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ili GLUCOSE METABOLIC DISORDERS AT LIVER CIRRHOSIS 1 S u zan n a N dr aha, 2M ar d i S an tos o, 3F endr a Wician 1 Gastroenterology and Hepatology consultant,

Department of Internal Medicine Faculty of Medicine Ukrida Jakarta 2 Metabolic endocrine and Diabetes consultant, Department of Internal Medicine Faculty of Medicine Ukrida Jakarta 3 Department of Internal Medicine Faculty of Medicine Ukrida Jakarta

ABSTRACT Introduction: A p p r o x i m a t e l y 3 0 % o f p a t i e n t s w i t h l i v e r c i r r h o s i s a l s o had diabetes mellitus, known as cirrhosis t ype DM. Insulin resistance and hyperinsulinemia was thought have a role in the pathophysiology. The purpose of this study was t o evaluate the glucose metabolic disorders in patients with liver cirrhosis in Koja Hospital, and to see the effect of insulin resistance in cirrhosis t ype diabetes mellitus. Method: R e s e a r c h t h a t c o n d u c t e d i n t h e p e r i o d F e b r u a r y - J u l y 2 0 1 3 i s divided into 2 phases. The first stage uses an observational design. The inclusion criteria is all liver cirrhosis patients, but the exclusion criteria is patients who suffering acute complications. We recorded their nutritional status, child pugh criteria and the re sults of glucose tolerance. Patients who meet the DM criteria continued to second phase, with t ype 2 diabetes mellitus patients as controls. Next assessed the difference in average of 2-h postprandial plasma glucose/ Fasting plasma glucose and fasting insulin levels between cirrhosis type DM with T2DM. Result: Obtained 24 patients with liver cirrhosis. The majority has normal nutritional status (62.5%), the rest has mild malnutrition (37.5%). The Child Pugh B largely (66.7%), the rest is Child Pugh C (25%). Normal glucose tolerance test results in 29%, impaired glucose tolerance (IGT) in 25% and 46% cirrhosis t ype DM. From anal ytic study in second phase, we obtained the ratio of 2-h postprandial plasma glucose/ F a s t i n g p l a s m a g l u c o s e i n p a t i e n t s w i t h c i r r h o s i s t y p e D M a r e 20 ,5 a n d T 2 D M p a t i e n t s a r e 1 ,5 0 ,4 (p = 0,0 1 ). A v e r a g e f a s t i n g i n s u l i n levels in patients with diabetes mellitus t ype cirrhosis type diabetes a r e 1 0 ,84 ,2 IU / mL a n d T 2 D M i s 9 9 ,3 5 ,3 IU / mL (p = 0 ,5 ). T h e s e r e s u l t s indicate the proportion of cirrhosis t ype DM is higher than previous studies. The ratio of 2-h postprandial plasma glucose/ Fasting plasma glucose is higher in DM t ype cirrhosis, and statisticall y significant. Conclusion: A s m a n y a s 7 1 % o f p a t i e n t s w i t h l i v e r c i r r h o s i s h a s glucose metabolic disorders, IGT 25% and 46% DM. Effect of insulin resistance and hyperinsulinemia appears to play a role in cirrhosis type diabetes

mellitus.

K e y w o r d s : C i r r h o s i s t y p e d i a b e t e s m e l l i t u s , T 2 D M , The ratio of 2-h postprandial plasma glucose/ Fasting plasma glucose

