Glycogenic hepatopathy

Introduction

Several years after introducing insulin as a treatment modality in type 1 diabetes mellitus(T1DM),Mauriac described patients with uncontrolled T1DM who had short stature,delayed puberty,cushingoid features,hepatomegaly and elevated liver enzymes(Mauriac syndrome)[1].Since Mauriac’s first description,involvement of the liver in diabetes mellitus(DM)has been described in several case reports with different clinical symptoms and signs[2].The common signs are hepatomegaly and elevated liver enzymes due to hepatocellular glycogen accumulation.Terms such as “liver glycogen storage”, “liver glycogenosis”,and lately“glycogenic hepatopathy”have been used to describe this clinical picture.

Glycogenic hepatopathy(GH)is an under-diagnosed condition.The real incidence is unknown,few case reports and case series were published but it is believed that the prevalence is much higher than reported.GH is de fined as pathological overloading of hepatocytes with glycogen,leading to hepatic enlargement and/or derangement of liver enzymes,is usually seen in patients with longstanding,poorly controlled T1DM[3–5].It is now recognized that glycogen accumulation within hepatocytes can be present without all the components described in Mauriac syndrome.Inadequate control of T1DM results in the concomitant presence of exogenous insulin and excess glucose,leading to increased glycogen storage in the liver[3].

The aim of this review is to increase the awareness of this condition,which is under-diagnosed,and on the other hand,to present a diagnostic way which can help reducing the use of unnecessary tests,especially invasive ones.

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Literature review

A PubMed search was done with the words“glycogenic hepatopathy”, “hepatic glycogenosis”, “liver glycogenosis”and “diabetes mellitus-associated glycogen storage hepatopathy”.The search was limited to articles in English,full-text available.We reviewed all the results published before 1 July,2017.Articles in which diabetes mellitus-associated liver glycogen accumulation was described were included in this review.

Results

Forty-seven articles(126 patients)were included in this study.Raw data was available in 46 articles describing 39 males(31.0%)and 87 females(69.0%).Forty-two(33.3%)were younger than 18 years of age and 84 were adults(66.7%).The mean age of all subjects was 23.4 years.All but one of the patients included in the review suffered from insulin-dependent DM,for a mean duration of 10.5 years.

The major problem in diagnosing GH is that histological examination is the only reliable tool with which to distinguish GH from NAFLD[3,5,17,22,35].Abdominal US typically shows hepatomegaly with some degree of fatty changes,although this test can be totally normal.There is no role for noninvasive tests like fibroscan or fibrotest for the diagnosis of GH or for differentiation of this situation from NAFLD.GH may be diagnosed also after elevated liver enzymes in routine blood tests.

Discussion

GH is an under-recognized condition.The disease appears primarily in patients with uncontrolled T1DM.The clinical presentation,laboratory tests,more commonly hepatocellular pattern,and abdominal US do not usually reveal GH.Abdominal CT can provide a clue when considering GH,and dual-echo MRI/CT can provide important information regarding the diagnosis.The disease is benign and no cases of advanced liver disease have been described in association with this condition.It is important to exclude other etiologies of liver diseases.Tight glycemic control can result in rapid improvement and normalization of liver enzymes.

Table 1 Epidemiological,clinical and biochemical data,summarizing the literature regarding patients with GH.

Data were expressed as mean±SD or number(percentage).

Variables Data Male 39(31.0%)Age(yr) 23.4±9.6 Adults(≥18 yr) 84(66.7%)Children(＜18 yr) 42(33.3%)Duration of DM(yr) 10.5±5.2 Insulin dependent 125(99.2%)Hepatomegaly 103(81.7%)Abdominal tenderness 59(46.8%)AST(U/L) 692±1243 ALT(U/L) 465±484 ALP(U/L) 365±360 GGT(U/L) 305±248 Bilirubin(mg/dL) 0.70±0.65 INR 0.99±0.02 Albumin(g/dL) 3.24±1.20 Hemoglobin A1C(%) 11.8±3.0

Table 2 Comparison between adults and children with glycogenic hepatopathy(mean or%).

This table does not contain the data presented by Mukewar et al.,that does not provide raw data.

