Zusammenfassung
Hintergrund: Patienten mit Leberzirrhose entwickeln häufig Störungen des Glukosemetabolismus wie Glukoseintoleranz oder einen hepatogenen Diabetes, welche neben der hepatozellulären Funktionseinschränkung durch die ausgeprägte Insulinresistenz als Folge der chronischen Lebererkrankung verursacht sind. Diskussion: Empfehlungen mit Leitliniencharakter zur Diagnostik und Therapie des hepatogenen Diabetes fehlen bislang. Im Hinblick auf basistherapeutische Maßnahmen sollte eine ausreichende Deckung des Energie- und Proteinstoffwechsels gewährleistet sein, da ein Großteil der Zirrhosepatienten mangelernährt ist. Bei der medikamentösen Behandlung des hepatogenen Diabetes muss auf die erhöhte Hypoglykämie-Gefährdung geachtet werden. Aufgrund der Nebenwirkungen sind Biguanide sowie PPAR-gamma-Liganden bei Leberzirrhose kontraindiziert. Geeignete orale Antidiabetika sind insbesondere Sulfonylharnstoffanaloga und kurz wirksame Sulfonylharnstoffe. Wenn eine suffiziente Diabetes-Einstellung mit oralen Antidiabetika nicht gelingt, sollte eine prandiale Insulintherapie mit Insulinen von kurzer Wirkdauer oder kurz wirksamen Insulinanaloga eingesetzt werden. Schlussfolgerung: Die Optimierung einer diabetischen Stoffwechsellage hat neben der Vermeidung typischer diabetischer Spätkomplikationen eine wichtige Bedeutung für die Vermeidung und Reduzierung von Zirrhose-assoziierten Komplikationen, wie z. B. gastrointestinale Blutungsereignisse, hepatische Enzephalopathie oder das Auftreten eines hepatozellulären Karzinoms.
Abstract
Background: Patients with liver cirrhosis develop frequently disturbances of glucose metabolism e. g. glucose intolerance or hepatogenous diabetes which are caused by the hepatocellular functional loss and insulin resistance due to chronic liver disease. Discussion: Until now there are no recommendations comparable to guidelines on the diagnosis of and therapy for hepatogenic diabetes. Regarding basic treatment a sufficient daily energy and protein supply should be guaranteed since the majority of patients with liver cirrhosis are malnourished. The risk of hypoglycaemia must be considered carefully under pharmacological treatment of hepatogenous diabetes. Biguanide and PPAR gamma agonists are contraindicated due to side effects in liver cirrhosis. Suitable oral antidiabetics are glinides and short-acting sulfonylureas. If a sufficient diabetes adjustment does not succeed by oral antidiabetics a prandial insulin therapy using short-acting insulins or rapid-acting insulin analogues should be applied. Conclusion: Optimisation of diabetic metabolic conditions is not only important to avoid typical diabetic late complications but also cirrhosis-associated complications, e. g., gastrointestinal bleeding, hepatic encephalopathy or the occurrence of hepatocellular carcinoma.
Schlüsselwörter
Leber - Diabetes - Glukosestoffwechselstörungen
Key words
liver - diabetes - glucose metabolism dysfunction
Literatur
-
1
AlDosary A A, Ramji A S, Elliott T G. et al .
Post-liver transplantation diabetes mellitus: an association with hepatitis C.
Liver transp.
2002;
8
356-361
-
2
Baggio L L, Drucker D J.
Biology of incretins: GLP-1 and GIP.
Gastroenterology.
2007;
132
2131-2157
-
3
Bianchi G P, Marchesini G, Fabbri A. et al .
Vegetable versus animal protein diet in cirrhotic patients with chronic encephalopathy. A randomized cross-over comparison.
J Intern Med.
1993;
233
385-392
-
4
Bosch J, Gomis R, Kravetz D. et al .
Role of spontaneous portal-systemic shunting in hyperinsulinism of cirrhosis.
Am J Physiol.
1984;
247
G206-G212
-
5
Campillo B, Paillaud E, Uzan I. et al .
Value of body mass index in the detection of severe malnutrition: influence of the pathology and changes in anthropometric parameters.
