Alterations in Hepatic Mitochondrial Function during Total Parenteral Nutrition in Immature Rats

Katayama, Tetsuo; Tanaka, Mitsuru; Tanaka, Kōichi; Asonuma, Katsuhiro; Üemoto, Shinji; Okamura, Ryuji; Utsunomiya, Hirofumi; Fujita, Shiro; Ueda, Jun-ichi; Ozawa, Kazue

doi:10.1177/0148607190014006640

Cited by 18 publications

(12 citation statements)

References 29 publications

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“…In cases of liver cirrhosis, fatty liver, or injury from xenobiotics, oxidative metabolism of various substrates is impaired because of the dysfunction of the electron transport chain in hepatic mitochondria [9,10]. A study designed to evaluate mitochondrial function in immature rats suggested that PN use induced marked metabolic changes to the mitochondria leading to deficiencies in mitochondrial phosphorylation and respiratory chain function compared to a control group [11]. …”

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confidence: 99%

Novel intravenous 13C-methionine breath test as a measure of liver function in children with short bowel syndrome

Duro

Duggan

Valim

et al. 2009

Journal of Pediatric Surgery

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Monitoring hepatic function in children with short bowel syndrome (SBS) and parenteral nutrition-associated liver disease (PNALD) is currently limited to conventional blood testing or liver biopsy. Metabolism of the stable isotope L[1-13 C]methionine occurs exclusively in liver mitochondria and can be noninvasively quantified in expired breath samples. We hypothesized that the 13 C-methionine breath test ( 13 C-MBT) could be a safe, noninvasive, and valid measure of hepatic mitochondrial function in children with SBS and PNALD.Methods-Baseline breath samples were collected in 8 children with SBS before intravenous administration of 2 mg/kg of L[1-13 C]methionine. Six paired breath samples were obtained at 20-minute intervals. The 13 CO 2 enrichment was analyzed using isotope ratio mass spectrometry.Results-All 8 patients (5 males; mean age, 8.9 months) tolerated the 13 C-MBT without adverse events. Two patients underwent serial testing. One patient, tested before and after resolution of cholestasis, demonstrated increased cumulative percentage dose (4.7% to 6.6%) and area under the curve (AUC) . A second patient with progressive PNALD demonstrated decreased cumulative percentage dose (from 7.8% to 5.9%) and AUC (from 335 to 288). 13 C-MBT is a feasible, safe, and potentially clinically relevant measure of hepatic mitochondrial function in children with SBS and PNALD. [3][4][5][6]. Parenteral nutrition (PN) has become widely accepted as the primary supportive therapy in infants with SBS, and mortality because of dehydration and malnutrition has been essentially eliminated [7]. This lifesaving therapy, however, has been plagued by the recognition that infants with prolonged dependence on PN commonly develop progressive and severe hepatic dysfunction. Our own data confirmed a 90% mortality rate in infants with SBS and cholestatic liver disease who were unable to wean from PN [8]. Conclusion-TheThe diagnosis of PN-associated liver disease (PNALD) has historically been performed with routine biochemical tests of hepatic function, including hepatic transaminases, conjugated bilirubin, albumin, and prothrombin time. The "gold standard" test remains liver histopathologic examination, but the young age, small size, and precarious medical status of many infants with SBS and suspected PNALD make routine liver biopsy difficult to perform. Because PNALD has been associated with a poor prognosis among SBS patients, early identification of infants with progressive disease is needed and should allow earlier treatment and potentially avoid the need for liver or liver-intestine transplantation.Hepatic mitochondrial dysfunction is a consequence of a wide range of liver pathologic condition and is a useful marker of overall liver function. In cases of liver cirrhosis, fatty liver, or injury from xenobiotics, oxidative metabolism of various substrates is impaired because of the dysfunction of the electron transport chain in hepatic mitochondria [9,10]. A study designed to evaluate mitochondrial function in immature rats sug...

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confidence: 99%

Novel intravenous 13C-methionine breath test as a measure of liver function in children with short bowel syndrome

Duro

Duggan

Valim

et al. 2009

Journal of Pediatric Surgery

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“…12 With the administration of TPN, changes in liver metabolism occur, resulting in a decreased lipoprotein and drug metabolism.3 1 ,3'2 Prolonged administration of TPN eventually results in hepatomegaly and elevated liver lipids not consistently observed in enterally fed animals, which may result in impairment of hepatic function. [32][33][34][35] As demonstrated in this study, there was an increase in liver lipid in both the TB-TPN and TB-EN groups, although the increase was greater in the TB-TPN group.…”