PR E F A C E Approximately 30% of patients with liver cirrhosis ( LC) also had diabetes mellitus (DM). DM as a complication of liver cirrhosis known as 'hepatogenous diabetes' or ' cirrhosis t ype diabetes mellitus ' .1,2 Insulin resistance in muscle and fat tissue and hyperinsulinemia was thought has a role in the pathophysiology. Disruption of pancreatic beta cell function and hepatic insulin resistance also played a role. 'Hepatogenous diabetes' or 'cirrhosis t ype diabetes mellitus' is a disease th at is clinicall y different from t ype 2 diabetes mellitus (T2DM), because macroangiopatic complications are rarely seen and patients more frequently ex perienced cirrhosiss chronic complications. DM increases liver cirrhosis mortalit y. Treatment is become more complex because it must consider the damage of the liver and its oral hypogl ycemic drug hepatotoxicity (OHD) . On the other hand, there is a assumption that spread in the community that liver disease requires a high sugar intake. This makes patients with chronic liver disorders will increase his/her sugar intake. Eventhough these patients have been known to suffer from diabetes, they still choose high glucose intake for their liver disease improvement efforts. It is often missed by medical practioners, and may be another factor that complicates the management of DM in liver disease. Not many researchers wr ote about the cirrhosis type DM. In the earl y 80s, Budisantoso2 get the DM population in 1981, 25% had impaired glucose tolerance, and 32% had diabetes mellitus. In 1985 Budisantoso3, 4 got 34.7% had impaired glucose tolerance, and 48.6% had cirrhosis t ype diabetes mellitus. However, subsequent publications on cirrhosis t ype diabetes mellitus w as difficult to obtain. American Diabetes Association (ADA) 2005 5 classified DM in 4 groups, there is [1] Type 1 Diabetes Mellitus or Insulin Dependent Diabetes Mellitus / IDDM, [2] Type 2 Diabetes Mellitus or Non Insulin Dependent Diabetes Mellitus / NID DM [3] Other Types of Diabetes Mellitus and [4] Gestational Diabetes Mellitus. Other t ypes of Diabetes Mellitus which intended in the classification of ADA 2005 are a genetic defect cell function, genetic defects of insulins work, pancreatic exocrine gland disease, endocrinopatic, drugs or chemicals, infections, uncommon forms of immune-mediated diabetes and other genetic syndromes associated with diabetes . In this classification, there is no longer cirrhosis t ype diabetes mellitus (Table 1). The question arises, how the presence of cirrhosis type diabetes mellitus in the classification of diabetes mellitus today. T a bl e 1. Classification of diabetes mellitus according to ADA 20055 Etiologic Classification of Diabetes Mellitus I. Type 1 d iabetes ( - cell d estru ction, u su ally lead ing to absolute d eficiency) a. I mmune med iated

insu lin

b. I d iop ath ic I I . Type 2 d iabetes ( may rang e from pred omin an tly insu lin resistance with relative insu lin d eficiency to a pred ominan tly secretory d ef ect with insulin resistance) I I I . Other sp ecific typ es A. Genetic d efects o f - cell fu nction a. C h romosome 1 2 , HNF- 1 ( MODY3 ) b. C h romosome 7 , g lu cok inase ( MODY2 ) c. C h romosome 2 0 , HNF- 4 ( MODY1 )

d. C h romosome 1 3 , insulin promoter factor- 1 ( I PF- 1 ; MODY4 ) e. C h romosome 1 7 , HNF- 1 ( MODY5 ) f. C h romosome 2 ,NeuroD1 ( MODY6 ) g . Mitochondr ial DNA h. Others B. Genetic d efects in insulin action a. Type A insu lin resistance b. Lep rechaun ism c. Rabson- Mend en hall synd rome d . Lip oatrophic d iabetes e. Others C . Diseases o f the ex ocrine p ancreas a. Pancreatitis b. Trauma/pancreatectomy c. Neop lasia d. Cystic fibrosis e. He moc hroma tosis f. Fibrocalcu lou s p ancreatop athy g . Others D. End ocrinop athies a. Acromeg aly b. C u sh ing s synd rome c. Glu cag onoma d. Pheochromocytoma e. Hyp erthyroid ism f. Somatostatinoma g . Ald osteronoma h. Others E. Dru g- or chemical- in d u ced a. Vacor b. Pentamid ine c. Nicotinic acid d. Glu cocorticoid s e. Thyroid hormone f. Diazox id e g. -adrener g ic ag on ists h . Thiazid es i. Dilan tin j. - I n terferon k . Others F. I nfections a. C ong en ital ru bella b. Cytomeg aloviru s c. Others G. Uncommon forms of immune- med iated d iabetes a. Stif f- man synd rome b. An tiinsu lin recep tor an tibod ies c. Others H. Other g enetic synd romes sometimes associated with d iabetes Do wn s synd rome b. Klinefelter s synd rome c. Tur ner s syndrome d. Wolfram s syndrome e. Friedreich s atax ia f. Hu ntington s chorea g. Lau rence- Mo on- Bied l syndrome

a.

h. j. I V.

Myotonic d ystrop hy i. Porp hyria Prad er- Willi syndrome k . Others Gestation al d iabetes mellitu s ( GDM)

'Hepatogenous diabetes' or 'cirrhosis t ype diabetes mellitus ' is a disease that is clinicall y different from type 2 diabetes mellitus (T2DM). A study comparing cirrhosis t ype DM with T2DM. Obtained ratio 2-h postprandial plasma glucose / fasting plasma glucose = 2.27 in cirrhosis t ype DM, and 1.69 in T2DM. Fasting insulin in cirrhosis t ype diabetes mellitus 23.2 IU / m L, and 11.6 IU / m L in T2DM. Homa IR index on cirrhosis t ype DM 8.38, and 3.52 at DMT2.6

