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© Borgis - Postępy Nauk Medycznych 4/2013, s. 267-274
*Wojciech Lisik1, Paweł Ziemiański1, Rafał Marszałek1, Maciej Kosieradzki1, Tomasz Gryczewski1, Zbigniew Wierzbicki1, Agnieszka Perkowska-Ptasińska2, Justyna Domienik-Karłowicz3, Piotr Pruszczyk3, Andrzej Chmura1
Niealkoholowa stłuszczeniowa choroba wątroby w otyłości olbrzymiej
Nonalcoholic fatty liver disease in patients with morbid obesity
1Department of General Surgery and Transplantology, Transplantation Institute, Medical University of Warsaw
Head of Department: prof. Andrzej Chmura, MD, PhD
2Department of Transplantology and Nephrology, Transplantation Institute, Medical University of Warsaw
Head of Department: prof. Magdalena Durlik, MD, PhD
3Department of Internal Diseases and Cardiology, Medical University of Warsaw
Head of Department: prof. Piotr Pruszczyk, MD, PhD
Cel pracy. Celem pracy była ocena częstości występowania niealkoholowej stłuszczeniowej patologii wątroby (NAFLD), zaburzeń biochemicznych towarzyszących tej patologii, jak również opracowanie sposobu pozwalającego na prognozowanie wystąpienia NAFLD lub niealkoholowego zapalenia wątroby (NASH) wśród chorych patologicznie otyłych.
Materiał i metody. Analizie retrospektywnej poddano badania biochemiczne krwi i wycinki wątroby uzyskane w trakcie zabiegu bariarycznego od 144 chorych. Badaniem prospektywnym objęto 54 chorych, u których dodatkowo oceniano stężenia cytokin prozapalnych i ich receptorów.
Wyniki. W 144 wycinkach wątroby badanie było prawidłowe w 23%, izolowane włóknienie stwierdzono w 5%, stłuszczeniową patologię wątroby aż w 72% (gdzie izolowane stłuszczenie – NAS stanowiło 28% i NASH – 44%). Analiza danych pomiędzy grupą z prawidłowym badaniem histopatologicznym i NAS wykazała, że w tej drugiej notuje się znamiennie wyższy poziom ALT (26,6 ± 11,3 vs 36,3 ± 18,3; P < 0,05) i trójglicerydów (112,5 ± 49 vs 164,1 ± 93,2 ; P < 0,05) natomiast niższy HDL (54,5 ± 13,9 vs 45,8 ± 11,7; P < 0,04). Porównując osoby z prawidłową wątrobą i NASH i stwierdzono odpowiednio w pierwszej grupie niższe stężenie ALT (26,6 ± 11,3 vs 56,6 ± 28,4; P < 0,002), niższe stężenie GGTP (9,3 ± 1,5 vs 36,0 ± 11,1; P < 0,02), jak również niższy poziom trójglicerydów w surowicy (112,5 ± 49 vs 180,6 ± 89,3; P < 0,02). Poziom HDL był znamiennie wyższy w grupie NASH (55,4 ± 13,9 vs 46,2 ± 10; P < 0,02). Średnie stężenie ALT w grupie NASH przekraczało normę. Oceniając wyniki badań biochemicznych, stężeń cytokin i ich receptorów opracowano schematy pozwalające prognozować wystąpienia NAFLD i NASH w grupie patologicznie otyłych pacjentów.
Wnioski. U większości chorych zakwalifikowanych do zabiegu chirurgicznego leczenia otyłości występuje NAFLD. Zwiększenie aktywności ALT i AST, podwyższenie stężeń TNF-α i leptyny oraz obniżenie stężenia adiponektyny u osób patologicznie otyłych towarzyszą NAFLD. Opracowany model regresji logistycznej, pozwala na przewidzenie wystąpienia związanych z otyłością zmian histologicznych w wątrobie, bez konieczności wykonywania biopsji tego narządu.
Introduction. Accumulation of fat in obese individuals can impact hepatocytes and contributes to the inflammatory process, which in extreme cases results in fibrosis, cirrhosis, and failure of the liver.
