Diabetic Hepatopathy a Syndrome in Evolution

7/22/2019 Diabetic Hepatopathy a Syndrome in Evolution

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Diabetic Hepatopathy :A Syndrome lnEvolutionSidhartha Das, Bijay Misra, Debmalya Bhattacharyy3

Abstract:The prevalence of Diabetes Mellitus (DM) has shown an alarming rise in lndia over the past few decades.Liver plays a key role in the glucose homeostasis as insulin released to the portal circulation is first utilisedby the liver for various metabolic functions. lnsulin modulates the expression genes regulating various'enzymes involved in the carbohydrate cycles in Hepatocytes. lnsulin resistance, sensiiivity as well asexcess extraction of insulin by liver holds the key to hepatic glucose output and subsequent non-suppressible hyperglycemia. Similarly, the lipid metabolism and hepatic:gteatosis is largely influencedby insulin resistance. Spectrum of liver diseases in patients with DM vary from abnormailiver enzymes,nonalcoholic fatty liver disease (NAFLD), cirrhosis, hepatocellular carcinoma to acute liver cell failure.Cirrhosis is an insulin-resistant state and'two third of them will develop DM (hepatogenous diabetes).The prevalence of hepatitis C virus (HCV) is higher in patients with diabetes thin in the general poputation.Though fatty liver is a common finding in DM, few cases progress to NASH,NAFLD-related cirrhosis orprimary liver cancer. Understanding diabetic-hepatopathy L therefore very vital in the current daycontext of appreciating both pathogenesis and complications in subjects with DM.lntroduction:Diabetes Mellitus(DM), by most estimates, is now the most common cause of liver disease in the U.S.Cryptogenic cirrhosis of which DM is, by far the most common cause, has become the third leadingindication for liver transplantation in the U.S. 1,2 The prevalence of DM has shoWn an alarming rise inlndia overthe past few decades. While ICMR reported a prevalence of 2.3loin t97Z,the currentprevalence of DM and impaired glucose tolerance (lGT) in lndia is about 12.2% in adult population.3 Thespectrum of liver disease in patients with Type 2 diabetes includes abnormal liver enzymes, nonalcoholicfatty liver disease (NAFLD), cirrhosis, hepatocellular carcinoma, and acute liver failure.4 There is anunexplained association of diabetes with hepatitis.s Finally, the prevalence of DM in cirrhosis is 15-30% 6.Thus, patients with DM have a high prevalence of liver disease and patients with liver disease have ahigh prevalence of DM. This review deals with(A) Normal glucose homeostasis(B) The role of liver in glucose metabolism(C) The metabolic alteration in liver due to DM(D) Structural alteration of liver in DM(E) Spectrum of liver disease in DM(F) DM in advanced liver disease (Hepatogenic Diabetes).(A) NormalGlucose Homeostasis :Glucose, a fundamental source of cellular energy, is released by the breakdown of endogenous glycogen


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stores that are primarily located in the liver. ln the fasted state approximately 85% of endogenous glucoseproduction is derived from the liver, with glycogenolysis (conversion of glycogen to glucose) andgluconeogenesis (glucose formation) contributing equally to the basal rate of hepatic glucose production.ihe remainin g-15% of glucose is produced by the kidneys.T After a meal or fed state, 30% of the ingestedglucose is taken up by the liver and 70% is released into the systemic circulation. Of this 7O%,2O% isIgain extracted by the liver,ZOYo is taken up by the brain, 40% is taken up by skeletal muscle, and theremaining 20% is taken up by kidney, adipose tissue, skin, and RBC (Figure-1)'Fig-1: Utilization of Glucose after lngestion by Different Organs.