Variables Adults(n=60) Children(n=30)Male 28.3% 53.3%Age at presentation(yr) 25.1 13.7 Age at diagnosis of DM(yr) 16.1 8.5 Duration of DM(yr) 11.4 5.5 Hepatomegaly 84.7% 89.0%Abdominal tenderness 47.0% 35.0%ALT(U/L) 518 499 AST(U/L) 952 586 ALP(U/L) 359 265 GGT(U/L) 369 177 Bilirubin(mg/dL) 0.82 0.47 INR 1.00 0.98 Albumin(g/dL) 3.16 3.72 Hemoglobin A1C 12.3% 11.3%

Pathophysiology

Fig.1.The pathophysiologic process leading to glycogen accumulation.Two conditions are needed to cause GH:high glucose levels and high insulin levels.High glucose levels diffuse into the hepatocytes,while both glucose and insulin activate phosphorylase which,in turn,activates glucokinase,leading to glycogen formation from glucose through glucose-6-phosphate(G6P).Also,phosphorylase,an enzyme that decomposes glycogen,is deactivated by insulin,which also has a negative feedback on epinephrine and glucagon.GLS:glycogen synthase;GCK:glucokinase.

Good control of DM leads to regression of the hepatomegaly and normalization of liver enzymes,usually during a period of weeks to months.This is mostly achieved by subcutaneous insulin administration[17,35,36].One case report showed that GH appeared only four months after changing the insulin treatment regimen and resolved rapidly after extensive insulin therapy.This case suggests that GH can appear even after a short time of uncontrolled T1DM but,fortunately,can also resolve in a short-time after improving glycemic control[20].In two cases,poorly controlled T1DM patients with frequent episodes of hypoglycemia were diagnosed with GH;the patients underwent pancreatic transplantation for other indications and,in both cases,the GH was resolved[37].

One study on the glycogen phosphorylase gene(PYGL)showed that a defect in the structure of PYGL coding sequence is probably not the reason for glycogen accumulation[18].However,it is clear that fluctuations in blood glucose and insulin levels are essential elements of GH.Although the mechanism of its development is unclear,GH is treated most effectively via intensive glycemic control,and the prognosis is favorable[19].

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Fig.2.Liver biopsy from a patient diagnosed by our group,showing GH.HE staining(A,original magni fication×100;B,original magni fication×400)of liver biopsy demonstrating GH.It can be seen that the architecture is normal with diffuse hepatocellular change characterized by pale hepatocytes with cytoplasmic rarefaction and accentuation of the cell membranes.Few glycogenated nuclei are noted.No in flammation is seen.C:Diastase and PAS staining(original magni fication×400),glycogen disappears after digestion with diastase.D:PAS staining(original magni fication×400),demonstrating abundant cytoplasmic glycogen deposition.

Clinical presentation

Elevated serum aminotransferases in patients with T1DM or T2DM are mostly caused by NAFLD[17].The differentiation between NAFLD and GH is critical,since the treatment and the prognosis are very different.GH cannot be completely distinguished from NAFLD,neither clinically nor by ultrasound(US)or computed tomography(CT),and con firmation may requires a liver biopsy[14].

Laboratory results

Liver enzymes are elevated with combined hepatocellular and cholestatic injury,but the hepatocellular component is often predominant[3,4,16].Bilirubin is usually normal or slightly elevated and synthetic liver function is preserved[4,19,20].

The clinical presentation usually includes abdominal pain,nausea and vomiting,along with abnormalities in liver function tests[20,21].While deranged liver function tests in T2DM are usually due to nonalcoholic fatty liver disease(NAFLD),in T1DM this may also result from GH[22,23].The diagnosis should be suspected when liver enzymes elevation occurs in patients with uncontrolled T1DM,usually with exaggerated hemoglobin A1C levels,especially after viral,autoimmune and metabolic liver diseases are excluded by speci fic laboratory investigations[16].

Imaging studies

Abdominal US typically shows hepatomegaly with some degree of fatty changes[6,24,25],although this test can be totally normal.Thus,abdominal US is not a useful modality with which to distinguish glycogen accumulation from fat deposition[9].CT often shows hepatomegaly.Sweetser and Kraichely[26]reported the usefulness of CT scan for distinguishing GH from NAFLD;liver density on CT in patients with GH is increased as compared to the spleen due to glycogen accumulation,giving the liver a bright appearance,whereas the liver density is decreased in patients with fatty liver.Therefore,these authors claimed that increased liver density in the CT scan would be a clue for the diagnosis of GH.Indeed,Doppman et al.[27]reported a dose-dependent increase and decrease in CT density as the glycogen content increases and as fat content increases,respectively,by studying arti ficial specimens.