METHOD The study was conducted in Koja Hospital in the period February 2013 - June 2013. This research was divided into two stages, the first stage used an observational design, and the second stage used anal ytic. Affordable population was all liver cirrhosis patients who went to Internal Medicine Unit or treated in Koja Hospital . Which made the inclusion of first phase was all of liver cirrhosis patients, for second phase was all cirrhosis t ype DM. Patients were excluded if there was an acute complication, refused to be included, or already suffering hepatoma. All patients who passed the inclusion phase, we recorded their identity, checked their nutritional status (body mass index and mid-arm muscle circumference), recorded their su b j ect i ve g l o b a l assessm en t ( S G A ) , c h e c k e d t h e i r a l b u m i n , b i l i r u b i n , prothrombin time, glucose tolerance tests ( GTT) and fasting insulin in laboratory . Nine people got GTT results appropriate with cirrhosis type DM, so the nine subjects were included for second phase studies. At the end of this stage, the patient ss nutritional status, child-pugh criteria, and sugar metabolism status (normal, impaired glucose tolerance or cirrhosis type diabetes mellitus) were concluded. (Subjects were stated cirrhosis t ype DM when the result of GTTs 2nd hour was aboved 200 mg / dl. In second stage, 9 patients was taken from first stage who met the criteria for cirrhosis type diabetes mellitus and for the control group, 9 T2DM patients was taken with the same sex, and the age range was not more than 5 years difference from cirrhosis type DM group. Inclusion criteria for the control group was uncontrolled diabetes that was not using oral hypoglycemic drugs or insulin for more than 1 week. In the group of cirrhosis t ype DM and t ype 2 DM, fasting insulin, fasting plasma glucose, post -prandial plasma glucose were examined, and then the ratio GDPP / GDP was calculated. For univariate anal ysis, all categories data were presented in n (%) and normally distributed numerical data are pr esented as mean (SD). Unpaired mean test was used for bivariate anal ysis to determine differences in the average ratio of postprandial plasma glucose/fasting plasma glucose and fasting insulin levels between

groups of cirrhosis type DM and t ype 2 DM . The data were processed using a computer with SPSS 20.

RESULT During 5 months period, in February 2013 - June 2013, we got 24 liver cirrhosis liver cirrhosis who met the inclusion criteria. Data characteristics of patients can be seen in Table 2. Tabl e 2 . C h a r a c t e r i s t i c o f 2 4 liver cirrhosis p a t i e n t s a t K o j a H o s p i t a l Characteristic F r e q u e n c y (n ) Sex a. Male 15 b. Female 9 Age a. <4 0 5 b. 40-60 11 c. >6 0 8 Clinical findings a. Jaundice 6 b. Ascites 20 c. Sp lenomeg aly 4 d. Palmar er ythema 2 e. C ap u t med u se 1 f. Melena 11 g. Hematemesis 13 h. 2 Al bu m in Encephalopa a. >3 .5 mg /d L 6 t h y 2 .8 - 3.5mg /d L b. 12 c. <2 .8 mg /d L 6 B iliru b in a. <2 mg /d L 17 b. 2 - 3 mg /d L 2 c. >3 mg /d L 5 Prothombin time a. <4 s 22 b. 4-6 s 4 c. >6 s 6 Body mass Index a. U nd er 3 b. N ormo 18 c. O verw eig ht 2 d. o bese 1 MAMC a. <5 0 b. 5-15 9 c. >1 5 15 SGA a. SGA A 8 b. SGA B 8 c. SGA C 8 Ch ild Pu gh C l a c i f i c t i o n a A 2 b B 16 . c C 6 . . Percentage (%) 6 2 ,5 3 7 ,5 2 0 ,8 4 5 ,8 3 3 ,4 25 8 3 ,3 1 6 ,7 8 ,3 4 ,2 4 5 ,8 5 4 ,2 8 ,3 25 50 25 7 0 ,9 8 ,3 2 0 ,8 5 8 ,3 1 6 ,7 25 1 2 ,5 75 8 ,3 4 ,2 0 3 7 ,5 6 2 ,5 3 3 ,4 3 3 ,3 3 3 ,3 8 ,3 6 6 ,7 25

From the 24 patients which were examined, we found that 17 (71%) of patients with liver cirrhosis suffered sugar metabolic disorders, and 7 subjects (29%) had a normal glucose tolerance. From the 17 people, 6 subjects (25% of the total subjects, 35% of 17 subjects) met the criteria for impaired glucose tolerance (IGT) and 11 people (46% of the total subjects, 6 5% of 17 subjects) were cirrhosis t ype diabetes mellitus . Figure 1 showed the proportion of cirrhosis t ype DM to all patients with liver cirrhosis.