The pancreas has a remarkable capacity to adapt to conditions of increased insulin demand (eg, inobesity, pregnancy, cortisol excess and critical illness) to maintain normoglycemia. Das S et al studiedthe response of B cell in acute stress (MODS). lnitially, there occurs hyperfunctioning of beta cell leadingto hyperinsulinemia maintaining glucose homeostasis, later if the stress persisted, B cell failure ensues 8.However, when B-cell secretion of insulin becomes inadequate for the glucose load, hyperglycemia setsin. Progressive deterioration in B-cell function and mass is well known to occur in Type 2 DM and theresultant state of impaired insulin secretion is found uniformly in Type 2 DM patients of all ethnicorigin.g,1o the major factors implicated in progressive loss of B-cell function and mass include glucotoxicity,lipotoxicity, proinflammatory cytokines, kiptin, and islet cell amyloid.(B) Role of tiver in glucose metabolism:The role of liver is to take up glucose'after carbohydrate consumption and produce glycogen. Portalblood reaches the liver before the per:ipheral tissues, so the liver gets more glucose in the absorptivephase after a meal. Glucose is freely permeable into hepatocytes and do not need the action of insulinfor its entry. The subsequent metabolism of glucose inside hepatocytes depends upon number ofenzymes whose expression are regulated by genes in nucleus and insulin plays an important role inpriming these genes. As blood glucose rises in the absorptive phase, glucose transporter 2 (GLUT 2) andthe enzyme glucokinase (GK; also called hexokinase lV) are both expressed in liver. The function ofglucokinase in the liver is to remove glucose from the blood following a meal to provide glucose 6-phosphate in excess of requirements for glycolysis, which is used for glycogen synthesis and lipogenesis

Systemic cireulation : 70% of ingested glucose is releasedinto the systemic circulation. Of this 70%. 20% is extracted by the livero 2O%o is taken up bythe braino 4o%isnta(en up by skeletal muscleo 20% is taken up by the kidney, adipose tissue, skin,and re.d blood cells.

Liver : 30% of ingestedglucose is taken up bythe liver

(Adapted from Gerich JE. Diabetes Obes Metab. 20OO;2:345-350)


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:,[-*"Glucokinase i

Glucose +-ATIr glucose-6-P + ADPGlucokinase (GK) is localized in the nucleus of liver cells at low glucose concentration but translocatesto the cytosol at higher glucose concentration. ln the presence of GK regulatory protein (GKRp), whichstays localized in the nucleus, translocation to the cytosol does not occur at the higher glucoseconcentration. The next reaction in glycolysis is reversible, so G-6-P equilibrates with fructose-6-P.Phosphoglucose isomeraseGlucose-6-P fructose-6-PFructose-6-P promotes the inhibitory effect of GKRP, but fructose-L-P counteracts the effects of fructose-6-P on GKRP (prevents binding of GKRP to GK). Fructokinase produces fructose-1-pfructokinaseFructose + ATP fructose-l-P + ADP

Since the liver is important in regulation of glucose traffic through the body, it can take up fructose (fromhoney, soda sweeteners, sucrose, etc.), metabolize it to glucose by gtuconeogenesis. Low fructoseconsumption can pull more glucose into liver. lt leads to production of fructose-L-P by fructokinaseresulting more glucose-6-P release by glucokinase inducing glycogen synthesis and lipogenesis . ln orderto study the glucose handling by the liver at basal state with special reference to glucokinase.Das S et al had estimated the FBG and serum glucokinase levels iQ patients with different subtypes ofType 2 DM. The low body weieht (LB)Type 2 diabetics had highest FBG and highest circulating glucokinasesuggesting excess futile cycles of carbohydrate metabolism in liver due to interconversion of Glucoseto Glucose 6 phosphate and again back to glucose causing excess rise of hepatic glucose output. 11(Table-1)(C) Metabolic alteration in liver due to DM:DM per se may generate liver disease of metabolic origin in association with obesity, dyslipidemia andhypertension. Non alcoholic fatty liver disease (NAFLD) is now considered as the hepatic manifestationof the metabolic syndrome, and is present in approximately 80% of Type 2 DM. The liver helps to maintainnormal blood glucose concentration in the fasted and postprandial states. lnsulin through paracrineeffect inhibit the production of glucagon from crcell and also inhibit lipolysis in adipocytes and consequentFFA release.(Figure-2)Loss of insulin effect on the liver leads to glycogenolysis and an increase in hepatic glucose production.Ab4ormalities of triglyceride storage and lipolysis in insulin-sensitive tissues such as the liver, are anearly manifestation of insulin resistance (lR) and are detectable earlier than fasting hyperglycemia. Theprecise genetic, environmental, and metabolic factors and sequence of events that lead to the underlyinginsulin resistance, however, is not fully understood.l2 The excess of free fatty acids (FFA) found in theinsulin-resistant state bears a direct toxic effect on hepatocytes, causing mitochondrial dysfunction,Table-l. Mean SD of FBG and plasma tevels of Gtucokinase in controls and Type 2 Diabetic patients.(Ref-l1)