In patients with T1DM,dual-echo MRI or CT scan can suggest the diagnosis of GH.The first step is to try to achieve optimal glycemic control,mostly by subcutaneous insulin administration.If liver enzymes are normalized,there is no need for other investigations.If liver enzymes remain elevated or if there is a suspicion of another etiology,a liver biopsy must be done.

Fig.3.Flow chart describing the work-up for evaluating a diabetic patient with mild elevated liver enzymes and with preserved synthetic liver function.

Histopathology

Histologically,GH is characterized by several features:1)marked glycogen accumulation leading to pale,swollen hepatocytes;2)no or mild fatty change;3)no or minimal in flammation;4)no or minimal spotty lobular necrosis;and 5)intact architecture with no signi ficant fibrosis[28].Steatosis may be present,usually mild,or absent.Glycogen accumulation,the hallmark of this condition,is demonstrated by periodic-acid Schiff(PAS)-diastase staining[3,20].On hematoxylin and eosin staining,the histopathologic appearance of clear glycogen is similar to that seen in primary glycogen storage diseases[32,33]and certain drug exposures(e.g.,phenytoin)[34].These etiologies,however,can usually be excluded on the basis of clinical history.Staining with PAS shows abundant cytoplasmic glycogen deposits,which disappear after digestion with diastase[3,20].Fig.2 shows a pathologic accumulation of glycogen in a liver biopsy from a patient diagnosed with GH.

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Treatment

GH results from an excess accumulation of glycogen in the hepatocytes(Fig.1)[12,13].In the hepatocytes,extrahepatic glucose is in equilibrium with intrahepatic glucose,due to the main hepatic glucose transporter GLUT-2[14].High glucose levels lead to passive in flux of glucose into the hepatocytes,independent from insulin levels.In the hepatocyte,glucose is phosphorylated by glucokinase into glucose-6-phosphate,which transforms into glycogen by the enzyme glycogen synthase.Glucokinase is the predominant glucose phosphorylating enzyme in hepatocytes and its activity is modulated by a glucokinase regulatory protein[14].When blood glucose is below 5 mmol/L,there is no signi ficant flux through glucokinase because of its low affinity for glucose.Only when the blood glucose concentration increases above a threshold level does glucokinase start producing glucose-6-phosphate,which binds to liver glycogen synthase,causing allosteric activation[14].Glycogen synthase is activated by phosphatase,an enzyme whose levels depend on the presence of glucose and whose concentration is maintained by insulin.On the other hand,glycogen undergoes glycogenolysis by the enzyme phosphorylase,which is activated by phosphorylase kinase in the presence of epinephrine and glucagon via cAMP.Glucose deactivates phosphorylase kinase.In GH,the concomitant high glucose levels and exogenous insulin lead to over glycogenesis and eventually GH[5,6,12,13,15–17].

Comparison with nonalcoholic steatohepatitis

While nonalcoholic steatohepatitis(NASH)may progress to liver cirrhosis[38],GH has a benign course.After achievement of glycemic control,hepatomegaly regresses and liver enzymes normalization.Fatal complications of GH itself,such as end-stage liver damage,synthetic dysfunction,hepatocellular carcinoma or portal hypertension,have never been reported.However,GH can have a relapsing course[16],and it is important to remember that the underlying condition which leads to GH,uncontrolled DM,may lead to life-threatening conditions,including diabetic ketoacidosis and non-ketotic hyperosmolar state[39],as well as long-term microand macro-vascular complications[40,41].

Diagnosis and management

Standard evaluation of hepatomegaly and liver injury do not provide the diagnosis of GH,as serologic tests are all negative and radiological tests are not pathognomonic[6,9,14].However,these tests can help in excluding other conditions.Dual-echo MRI was proposed as a non-invasive,precise diagnostic test[28],but its sensitivity and speci ficity on diagnosing GH should be compared to tissue biopsy in further research.

We suggest an algorithm for the diagnosis of GH(Fig.3).In patients with elevated liver enzymes and uncontrolled DM,especially those with T1DM,GH must be suspected.First,other etiologies of liver diseases have to be excluded by a thorough history,physical examination,serologic tests for viral,autoimmune and metabolic etiologies,and abdominal US.If the patient has T2DM,after excluding other etiologies,the diagnosis most probably is NAFLD.In these patients the first recommended step is weight loss and physical activity.Liver biopsy is indicated if there is no improvement in liver enzymes.Liver biopsy is also recommended if there is a suspicion of another etiology or advanced disease.