Section: Discussionmentioning

confidence: 81%

Parenteral vs Enteral Nutrition in Tumor‐Bearing Rats

Stallion

Foley-Nelson

Chance

et al. 1994

J Parenter Enteral Nutr

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The development of cachexia may complicate cancer therapy, yet controversy exists concerning its nutritional management. For example, use of total parenteral nutrition (TPN) may not be appropriate because of gut atrophy, possible stimulation of tumor growth, and lack of total host protein repletion. In the present experiment, host and tumor responses were compared after identical parenteral or enteral nutritional supplementation (EN). Eighteen days after subcutaneous inoculation of adult male Fischer-344 rats with fresh methylcholanthrene-induced sarcoma (tumor-bearing [TB] rats), catheters were placed into either the external jugular vein or the stomach. Four days later, rats were started on an 11-day course of either TPN or EN with a Freamine-III-based formula (amino acids = 6%, dextrose = 21.5%, lipid = 1.5%). When the rats were killed, there was no difference in tumor weight between the various TB groups. Carcass weight was increased significantly in both the TB-TPN and TB-EN groups, and there was an elevation in gastrocnemius protein content in both groups compared with the TB-rat food group. Small intestine protein was preserved in the TB-EN group to the level observed in the control-rat food animals. Total lipids in the liver were increased in both TB-TPN and TB-EN groups; however, the magnitude of the increase was less in the TB-EN animals. Neither treatment resulted in complete protein repletion of tumor-bearing rats. EN may be more appropriate than TPN in that gut mass is preserved. The maintenance of gut mucosa may prove to be beneficial in the treatment of the depleted, immunocompromised, and metabolically stressed host.

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“…10,11 Little information is available, however, to explain the mechanism whereby d-TPN attenuates postoperative liver injury, although possible effects on hepatic mitochondrial function have been postulated. 12 Katayama et al 12 reported that continuous TPN (c-TPN) resulted in decreased hepatic energy charge and rates of oxidative phosphorylation in the hepatic mitochondria of immature rats, and speculated that this deterioration in mitochondrial function may contribute to hepatic dysfunction in infants. Because cholestasis, a major hepatic complication of TPN in infants, is closely associated with adenosine triphosphate breakdown in hepatocytes, 13 it is not unreasonable to examine whether TPN may alter the susceptibility of mitochondrial function in the liver, particularly following surgical intervention.…”

Section: Although Discontinuous Total Parenteral Nutrition (D-tpn)mentioning

confidence: 99%

Discontinuous Total Parenteral Nutrition Prevents Postischemic Mitochondrial Dysfunction in Rat Liver

et al. 1998

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Although discontinuous total parenteral nutrition (d-TPNAlthough total parenteral nutrition (TPN) is a lifesaving therapy for those who are unable to be nourished enterally, its associated hepatic complications of steatosis, cholestasis, and hepatic failure restrict its application. 1 In neonates and infants undergoing the TPN treatment, cholestasis is a major complication that can occur progressively, often resulting in death from chronic hepatic failure. 2 Although multiple factors including calorie excess, 3 essential fatty acid deficiency, 4 amino acid imbalance, 5 loss of enteric stimulation, 6 and bacterial translocation 7,8 might contribute to TPN-associated hepatobiliary dysfunction, its etiology and mechanisms have not fully been investigated experimentally.Continuous infusion of a high-calorie solution is thought to contribute to TPN-induced steatosis by enhancing de novo liver fatty acid synthesis and by suppressing fatty acid oxidation as a result of high plasma insulin. 9 Discontinuous TPN (d-TPN) has been therefore devised to mimic the physiological circadian pattern of feeding in an attempt to lower the high levels of insulin. This strategy has thus been applied clinically to prevent the liver from incurring steatosis. 10,11 Little information is available, however, to explain the mechanism whereby d-TPN attenuates postoperative liver injury, although possible effects on hepatic mitochondrial function have been postulated. 12 Katayama et al. 12 reported that continuous TPN (c-TPN) resulted in decreased hepatic energy charge and rates of oxidative phosphorylation in the hepatic mitochondria of immature rats, and speculated that this deterioration in mitochondrial function may contribute to hepatic dysfunction in infants. Because cholestasis, a major hepatic complication of TPN in infants, is closely associated with adenosine triphosphate breakdown in hepatocytes, 13 it is not unreasonable to examine whether TPN may alter the susceptibility of mitochondrial function in the liver, particularly following surgical intervention. This study was thus designed to compare the changes in hepatic mitochondrial membrane potential (⌬⌿) and biliary function during c-TPN and d-TPN. MATERIALS AND METHODSAnimal Pretreatment With TPN. Protocols for the present study were approved by the guidelines of Animal Care Facility in Keio University School of Medicine. Male Wistar rats weighing 200 to 250 g were randomized into four groups: 1) a group treated with an ordinary chow diet followed by overnight fasting; 2) a c-TPN group; 3) a d-TPN group in which the livers were excised in a fed state (fed d-TPN); and 4) a d-TPN group in which the livers were excised in a fasted state (fasted d-TPN). Compositions of the chow diet were as follows: fibers, 3.5%; fats, 4.8%; proteins, 27.1%; soluble nonAbbreviations: d-TPN, discontinuous total parenteral nutrition; c-TPN, continuous total parenteral nutrition; LDH, lactate dehydrogenase; Rh123, rhodamine 123; ⌬⌿, membrane potential; PI, propidium iodide; FITC-BSA, fluorescein isothi...

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Alterations in Hepatic Mitochondrial Function during Total Parenteral Nutrition in Immature Rats

Cited by 18 publications

References 29 publications

Novel intravenous 13C-methionine breath test as a measure of liver function in children with short bowel syndrome

Novel intravenous 13C-methionine breath test as a measure of liver function in children with short bowel syndrome

Parenteral vs Enteral Nutrition in Tumor‐Bearing Rats

Discontinuous Total Parenteral Nutrition Prevents Postischemic Mitochondrial Dysfunction in Rat Liver

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