Aim. The aim of this study was to assess the prevalence of nonalcoholic fatty liver disease (NAFLD), biochemical abnormalities accompanying this pathology, as well as the development of diagnostic method allowing the prediction of NAFLD or nonalcoholic steatohepatitis (NASH) among pathologically obese patients.
Material and methods. We retrospectively analyzed blood chemistry and liver biopsies obtained during surgery from 144 bariatric surgery patients. We also included 54 patients with evaluated blood levels of pro-inflammatory cytokines and their receptors.
Results. Out of 144 liver biopsies the 23% were normal, and isolated fibrosis was found in 5%, NAFLD was found in 72% of biopsies (where the isolated steatosis – NAS occurred in 28% and NASH – in 44%). Comparison of the data between the group with normal histopathology and with NAS showed that the second group had a significantly higher ALT and triglyceride levels but lower HDL. Comparison of subjects with normal liver and with NASH, we found that the first group had the lower concentration of ALT and GGTP, as well as lower levels of serum triglycerides. The average concentration of ALT in NASH group exceeded the normal limits. In assessing the concentrations of cytokines and their receptors we were able to develop formulas, which allow prediction of the NAFLD and NASH occurrence in a group of morbidly obese patients.
Conclusions. NAFLD occurs in most patients awaiting bariatric surgery. Elevation of ALT and AST activity, elevated concentrations of TNF-α and leptin and lower adiponectin levels in pathologically obese people are risk factors for NAFLD. Logistic regression model that applies above parameters allows prediction of the occurrence of obesity-related histological changes in the liver, without need for performing the liver biopsy.

Accumulation of fat in the organism affects almost all organs, and when it occurs in liver cells it contributes to the inflammatory process, which in extreme cases result in fibrosis, cirrhosis, and failure of the liver (1). Despite the fact that fatty liver is only the morphological feature, it presence correlates with diseases and metabolic disorders. The process of liver deterioration, which eventually results in liver failure is slow and for a long time asymptomatic. Clinical differentiation between simple steatosis and that with inflammatory reaction is impossible if one relies solely on biochemical analysis. The only method that allows for certain diagnosis is histopathological examination of the tissue, which, due to the risk of complications is performed very rarely. So far nonsurgical attempts to identify fatty liver disease, did not bring the expected results, mainly because the commonly used imaging techniques are non-specific and not sensitive enough to allow the assessment of the disease severity (2, 3).
Increasing hepatic lipid resources, increase the hepatocellular damage, through the oxidative stress of inflammation and proinflammatory cytokine activity. Not without significance is the phenomenon of insulin resistance found in obesity. Metabolic activity of adipose tissue is controlled by the endocrine system and its downstream components such as insulin, sex hormones and adrenal catecholamines.The morphological changes associated with steatosis of liver, not related to alcohol abuse, are called nonalcoholic fatty liver disease (NAFLD). Course of NAFLD, initially mild, is an insidious, contributing to the creation, in every fifth patient, a nonalcoholic steatohepatitis (NASH), which may progress in 19-33% of cases, into cirrhosis. The next step of the disease, launched by a simple accumulation of fat can progress from cirrhosis to the hepatocellular carcinoma (HCC) (4, 5). Incidence risk of NASH increases with the enlargement of body weight, from 7% in the general population to 80% in obese population (6-8).
Search for the causes of NAFLD highlighted its relationship with insulin resistance. Insulin alters lipid metabolism by increasing lipolysis in peripheral tissues, increasing the synthesis of triglycerides and severity of hepatic uptake of free fatty acids (9, 10). In the first phase of insulin resistance, the hyperinsulinemia, in combination with low levels of adiponectin and elevated TNF-α and leptin causes fatty degeneration leading to a second stage, the steatotic liver, which is more prone to hepatocyte injury. The oxidative stress, which affects lipid peroxidation and activates inflammatory cytokines that cause NASH, and the activation of fibrosis promoters ultimately lead to liver fibrosis and cirrhosis (11, 12).