Type 2 DM FBG(Me/dl) Glucokinase(lUlL)Low -body weight 181.11 105.7 40.461 9.65Standard weight 110.0 t 34.78 33.55t 8.65Obese 122.0r 38.0 36.13r 6.20Healthy control 82.8r 10.3 36.3315.92


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ric-2: Mechanism of insulin inhibition of glucose produution by liver

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t$*mn*+ffiifficsft*ketone bodies formation, and activation and inhibition of key steps in the regulation of metabolism.l3The peripheral resistance to insulin is responsible for increased lipolysis and can augment the deliveryof FFA to the liver. Massive FFA hepatic upload leads to PPAR-cr-mediated activation of the enzymesresponsible for oxidation, thereby increasing peroxide levels. The oxidant stress from reactive lipidperoxidation, peroxisomal beta-oxidation, and recruited inflammatory cells are the cause of elevatedtransaminases.It is also hypothesized that, elevation in alanine transaminase (ALT), a gluconeogenic enzyme whosegene transcription is suppressed by insulin, could indicate an impairment in insulin signaling rather thanpurely hepatocyte injury. 1aThe subsequent formation of free oxygen radicals might induce the release of proinflammatory cytokinessuch as tumor necrosis factor-u (TNF-cr).TNF- cr acts by:(i) Downregulating the insulin-induced phosphorylation of insulin receptor substrate-1(lRS-1) andreducing expression of GLUT-4 in the target cells,(ii) lnducing resistance to insulin, thus producing increased levels of FFA,(iii) Leading to mitochondrial iesions and'inducing hepatocyte apoptosis and necrosis.15


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The final result could be a progression to more severe liver damage and a higher risk of developrnqnlof liver cancer.(D) Structural alteration of tiver in DM:Glycogen deposition:During periods of hyperglycemia glucose freely enters the hepatocytes driving glycogen synthesis, whichis augmented further by administration of insulin to supraphysiologic levels. The accumulation ofexcessive amounts of glycogen in the hepatocytes is a function of intermittent episodes of hyperglycemiaand hypoglycemia and the use of excessive insulin. Hepatic glycogenosis occurs in 80% of patients w1hpoorly controlled Type 1 or Type 2 DM Patients showing solely excessive glycogen deposition may exhibithepatomegaly and liver enzyme abnormalities and rnay have abdominal pain and even nausea andvomiting and rarely ascites. All these abnormalities may improve with sustained glucose control.16Fattyliver (Steatohepatitis) :Non-alcoholic fatty liver disease (NAFLD) is a common clinical condition which is fast assuming importanceas a possible precursor of more serious liver disorders, including cirrhosis of the liver and hepatocellularcarcinoma. The incidence in general population is (24.5%lL7 .ln one study from south lndia showed theprevalence of NAFLD in diabetic patient is54.5% compared to those with prediabetes (lGT/lFG), isolatedIGT(32.4%),isolated IFG (27.3%) and normalglucose tolerance (22.5%1.18 Hepatic fat accumulation isa well-recognized complication of DM with a reported frequency of 4O-70%.Type 1 DM is not associatedwith fat accumulation if glycemia is well controlled, but Type 2 diabetes may Have a 70% correJationregardless of blood glucose control. Fat stored in the liver in form of triglyceride. The steatosls may bemicrovesicular or macrovesicular and may progress to fibrosis and cirrhosis. 16 lmaging studies, althoughuseful in determining the presence and amount of fatty infiltration of the liverycannot be used todetermine accurately the severity of liver damage.A liver biopsy is obviously the best method for detecting hepatic fat accumulation. Biopsy probablyshould be performed when the diagnosis is unclear, and in all cases to confirm the diagnosis and assessthe degree of fibrosis.Nonalcoholic steatohepatitas (NASH) is an advanced stage of fatty liver in which fat in the hepatocytesis accompanied by lobular inflammation and steatonecrosis. Study by Das S et al 2011 showed thatdiabetics had higher lR and higher levels of lipids as compared to nondiabetics (Table-2) and subjectswith Type 2 DM, mild, moderate and severe NASH were present in 179 (36.84%1, 5lL9 (26.3t%l andItg (36.84%) patients while fibrosis was present in t2179 163.75%l patients.l9 The morphologicalpattern of diabetic steatohepat[tis resembles that seen in alcoholic hepatitis. Howevet the histopathologicalchanges in diabetes tend to be periportal (situated in zone l), while those in alcoholic hepatitis arepredominantly pericentral (in zone lll).(E) Spectrum of liver disease in diabetesCirrhosis:Diabetic patient may have only fatty liver (NAFL) or associateid inflammation (NASH), fibrosis and finallymay progress to cirrhosis and hepatocelluar carcinoma. There is an increased incidence of.cirrhosis indiabetic patients, and, conversely, at least 80% of patients with cirrhosis have glucose intolerance, frankdiabetes is present in 30-60% zo Obesity is a significant confounding variable in determining the prevalenceof cirrhosis in diabetes. Even with normal glucose tolerance, obesity can cause steatohepatitis andcirrhosis.Hepatocellular carcinoma :Diabetes mellitus is associated with more advanced lesion and poor outcome in patients with HCC.21