C i r r h o s i s t y p e D M ( 46% ) 7 I GT (2 5 % ) 11 Norma l (29%)

Figure 1. Distribution of patients with liver cirrhosis according to the results of glucose tolerance test (n = 24) From the 11 subjects who met the criteria of cirrhosis t ype DM, we took 9 people to continue into second stage . In second stage, 9 hepatogenous diabetes subjects were compared with 9 T2DM patients, which had the same sex and no more than 5 years age range. In both groups, we took the data of fasting plasma glucose (FP G), 2h postprandial plasma glucose and fasting insulin. Presence of insulin resistance was assessed by the ratio 2-h postprandial plasma glucose / fasting plasma glucose and fasting insulin levels. Figure 2 shows the ratio 2-h postprandial plasma glucose / fasting plasma glucose, while Figure 3 shows fasting insulin levels in both groups. plasma glucose the ratio 2h postprandia l plasma glucose / fasting 2 1 .5

fasting insulin
( I U/mL)

1 0 .5 10

11 1 0 .5

2 1 . 5 9 . 5 9

1 0. 8 9.3

0 Cirrhosis t ype DM T2DM Figure 2: Average of the ratio 2-h postprandial plasma glucose / fasting plasma glucose (p = 0 ,0 1 )

8 . 5

Cirrhosis T2DM

type

DM

Figure 3 : Average of insulin fasting levels in both groups (p = 0 ,5 )

From the results of the examination, we obtained the ratio 2-h postprandial plasma glucose / fasting plasma in patients with c i r r h o s i s t y p e D M w a s 2 0 ,5 and T 2 D M p a t i e n t s w a s 1 ,5 0 ,4 (p = 0 ,0 1 ). Average fasting insulin l evels in patients with cirrhosis t ype d i a b e t e s w a s 1 0 ,84 ,2 IU / mL a n d T 2 D M w a s 9 ,3 5 ,3 IU /mL (p =0 ,5 ). DISCUSSION In this study, we found that liver cirrhosis wa s more common in male patients (62.5%), most aged 40 -60 years (45.8%), most clinical findings were ascites (83.3%), hematemesis (54.2%), and melena (45.8%). This is consistent with the findings that have been obtained before.7, 8.9 Nutritional status assessment in this study was based on 3 differ ent t ypes of parameters, using BMI, MAMC, and SGA. Based on BMI, we obtained 75% of subjects had an adequate nutrition, malnutrition was 12.5%, and 8.3% was over nutrition. Based on MAMC, 62.5% was obtained had no malnutrition (normal), and 37.5% suffered mildly malnourished. Based on SGA, we obtained 33.3% was manultrition . From these 3 nutrient parameters, we found that nutritional status, which was based on MAMC measurement did not vary much with SGA (37.5% and 33.3%), but when we used the BMI, the results of malnutrition was much lower (12.5%). This difference wa s due to the bias which were caused by edema and ascites when using BMI, so that MAMC and SGA were preferred over IMT.9, 10,11 Cirrhosis t ype DM is generally subclinical, and has a normal fasting glucose level, so the oral glucose tolerance test is necessary to be done to detect a diagnosis.6 From the oral glucose tolerance test results, we obtained 46% of liver cirrhosis patients in Koja Hospital also had diabetes, 25% had impaired glucose tolerance test and only 29% had no other metabolic abnormalities of glucose. Compean 6 argued, in liver cirrhosis, he obtained an impaired glucose tolerance up to 96%, and 30% of them were cirrhosis t ype DM. On our data, we obtained impaired glucose tolerance as much as 71%, and 65% of them were cirrhosis type DM. Compared to the Compean data, we had a lower rating for impaired glucose tolerance in overall (71% vs. 96%), but who met the criteria for diabetes were higher (46% of the total subjects, or 65% of total impaired glucose tolerance). Liver plays an important role in the metabolism of carbohydrates, particularly through the process of glikogenogenesis and gl ycogenol ysis. The presence of chronic liver disease , glucose metabolism becomes impaired, there was insulin resistance, glucose intolerance and cirrhosis t ype diabetes. Insulin resistance and hyperinsulinemia are thought as a basic pathophysiology of cirrhosis t ype diabetes mellitus . Management of cirrhosi s t ype DM is slightly different from t ype 2 DM because in cirrhosis t ype DM, rarel y found micoangiopatic complications , and the importance to anticipate the hepatotoxic effects of oral hypogl ycemic drugs. However, in the classification of diabetes according to the ADA 2005 of cirrhosis t ype diabetes mellitus or "hepatogenous diabetes" wa s not explicitly