The diagnosis of NAFLD is difficult. In half of the cases it is asymptomatic, sometimes it is accompanied by excessive fatigue, and nonspecific abdominal pain. In 75% of cases the physical examination shows hepatomegaly, splenomegaly and also less common disorders and symptoms of portal hypertension. Biochemical analysis of peripheral blood serum shows moderately elevated transaminase levels, but in contrast to the alcohol related fatty degeneration, the ratio of AST/ALT (de Ritis ratio) is usually less than 1 (13). The imaging tests can help in diagnosis, however, because of their low sensitivity and specificity they are not able to diagnose an early stage of the disease. They may only indicate a suspicion of the significant fibrosis and evaluate portal hypertension. They may, however, be useful when applied for the monitoring of the treatment. A very important role in the diagnosis of liver disease in obese patients plays a past medical history, allowing the identification of patients exposed to toxic etiology of the liver disease. NAFLD should not be identified in patients that consumed pure alcohol in an amount more than 40 g per week for men and 20 g for women (14).
In the presence of risk factors (such as obesity, type 2 diabetes, hyperlipidemia, and hypertension), and exclusion of other causes that may be responsible for an average increase of transaminases (such as hepatotropic virus infection, autoimmune hepatitis, hemochromatosis, α1-antitrypsin deficiency, galactosemia, tyrosinemia, Wilson’s disease or inflammatory bowel disease) diagnosis of NAFLD is reliable only after histopathological evaluation (15). Only this examination allows to determine the degree of fatty degeneration, the presence of inflammatory infiltrates with foci of necrosis or advanced fibrosis. However, histopathological examination alone, excluding the medical history, not allows to distinguish NAFLD pathology from the damage caused by alcohol consumption (16-18).
Complexity of NAFLD prevention does not allow defining commonly acceptable treatment guidelines. The NAFLD treatment comprises of weight loss and the compensation of dyslipidemia and hyperglycemia (19).
Weight reduction in obese person results in an improvement in the metabolic, endocrine and psychological condition. In case of failure of conservative treatments for obesity, such as dietary therapy, lifestyle changes, psychotherapy and pharmacotherapy, a surgical treatment should be considered. Negative energy balance obtained after surgery is due to the reduced amounts of food eaten at single meal, and the effect of malabsorption. Surgery usually provides a much larger and longer-lasting weight loss than the conservative treatment.
The data obtained from the medical records of patients undergoing bariatric surgery in the Division and the Department of General Surgery and Transplantology between 2001 and 2009 were retrospectively analyzed. The sera (obtained at least 24 hours before surgery) of these patients were analyzed for lipid content, markers of liver function and the level of high sensitive C-reacitve protein (hsCRP). During the procedure, a routine wedge biopsies of liver were also taken.
The histopathological evaluation data of the liver wedge biopsy were collected from 165 people. The total 21 patients were excluded from the study: 7 patients because of the symptoms indicating prior infection with hepatitis B virus (HBsAg positive or the presence of anti-HBc), 2 patients with hepatitis C virus (presence of anti-HCV antibodies in the serum) and 12 patients with uncertain history of alcohol abuse. Overall assessment of the liver biopsy was performed in 144 patients. In this group, the average age was 39.9 years, 79.2% were women, women were statistically younger than men (38.9 vs 43.6 years, P < 0.02). Mean BMI was 47.1 kg/m2 and not statistically different between the two sexes.
The plasma from a group of prospective patients was analyzed using ELISA, for the level of adiponectin, leptin, interleukin-6 (IL-6), soluble receptor for IL-6 (sIL-6 R), an hsCRP, tumor necrosis factor α (TNF-α) and soluble receptors for TNF-α (sTNF RI and sTNF RII). Tests were performed immediately before surgery and 12 months later. The people who have had an uncertain history of alcohol abuse (more than 40 g of pure alcohol per week for men and 20 g for women) and those with a history of features of viral hepatitis were excluded from the analysis. A total of 54 patients, at the age of 39.9 years (21.1-58.7), were enrolled. 70.4% of all patients were women. Weight and BMI did not differ between the genders.
Out of total 144 liver biopsies taken from morbidly obese, the normal results were present in only 23% of biopsies. Isolated fibrosis was found in 5%, and fatty liver disease in 72% (which represented 28% of the NAS and 44% of NASH).