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?9"? :Table-2: Comparision of lR and lipid profile of patients with and without Diabetes Mellitus.(Ref-19)

** Significant valuesIt is not known whether the increased prevalence of HCC is unique to diabetes or the increased prevalenceof cirhosis, the precursor lesion of HCC. The pathogenic sequence of events leading to HCC appearsto be lR, increased lipolysis, lipid accumulation in the;hepatocytes, oxidative stress, and cell damagefollowed by fibrosis and cell proliferation, which are procarcinoge nig.22,23'Biliary Disease, Cholelithiasis, Cholecystitis:There is increased incidence of cholelithiasis in subjects with'DM.Gallbladder emptying abnormalitiesfound in diabetic patients may predispose patients to cholelithiasis 24 Obesity and hyperlipidemia maybe confounding variables. Secretion of lithogenic bile by the llver probably predisposes them to forminggallstones, but this is likely a result of concomitant obesity rather than a result of the diabetes itself 2sProphylactic cholecystectomy cannot routinely be recommended for asymptomatic gallstones in patientiwith DM,:26 as relative risk of mortality following acute cholecystitis is not significantly greater in diabeticpatients than in the general population Patients with diabetes have comparable survival outcomes fromlaparoscopic or open cholecystectomy. 27Acute liver failure:The incidence of acute liver failure appears to be increased in patients with DM, 2.31 per 10,000 person-years as compared with 1.44 in the background population.28 lt remains unclear whether it is DM,medications, or some other factor that accounts for the increased risk of acute liver failure.Complications of Diabetic therapy:lnsulin therapy may increase patients risk of acquiring viral hepatitis because of the exposure to needles.There is a rare association between the use of oral hypoglycemics and hepatic injury but sulfonylureascan cause chronic hepatitis with necroinflammatory changes. Chlorpropamide is most hepatotoxic,causes cholestatic hepatitis occurring in 0.5% of people on the drug. Jaundice develops over 2-5 weeksand resolves in virtually all patients when the drug is stopped. At least two cases of granulomatoushepatitis, thought secondary to glyburide have been reported in the literature. 29 Troglitazone use wasassociated with a marked increase in risk of hospitalized acute idiopathic liver injury and ALF 30(F) Hepatogenous DiabetesAn insulin-resistant state may be demonstrated in approxirtntely 80% of patients with cirrhosis, and 20-63% of them will develop DM (hepatogenous diabetes).Once cirrhosis is established, hyperglycemia

HOMA IR TC{ms/dl}

TG(meldl) tDt(meldl) HDL(meldl) VtDt(meldl)Diabetic(n=19) 5.41!2.L8 210.58 t38.92 234.LL!53.09 131.08121.75 38.22!7.84 33.25 r10.44Non-diabetic(n=23)