stated as one of others t ype of DM.5, 6 To determine the existence of hyperinsulinemia, then the insulin levels fasting was examined in all 24 patients . We obtained 17 (70.8%) patients had fasting insulin levels within normal values (2.6 IU/mL-24, 9IU/mL), 4 (16.7%) had low levels (<2.6 IU / mL) and 3 (12.5%) had high fasting insulin levels (> 24.9 IU / mL). Kawaguchi12 recorded as many as 57% of patients with liver cirrhosis showed an increase in insulin resistance. Levels of insulin in patients with cirrhosis t ype diabetes mellitus werr higher than t ype 2 DM. H yperinsulinemia in liver cirrhosis could be due to damage to the liver parenchymal cells, so that the pro cess of degradation of insulin was impaired. In our subjects, hyperinsulinemia was obtained only at 12.5%. In the second phase , mean of fasting insulin levels mean in cirrhosis type DM group was compared to the group of t ype 2 diabetes. We obtained that an average fasting insulin levels in cirrhosis t ype diabetes mellitus p a t i e n t s w e r e 1 0 ,84 ,2 IU / mL a n d i n T 2 D M p a t i e n t s w e r e 9 ,3 5 ,3 IU / mL (p = 0 ,5 ). These data indicate d a relative hyperinsulinemia in cirrhosis type D M g r o u p t o t h e T 2 D M (1 0 ,84 ,2 IU / mL v s 9 ,3 5 ,3 IU / mL), b u t apparently this difference was not statistically significant. This was likely due to the lack of large samples, tekhik blood sampling is not an appropriate of blood sampling techniques, or bad processing techniques of material. Pad a p asien D M tip e sirosis did ap atk an rasio G D PP/ G D P sebesar 20 ,5 d an p asien D M tip e-2 sebesar 1 ,5 0 ,4 (p = 0 ,0 1 ). Rasio G D PP/ G D P leb ih ting gi p ad a D M tip e sirosis, d an bermakna secara statistik . D ata ini mend u k ung ad an ya resistensi in sul in yan g leb ih tin g gi p ad a D M tip e sirosis dibandin g k an D M tip e-2 . Furthermore, the ratio 2-h postprandial plasma glucose / fasting plasma glucose was assessed in both groups. The higher ratio 2-h postprandial plasma glucose / fasting plasma glucose indicated a failure of insulin to enter glucose into the cells, so that the higher the ratio, the higher the re sistance to insulin. In cirrhosis type DM, we obtained that ratio 2-h postprandial plasma glucose / fasting p l a s m a g l u c o s e w a s 20 ,5 a n d 1 ,5 0 ,4 i n T 2 D M (p = 0 ,0 1 ). T h e r a t i o 2 - h postprandial plasma glucose / fasting plasma glucose was higher in cirrhosis t ype DM, and statisticall y significant. These data support the existence of a higher insulin resistance in cirrhosis t ype DM compared with type 2 DM.

KESIMPU LA N Se ban ya k 7 1 % d a ri p end e rita sirosis ha ti mengalami g ang g u an me ta bolik g ula , 6 5 % d ianta ra n ya memenuh i k rite ria D M tip e sirosis . Pe ng a ru h re siste nsi in sul in d an h ip e rin sul in emia ta mp a kn y a be rp e ran p a d a D M tip e sirosis

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1 0 . H enk el AS, Bu ch man AL. N u trition al su p p ort in p atients w ith chron ic l iv er disease. N atu re Clinical Practice G astroenterology & H ep atology 2 0 0 6 ;3 : 2 0 2-9 1 1 . Kalaitzakis E, Olsson R, H enfrid sson P, H u g osson I, Beng tsson M, Jalan R. Maln u trition and diabetes mel litus are related t o hep atic enceph alop ath y in p atients with liv er cirrhosis. Liv er International 2 0 0 7;2 7 : 1 1 9 4-2 0 1 1 2 . Kawag u ch i T, Tan ig u ch i E, It ou M, Sak ata M, Sumie S, Sata M. Insulin resistance and chron ic liv er disease. World J H ep at ol 2 0 1 1; 3 (5 ): 9 9-1 0 7

Name: Suzanna Ndraha Institution: Faculty of Medicine, University of Krida Wacana Jakarta Mailing address: Tebet Timur Dalam Vlll -X no 22 Jakarta selatan Phone/Facs Number: 021-8313072, 02197103012, 085883311441 e-mail: susan_ndraha@yahoo.co.id