitochondrial cytopathies, given an increasing application of mitochondrial mutational studies in clinical hepatology.24

    The reason for the improved glycaemic control by the patients was not clear but we speculate that this was a result of further intensive counselling by their diabetes team and perhaps the realisation by the patient that they had significant end-organ damage from poorly controlled disease. Of note five children moved from injected insulin to insulin pump; however, numbers are too small to determine whether this made a significant difference to glycaemic control.

    In this series we have focused on the hepatic aspects of MS. Other complications of this syndrome have been previously well documented.8 ,25 ,26 Improved outcome, assessed by resolution of hepatomegaly and normalisation of liver function tests, was related to improvement in control of diabetes, measured by HbA1c. This simple message is logical and not surprising, but its implementation is not easy as it requires complex measures to improve overall management of children with diabetes mellitus. Early consideration for intensive insulin therapy including insulin pumps appears justified in children with MS.

    References

    1. ↵
      1. Mauriac P
      . Gros ventre, hepatomegalie, troubles de las croissance chez les enfants diabetiques traits depuis plusieurs annes parl'insuline. Gax Hebd Med Bordeaux 1930;26:402–10.
      OpenUrl
    2. ↵
      1. Torbenson M,
      2. Chen YY,
      3. Brunt E,
      4. et al
      . Glycogenic hepatopathy: an underrecognized hepatic complication of diabetes mellitus. Am J Surg Pathol 2006;30:508–13.
      OpenUrlCrossRefPubMedWeb of Science
    3. ↵
      1. Barbaro G,
      2. Di Lorenzo G,
      3. Belloni G,
      4. et al
      . Hepatic iron storage and megamitochondria formation in patients with chronic hepatitis C related to the hepatitis C virus genotype. Dig Liver Dis 2001;33:81–3.
      OpenUrlCrossRefPubMed
    4. ↵
      1. Bassett JT,
      2. Veerappan GR,
      3. Lee DH
      . Glycogenic hepatopathy: a rare cause of increased aminotransferase levels in a diabetic patient. Clin Gastroenterol Hepatol 2008;6:A26.
      OpenUrlPubMed
    5. ↵
      1. Dantuluri S,
      2. Karthik V,
      3. Stahlschmidt J,
      4. et al
      . Glycogenic hepatopathy. J Pediatr Gastroenterol Nutr 2012;54:307.
      OpenUrlCrossRefPubMed
    6. ↵
      1. Elder CJ,
      2. Natarajan A
      . Mauriac syndrome—a modern reality. J Pediatr Endocrinol Metab 2010;23:311–13.
      OpenUrlPubMed
    7. ↵
      1. Franzese A,
      2. Iorio R,
      3. Buono P,
      4. et al
      . Mauriac syndrome still exists. Diabetes Res Clin Pract 2001;54:219–21.
      OpenUrlCrossRefPubMed
    8. ↵
      1. Kim MS,
      2. Quintos JB
      . Mauriac syndrome: growth failure and type 1 diabetes mellitus. Pediatr Endocrinol Rev 2008;5(Suppl 4):989–93.
      OpenUrlPubMed
    9. ↵
      1. Lin YC,
      2. Kao CH
      . Glycogenic hepatopathy in type 1 diabetes mellitus. Liver Int 2012;32:1294.
      OpenUrlCrossRefPubMed
    10. ↵
      1. Mahesh S,
      2. Karp RJ,
      3. Castells S,
      4. et al
      . Mauriac syndrome in a 3-year-old boy. Endocr Pract 2007;13:63–6.
      OpenUrlCrossRefPubMed
    11. ↵
      1. Chatila R,
      2. West AB
      . Hepatomegaly and abnormal liver tests due to glycogenosis in adults with diabetes. Medicine 1996;75:327–33.
      OpenUrlCrossRefPubMed
    12. ↵
      1. Ferrer JC,
      2. Favre C,
      3. Gomis RR,
      4. et al
      . Control of glycogen deposition. FEBS Lett 2003;546:127–32.