Clin Nutr.
2004;
23
551-559
-
6
Caronia S, Taylor K, Pagliaro L. et al .
Further evidence for an association between non-insulin-dependent diabetes mellitus and chronic hepatitis C virus infection.
Hepatology.
1999;
30
1059-1063
-
7
Chupin M, Charbonnel B, Le Bodic L. et al .
Glucose tolerance in viral hepatitis. A study of twenty patients during the acute phase and after recovery.
Diabetes.
1978;
27
661-669
-
8 Creutzfeldt W, Sickinger K, Frerichs H. Diabetes und Lebererkrankungen. Pfeiffer EF Handbuch des Diabetes mellitus München; Lehmann 1971 Vol. 2: 807-859
-
9
Drucker D J, Nauck M A.
The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.
Lancet.
2006;
368
1696-1705
-
10
El-Serag H B, Tran T, Everhart J E.
Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.
Gastroenterology.
2004;
126
460-468
-
11 Empen K. Diabetes mellitus. Göke B, Parhofer K, Otto C München; Urban & Fischer Verlag 2002: 3-11
-
12
Ferenci P, Lockwood A, Mullen K. et al .
Hepatic encephalopathy – definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congress of Gastroenterology, Vienna, 1998.
Hepatology.
2002;
35
716-721
-
13 Geiss H C. Diabetes mellitus. Göke B, Parhofer K, Otto C München; Urban & Fischer Verlag 2002: 15-39
-
14
Gentile S, Guarino G, Romano M. et al .
A randomized controlled trial of acarbose in hepatic encephalopathy.
Clin Gastroenterol Hepatol.
2005;
3
184-191
-
15
Gentile S, Loguercio C, Marmo R. et al .
Incidence of altered glucose tolerance in liver cirrhosis.
Diabetes Res Clin Pract.
1993;
22
37-44
-
16
Gentile S, Turco S, Guarino G. et al .
Effect of treatment with acarbose and insulin in patients with non-insulin-dependent diabetes mellitus associated with non-alcoholic liver cirrhosis.
Diabetes Obes Metab.
2001;
3
33-40
-
17 Göke B. Diabetes mellitus. Göke B, Parhofer K, Otto C München; Urban & Fischer Verlag 2002: 61-74
-
18
Greco A V, Mingrone G, Mari A. et al .
Mechanisms of hyperinsulinaemia in Child’s disease grade B liver cirrhosis investigated in free living conditions.
Gut.
2002;
51
870-875
-
19
Häring H, Joost H, Labe H. et al .
Antihyperglykämische Therapie des Diabetes mellitus Typ 2. Evidenzbasierte Diabetes-Leitlinie DDG.
Diab Stoffw.
2003;
12
13-31
-
20
Holman R R, Cull C A, Turner R F.
A randomized double-blind trial of acarbose in type 2 diabetes shows improved glycemic control over 3 years (U. K. Prospective Diabetes Study 44).
Diabetes Care.
1999;
22
960-964
-
21
Holstein A, Hinze S, Thiessen E. et al .
Clinical implications of hepatogenous diabetes in liver cirrhosis.
Gastroenterol Hepatol.
2002;
17
677-681
-
22
Huo T I, Lui W Y, Huang Y H. et al .
Diabetes mellitus is a risk factor for hepatic decompensation in patients with hepatocellular carcinoma undergoing resection: a longitudinal study.
Am J Gastroenterol.
2003;
98
2293-2298
-
23
Huo T I, Wu J C, Lee P C. et al .
Diabetes mellitus as a risk factor of liver cirrhosis in patients with chronic hepatitis B virus infection.
J Clin Gastroenterol.
2000;
30
250-254
-
24
Imano E, Nishida T, Shibata M. et al .
Significance of Oral Glucose Tolerance Test for the Diagnosis of Diabetes mellitus in Patients with Liver Cirrhosis.
Int Med.
1999;
38
918
-
25
Kaczynski J, Hansson G, Wallerstedt S.
Diabetes: one of few remarkable differences in clinicopathologic features between cirrhotic and noncirrhotic Swedes with hepatocellular carcinoma.