2.12!0.56 153.47 t23.36 128.39 t49.4 93.91r20.5 38.43 r6.23 24.26 !6.34Control(n=12) 1.49 t 0.73 64.58 r18,L0 24.91!26.89 100.17 r13.55 39.41!4.98 22.L6',!3.15p value 0.001** 0.00L** 0.001** 0.001** 0.88 0.001**


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develops in up to 20% of cases within 5 years. Patients acquiring DM due to cirrhosis differ from typicaltype 2 DM patients due to a lower prevalence of family history of diabetes and a lower risk of macro-and microangiopathic complications. 31 The low prevalence of micro- and macrovascular disease maybe related to a shorter duration of DM, which may be related in turn to a reduced life expectancy, agwell as to liver disease-induced abnormalities (low cholesterol, low platelet count, etc.) protecting thecardiovascular system from atherosclerosis.DM has a low impact on chronic liver disease, so a non-aggressive approach for metabolic control isadvised. Dietary restrictions should be less stringent in hypercatabolic patients with cirrhosis. Oralhypoglycemic agents are contraindicated in the presence of advanced disease. Thus, insulin remains theelective treatment, however lR, a variable hepatic insulin metabolism, and difficulties in dietarymanagement, make glucose control extremely difficult to achieve. Acarbose improved glucose controlmainly postprandialglucose and reduced glycosylated hemoglobin without deleterious effects on liverfunction. This therapeutic option might thus be particularly appealing for improving hepaticencephalopathy.32Hepatitis C in DM:Hepatitis C virus (HCV) perturbs glucose metabolism already at early stages of the natural course ofinfection, i.e. prior to the establishment of significant liver fibrosis, it affects glucose homeostasis byinducing lR rather than impaired islet cell function. ln susceptible individuals, HCV appears to acceleratethe progression of lR towards overt type 2 DM 33 .q. )The prevalence of hepatitis C virus (HCV) is higher in patients with diabetes than in the generalpopulation.3a,3s Patients with HCV are mo,re likely to develop DM (2L%) than patients with hepatitis B(10%), suggesting that HCV rather than liverdisease per se, predisposes patients to develop DM.Patients who are transplanted for HCV (and universally become reinfected) are more likely to developDM than those who are transplanted for other. liver diseases36Patients with hepatitis C and fatty liver disease have elevated levels of TNF-alpha and reduced levelsof adiponectin, which in combination are proinflammatory and prosteatotic, 37,38 leading to oxidativestress in mitochondria 39 and steatosis in many genotype 3 patientsao Finally, there is an associationof DM with interferon treatment of HCV infection. Type 1 DM occurs more frequently in patients treatedwith interferon for HCV versus other conditions a1.The latency of DM ranges from L0 days to 4 yearsafter starting treatment. The interaction between HCV infection, DM, and interferon is the subject ofintensive investigation however it appears reasonable that all patients with type 2 DM and persistentlyelevated serum ALT should be screened for HCV. The metabolic alterations occurring in HCV infection- especially insulin resistance and type 2 DM - have a substantial impact on the morbidity and mortalityof chronic hepatitis C patients:lncreased incidence of hepatocellular carcinomaAcceterated progression of liver fibrosis

:

Reduced virological. response to antiviral therapyThe role of lR in increasing the incidence of cardiovascular events in chronic hepatitis C warrants furtherprospective studies to rule out the confounding role of superimposed NAFLD (Fig-3).Summary:There is definite evidence for an ominous association between DM and liver disease. The excessprevalence of chronic liver disease in Type 2 DM need exploration of pathogenesis between hepaticmetabolism and glucose homeostasis. The old concept of considering fatty liver a trivial, occasional


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271 i

Fig-3: Possible clinical outcomes of "the interaction between insulin resistance and c,hronic hepatitis C.(Ref-33)

finding of scarce clinical significance has progressively turned into a major concern regarding potentialepidemics of metabolic liver disease due to the growing prevalence of obesity and DM. They are bothprobably incorrect estimates of the real risk. Pure fatty liver, a common finding in DM, remains anonaggressive metabolic condition, but why in a few cases it progress to NASH, NAFLD-related cirrhosisor primary liver cancer, or may increase the risk associated with HCV infection is not clearly understoodtill now. Further studies needed for these unsolved questions.

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Diabetic Hepatopathy a Syndrome in Evolution