      OpenUrlCrossRefPubMedWeb of Science
    13. ↵
      1. Rahman S,
      2. Poulton J
      . Diagnosis of mitochondrial DNA depletion syndromes. Arc Dis Child 2009;94:3–5.
      OpenUrlFREE Full Text
    14. ↵
      1. Schwimmer JB,
      2. Deutsch R,
      3. Rauch JB,
      4. et al
      . Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease. J Pediatr 2003;143:500–5.
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      1. Schwimmer JB,
      2. Deutsch R,
      3. Kahen T,
      4. et al
      . Prevalence of fatty liver in children and adolescents. Pediatrics 2006;118:1388–93.
      OpenUrlAbstract/FREE Full Text
    16. ↵
      1. Pohl JF
      . Mauriac syndrome in a child with a positive antinuclear antibody screen. Gastroenterol Res Pract 2009;2009:765318.
      OpenUrlPubMed
    17. ↵
      1. Feldstein AE,
      2. Charatcharoenwitthaya P,
      3. Treeprasertsuk S,
      4. et al
      . The natural history of nonalcoholic fatty liver disease in children: a follow-up study for up to 20-years. Gut 2009;58:1538–44.
      OpenUrlAbstract/FREE Full Text
    18. ↵
      1. Tandra S,
      2. Yeh MM,
      3. Brunt EM,
      4. et al
      . Presence and significance of microvesicular steatosis in nonalcoholic fatty liver disease. J Hepatol 2011;55:654–9.
      OpenUrlCrossRefPubMed
    19. ↵
      1. French SW
      . Intragastric ethanol infusion model for cellular and molecular studies of alcoholic liver disease. J Biomed Sci 2001;8:20–7.
      OpenUrlCrossRefPubMed
    20. ↵
      1. Wakabayashi T
      . Megamitochondria formation—physiology and pathology. J Cell Mol Med 2002;6:497–538.
      OpenUrlCrossRefPubMedWeb of Science
    21. ↵
      1. Le TH,
      2. Caldwell SH,
      3. Redick JA,
      4. et al
      . The zonal distribution of megamitochondria with crystalline inclusions in nonalcoholic steatohepatitis. Hepatology 2004;39:1423–9.
      OpenUrlCrossRefPubMedWeb of Science
    22. ↵
      1. Teranishi M,
      2. Spodonik JH,
      3. Karbowski M,
      4. et al
      . Swelling of free-radical-induced megamitochondria causes apoptosis. Exp Mol Pathol 2000;68:104–23.
      OpenUrlCrossRefPubMedWeb of Science
    23. ↵
      1. Sanyal AJ,
      2. Campbell-Sargent C,
      3. Mirshahi F,
      4. et al
      . Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001;120:1183–92.
      OpenUrlCrossRefPubMedWeb of Science
    24. ↵
      1. Poulton J,
      2. Hirano M,
      3. Spinazzola A,
      4. et al
      . Collated mutations in mitochondrial DNA (mtDNA) depletion syndrome (excluding the mitochondrial gamma polymerase, POLG1). Biochimica et biophysica acta 2009;1792:1109–12.
      OpenUrlPubMed
    25. ↵
      1. Mauras N,
      2. Merimee T,
      3. Rogol AD
      . Function of the growth hormone-insulin-like growth factor I axis in the profoundly growth-retarded diabetic child: evidence for defective target organ responsiveness in the Mauriac syndrome. Metabolism 1991;40:1106–11.
      OpenUrlCrossRefPubMed
    26. ↵
      1. Avula H
      . Periodontal findings in a patient with Mauriac syndrome: a case report. Spec Care Dentist 2012;32:66–9.
      OpenUrlCrossRefPubMed

    Footnotes

    • Contributors EF designed the study, collected the data and co-wrote the manuscript, CC, SS and AQ reviewed the histology and contributed to the manuscript, MEF-A reviewed and contributed to the manuscript, NH developed the idea for the study and cowrote the manuscript.

    • Competing interests None.

    • Provenance and peer review Not commissioned; externally peer reviewed.