Dig Dis Sci.
2006;
51
796-802
-
26
Kihara Y, Ogami Y, Tabaru A. et al .
Safe and effective treatment of diabetes mellitus associated with chronic liver diseases with an alpha-glucosidase inhibitor, acarbose.
J Gastroenterol.
1997;
32
777-782
-
27
Knobler H, Schattner A.
TNF-{alpha}, chronic hepatitis C and diabetes: a novel triad.
QJM.
2005;
98
1-6
-
28
Knobler H, Stagnaro-Green A, Wallenstein S. et al .
Higher incidence of diabetes in liver transplant recipients with hepatitis C.
J Clin Gastroenterol.
1998;
26
30-33
-
29
Krauns P, Ruge W.
Plasma catecholamine levels in liver disease.
Z Gastroenterol.
1985;
23
64-73
-
30
Laubner K, Seufert J.
Pharmaceutical therapy of diabetes mellitus type 2.
Internist.
2007;
48
297-310
-
31
La V ecchia C, Negri E, Decarli A. et al .
Diabetes mellitus and the risk of primary liver cancer.
Int J Cancer.
1997;
73
204-207
-
32
Lawson D H, Gray J M, McKillop C. et al .
Diabetes mellitus and primary hepatocellular carcinoma.
Q J Med.
1986;
61
945-955
-
33
Leslie W D, Bernstein C N, Leboff M S. et al .
AGA Technical Review on Osteoporosis in Hepatic Disorders.
Gastroenterology.
2003;
125
941-966
-
34
Lochs H, Plauth M.
Liver cirrhosis: rationale and modalities for nutritional support – the European Society of Parenteral and Enteral Nutrition consensus and beyond.
Curr Opin Clin Nutr Metab Care.
1999;
2
345-3494
-
35
Mason A L, Lau J YN, Hoang N. et al .
Association of diabetes mellitus and chronic hepatitis C virus infection.
Hepatology.
1999;
29
328-333
-
36
McCullough A J, Bugianesi E.
Protein-calorie malnutrition and the etiology of cirrhosis.
Am J Gastroenterol.
1997;
92
734-738
-
37
Mehta S H, Brancati F L, Sulkowski M S. et al .
Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States.
Ann Intern Med.
2000;
17 (133)
592-599
-
38
Megeysi C, Samols E, Marks V.
Glucose tolerance and diabetes in chronic liver disease.
Lancet.
1967;
18 (2)
1051-1056
-
39 Moradpour D. Klinische Pathophysiologie,. Siegenthaler, Blum Georg Thieme Verlag 859-869
-
40
Moreau R, Chagneau C, Heller J.
Hemodynamic, metabolic and hormonal responses to oral glibenclamide in patients with cirrhosis receiving glucose.
Scand J Gastroenterol.
2001;
36
303-308
-
41
Moreau R, Delegue P, Pessione F. et al .
Clinical characteristics and outcome of patients with cirrhosis and refractory ascites.
Liver Int.
2004;
24
457-464 xxx
-
42
Moscatiello S, Manini R, Marchesini G.
Diabetes and liver disease: an ominous association.
Nutr Metab Cardiovasc Dis.
2007;
17
63-70
-
43
Moschen A R, Kaser A, Stadlmann S. et al .
The RANKL/OPG system and bone mineral density in patients with chronic liver disease.
J Hepatol.
2005;
43
973-983
-
44
Müller M J, Pirlich M, Balks H J. et al .
Glucose intolerance in liver cirrhosis: role of hepatic and non-hepatic influences.
Eur J Clin Chem Clin Biochem.
1994;
32
749-758
-
45 Müller M J. Ernährung von Leberkranken. Schmidt E, Schmidt FW, Manns MP Lebererkrankungen Pathophysiologie – Diagnostik – Therapie Stuttgart; Wiss. Verl.-Ges 2000: 1080-1104
-
46
Murphy E J, Davern T J, Shakil A O. et al .
Troglitazone-induced fulminant hepatic failure. Acute Liver Failure Study Group.
Dig Dis Sci.
2000;
45
549-553
-
47
Nationale Versorgungs-Leitlinie Diabetes mellitus Typ 2.