Anthropometric parameters (weight, age, sex) and biochemical test of serum were assessed in two groups of patients: with no liver pathology, and with abnormal picture in histopathological examination. We found that the group without liver pathology was younger (37.1 ± 12.2 vs. 40.7 ± 8.6 years, p < 0.05), had a lower concentration of alanine transaminase (25.9 ± 11.3 vs 47 , 9 ± 23.5 IU/L, P < 0.006), aspartate transaminase (26.6 ± 17.9 vs 31.6 ± 17,9 IU/L; P < 0.05), gamma-glutamyl transferase (9.3 ± 1.5 vs 31 ± 14.1 IU/L; P < 0.04), triglycerides (112.5 ± 48 vs 171.6 ± 81.8 mg/dL; P <0.03) and higher HDL cholesterol (54.5 ± 13.9 vs 46.3 ± 10.7 mg/dL; P < 0.01).
In patients with abnormal liver histology mean ALT levels exceeded normal limits.
Mean body weight and BMI did not differ between the groups. Gender also had no effect on the occurrence of the liver pathology.
Comparison of the data between the group with normal histopathology and the NAS showed that the second group had a significantly higher level of ALT (26.6 ± 11.3 vs 36.3 ± 18.3 IU/L; P < 0.05) and triglycerides (112, 5 ± 49 vs 164.1 ± 93.2 mg/dL; P < 0.05) but lower HDL (54.5 ± 13.9 vs 45.8 ± 11.7 mg/dL; P < 0.04).
Similarly, were analyzed a group of NASH and normal histopathological outcome. The group without pathology had significantly lower weight (128.2 ± 21.5 kg vs. 140 ± 24.2 kg, P < 0.02), lower BMI (45.3 ± 7.3 kg/m2 vs 48, 6 ± 6.1 kg/m2, P < 0.03), lower levels of ALT (26.6 ± 11.3 vs 56.6 ± 28.4 IU/L; P < 0.002), lower levels of GGT (9.3 ± 1.5 vs. 36.0 ± 11.1 IU/L; P <0.02), as well as lower levels of triglycerides (112.5 ± 49 vs 180.6 ± 89.3 mg/dL; P <0.02). HDL cholesterol was significantly higher in this group (55.4 ± 13.9 vs 46.2 ± 10 mg/dL; P < 0.02). The average level of ALT in NASH group exceeded normal limits.
Comparison between the group of NASH and NAS showed statistical differences only in ALT (56.6 ± 28.5 vs 36.3 ± 18.3 IU/L; P < 0.012) and AST (35.9 ± 20.5 vs 26.1 ± 10.4 IU/L; P < 0.03) levels.
Evaluation of the risk of isolated fibrosis showed no correlation between specific pathology (NASH, NAS) and the normal picture of the liver.
Using Cox proportional hazard model we analyzed the impact of the presence of comorbidities of the obesity in the study group, such as type 2 diabetes, glucose intolerance, hypertension, obstructive sleep apnea and dyslipidemia on the NAFLD and we found an increased risk of NASH only in patients with sleep apnea (χ2 = 9.040836 p = 0.0109).
In the prospective group, prior to surgery, we tested the levels of: adiponectin, leptin, interleukin-6 (IL-6), soluble receptor for IL-6 (sIL-6 R), hsCRP, tumor necrosis factor α (TNF-α) and soluble receptors for TNF-α (sTNF RI and sTNF RII). In this group NASH was diagnosed in 32 and NAS in 14 cases. Only 8 patients had no liver pathology.
We found that the distribution of specific liver pathology was equal for both genders, has not been influenced by age, excess weight, BMI or fat mass. NASH group had a statistically higher percentage of fat in relation to the NAS group (49.4 ± 5.9% vs 44.4 ± 7.5%, P < 0.04).
Analyzis of the correlation matrix showed that the level of leptin was significantly higher (48.75 vs. 33.04 ng/mL; P = 0.037), while sTNFRII was lower in females than in men (3.04 v. 3.73 ng/mL; P < 0.003).
Comparison of the model of body fat distribution (visceral or gynoid) demonstrated no effect on the concentration of each protein in the serum.

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otrzymano: 2013-02-19
zaakceptowano do druku: 2013-03-27

Adres do korespondencji:
*Wojciech Lisik
Department of General Surgery and Transplantology Medical University of Warsaw
ul. Nowogrodzka 59, 02-006 Warszawa
tel.: +48 (22) 502-17-84
e-mail: wojciech.lisik@wum.edu.pl

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