关于RockwoodⅢ型肩锁关节脱位是否需要手术治疗［5-7］目前已无争议。文献报道的手术方法达六十多种，其进展主要由肩锁关节的直接固定转为间接固定。锁骨钩钢板为间接固定的经典代表，近年来Endobutton带袢钢板逐渐被大家所接受，目前，另一种新的带袢钢板已应用于临床，即TightRope。在万方数据库检索国内文献，仅12篇文献报道TightRope治疗肩锁关节脱位，且很少有文献对其临床疗效进行对比研究。因此，本研究比较了TightRope与肩锁钩治疗肩锁关节脱位的临床疗效。

However,low liver density(associated with fatty changes)was also described in GH[28].Moreover,liver density observed on CT may not simply increase as in patients with glycogen storage disease[27,29],because of the glycogen deposition in the liver.Murata et al.[28]showed that a liver CT and/or US were very useful in con firming the diagnosis of GH.In contrast,a gradient dualecho magnetic resonance imaging(MRI)sequence was reported to be able to distinguish fat deposition from an edematous condition,such as in acute tissue injury[30,31],both of which appear as lowdensity areas on CT.They concluded that a gradient dual-echo MRI sequence could be a clue to diagnosing GH by combining it with a thorough clinical evaluation of the liver dysfunction and hepatomegaly,including US and/or CT scan,without an invasive liver biopsy[28].

The most common liver disease associated with DM is NAFLD[38].In contrast to NAFLD and NASH,GH is not associated with obesity;in fact,it is mostly associated with T1DM and a usually normal body mass index.In addition,in contrast to NAFLD and NASH,in which a variable progression to hepatic fibrosis,cirrhosis,and even hepatocellular carcinoma may occur[38],GH has little to no risk for the development of more advanced liver disease[4].Although hepatic glycogenosis typically resolves following a period of sustained euglycemia,hepatic steatosis may persist in spite of careful glycemic control[4,42].However,there is no rule for insulin therapy in treating NAFLD[38].Thus,the diagnosis of hepatic glycogenosis carries important prognostic and therapeutic information,and should be given due consideration in the diabetic patient with hepatomegaly and/or abnormal liver tests[6].

Hepatomegaly was reported in 103(81.7%)patients,while right upper quadrant tenderness was described in 59(46.8%).Combined hepatocellular and cholestatic liver enzyme elevation was described in 93%,even though hepatocellular predominance was described.Mean levels were as follows:aspartate aminotransferase(AST)692 U/L,alanine aminotransferase(ALT)465 U/L,gammaglutamyl transferase(GGT)305 U/L,alkaline phosphatase(ALP)365 U/L.Bilirubin was elevated in 15%of the cases where its level was reported,with a maximum level of 2.5 mg/dL.International normalized ratio(INR)was normal in all cases.Median hemoglobin(Hb)A1C level was 11.8%.Our findings are summarized in Table 1,including demographic information,clinical findings and laboratory tests of all the patients as reported on presentation.A comparison between the adults and the pediatric groups can be seen in Table 2.

Conclusions

GH appears to be under-recognized by clinicians,radiologists and pathologists,even though this entity has been described several times over the years in the medical literature[3,6].It mainly affects children and young adults with uncontrolled DM,especially type 1,with no gender predominance[3,6].GH has also been reported in patients with poorly controlled T2DM treated with insulin[7,8],as well as in a T2DM patient who injected 180 units of insulin glargine in a suicide attempt and was treated with intravenous hypercaloric infusion for three days[8].In addition,GH has been reported in a toddler with dumping syndrome associated with gastrostomy feeding without glucose intolerance[9],and in three children without DM taking high-dose glucocorticoid treatments[10].A recent study described a 15-year-old boy suffering from well controlled T2DM,was also diagnosed with GH[11].

Contributors

ST proposed and designed the study,and revised the final manuscript.KJ performed the literature review and wrote the first draft.ZY wrote the pathology part.SN revised the manuscript.ST is the guarantor.

Funding

None.

Fig.2 shows a schematic of the fiow duct test rig in the Fluid and Acoustic Engineering Laboratory(FAEL)at BUAA.Theflow is provided by a continuous wind tunnel consisting of a centrifugal fan,plenum with metal screens,and silencing ducts.

Ethical approval

Not needed.

刘培峰:在传统工艺保护的实践中有一种倾向,即把保护的责任推给政府,认为政府该出资、出力、出政策保护传统工艺。您认为在传统工艺保护的过程中,政府、企业、社区、艺人、专家等各自应该发挥什么作用?

Competing interest

No bene fits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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