Z Arztl Fortbild Qualitatssich.
2002;
95 (Suppl 2)
1-23
-
48 Naunyn B. Glykosurie und Diabetes durch experimentelle Insulte und Krankheiten der Leber. Naunyn B Der Diabetes mellitus Vienna, Austria; A. Holder 1898: 38-49
-
49
Niederau C.
Diabetes mellitus in hemochromatosis.
Z Gastroenterol.
1999;
Suppl 1
22-32
-
50
Niederau C, Fischer R, Pürschel A. et al .
Long-term survival in patients with hereditary hemochromatosis.
Gastroenterology.
1996;
110
1107-1119
-
51
Niederau C, Fischer R, Sonnenberg A. et al .
Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis.
N Engl J Med.
1985;
14 (313)
1256-1262
-
52
Nishida T, Tsuji S, Tsujii M. et al .
Oral glucose tolerance test predicts prognosis of patients with liver cirrhosis.
Am J Gastroenterol.
2006;
101
70-75
-
53
O’Brien T, Barrett B, Murray D M. et al .
Usefulness of biochemical screening of diabetic patients for hemochromatosis.
Diabetes Care.
1990;
13
532-534
-
54
Owen O E, Reichle F A, Mozzoli M A. et al .
Hepatic, gut, and renal substrate flux rates in patients with hepatic cirrhosis.
J Clin Invest.
1981;
68
240-522
-
55
Panzer S, Kronik G, Lechner K. et al .
Glykosylated hemoglobins (GHb): An index of red cell survival.
Blood.
1982;
59
1348-1350
-
56
Papatheodoridis G V, Chrysanthos N, Savvas S. et al .
Diabetes mellitus in chronic hepatitis B and C: prevalence and potential association with the extent of liver fibrosis.
Viral Hepat.
2006;
13
303-310
-
57
Perseghini G, Mazzaferro V, Sereni L P. et al .
Contribution of reduced insulin sensitivity and secretion to the pathogenesis of hepatogenous diabetes: effect of liver transplantation.
Hepatology.
2000;
31
694-703
-
58
Petrides A S.
New aspects of the regulation of glucose metabolism in chronic liver diseases.
Z Gastroenterol.
1993;
31 (Suppl 5)
53-55
-
59
Petrides A S.
Hepatogenic diabetes: pathophysiology, therapeutic options and prognosis.
Z Gastroenterol.
1999;
Suppl 1
15-21
-
60
Petrides A S, DeFronzo R A.
Glucose metabolism in cirrhosis: a review with some perspectives for the future.
Diabetes Metab Rev.
1989;
5
691-709
-
61
Petrides A S, Vogt C, Schulze-Berge D. et al .
Pathogenesis of glucose intolerance and diabetes mellitus in cirrhosis.
Hepatology.
1994;
19
616-627
-
62
Pirlich M, Lochs H, Ockenga J.
Enteral nutrition.
Internist.
2006;
47
405-422
-
63
Plauth M, Ferenci P, Holm E. et al .
DGEM-Leitlinie Enterale Ernährung: Hepatologie.
Aktuel Ernähr Med.
2003;
Suppl 1
S87-S92
-
64
Plauth M, Cabre E, Riggio O. et al .
ESPEN Guidelines on Enteral Nutrition: Liver disease.
Clin Nutr.
2006;
25
285-294
-
65
Plauth M, Merli M, Kondrup J. et al .
ESPEN guidelines for nutrition in liver disease and transplantation.
Clin Nutr.
1997;
16
43-55
-
66
Prijatmoko D, Strauss B J, Lambert J R. et al .
Early detection of protein depletion in alcoholic cirrhosis: role of body composition analysis.
Gastroenterology.
1993;
105
1839-1845
-
67
Proietto J, Dudley F J, Aitken P. et al .
Hyperinsulinaemia and insulin resistance of cirrhosis: the importance of insulin hypersecretion.
Clin Endocrinol.
1984;
21
657-665
-
68
Promrat K, Lutchman G, Uwaifo G I. et al .
A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis.
Hepatology.
2004;
39
188-196
-
69
Pugliese D, Lee S S, Koshy A. et al .
Systemic and splanchnic hemodynamic effects of intravenous hypertonic glucose in patients with cirrhosis.
Hepatology.
1988;
8
643-646
-
70
Riggio O, Merli M, Cantafora A. et al .
Total and individual free fatty acid concentrations in liver cirrhosis.
Metabolism.
1984;
33
646-651
-
71
Sakaida I, Tsuchiya M, Okamoto M. et al .
Late evening snack and the change of blood glucose level in patients with liver cirrhosis.
Hepatol Res.
2004;
30 S
67-72
-
72
Sarin S K, Dhingra N, Bansal A. et al .
Dietary and nutritional abnormalities in alcoholic liver disease: a comparison with chronic alcoholics without liver disease.
Am J Gastroenterol.
1997;
92
777-783
-
73
Schiefke I, Fach A, Wiedmann M. et al .
Reduced bone mineral density et altered bone turnover markers in patients with non-cirrhotic chronic hepatitis B or C infection.
World J Gastroenterol.
2005;
11
1843-1847
-
74
Schnedl W J, Wallner S J, Piswanger C. et al .
Glycated hemoglobin and liver disease in diabetes mellitus.
Wien Med Wochenschr.
2005;
155
411-415
-
75
Shankbar T P, Solomon S S, Duckworth W C. et al .
Growth hormone and carbohydrate intolerance in cirrhosis.
Horm Metab Res.
1988;
20
579-583
-
76
Shetty A, Wilson S, Kuo P. et al .
Liver transplantation improves cirrhosis-associated impaired oral glucose tolerance.
Transplantation.
2000;
69
2451-2454
-
77
Siegel E G, Gallwitz B, Schmidt W E. et al .
Hepatogenic diabetes – the current concepts of its pathophysiology and therapy.
Dtsch Med Wochenschr.
1999;
124
1530-1535
-
78
Siegel E G, Jakobs R, Riemann J F.
Pancreatic insufficiency-induced and hepatogenic diabetes. Special aspects in pathophysiology and treatment.
Internist.
2001;
42 (Suppl 1)
8-19
-
79
Sigal S H, Stanca C M, Kontorinis N. et al .
Diabetes mellitus is associated with hepatic encephalopathy in patients with HCV cirrhosis.
Am J Gastroenterol.
2006;
101
1490-1496
-
80
Smith-Laing G, Orskov H, Gore M BR. et al .
Hyperglucagonaemia in cirrhosis. Relationship to hepatocellular damage.
Diabetologia.
1980;
19
103-108
-
81
Tilg H, Wilmer A, Vogel W. et al .
Serum levels of cytokines in chronic liver diseases.
Gastroenterology.
1992;
103
264-274
-
82
Tsuchiya M, Sakaida I, Okamoto M. et al .
The effect of a late evening snack in patients with liver cirrhosis.
Hepatol Res.
2005;
31
95-103
-
83
Unger R H, Grundy S.
Hyperglycaemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes.
Diabetologia.
1985;
28
119-121
-
84
Uribe M, Dibildox M, Malpica S. et al .
Beneficial effect of vegetable protein diet supplemented with psyllium plantago in patients with hepatic encephalopathy and diabetes mellitus.
Gastroenterology.
1985;
88
901-907
-
85
Vidal J, Ferrer J P, Esmatjes E. et al .
Diabetes mellitus in patients with liver cirrhosis.
Diabetes Res Clin Pract.
1994;
25
19-25
-
86
Wettstein M, Kircheis G, Häussinger D.
Hepatische Enzephalopathie – Diagnostik.
Dtsch Med Wochenschr.
2003;
128
2654-2657
-
87
Wyke R J.
Problems of bacterial infection in patients with liver disease.
Gut.
1987;
28
623-641
Dr. Felix Gundling
II. Medizinische Abteilung Städtisches Krankenhaus München-Bogenhausen
Englschalkinger Straße 77
81925 München
Telefon: + + 49/89/92 70 20 61
Fax: + + 49/89/92 70 24 86
eMail: Felix.Gundling@gmx.de
