Choline deprivation: An overview of the major hepatic metabolic response pathways

Abstract Choline (Ch) is an important nutrient that is involved in many physiological functions. Deprivation of Ch (CD) may lead to hepatocellular modifications and/or even hepatic tumorigenesis and it can be a frequent problem in clinical settings; it can accompany various common pathological (alcoholism and malnutrition) or physiological states (pregnancy and lactation). The aim of this review is to provide an up-to-date overview of the major metabolic pathways involved in the hepatic response toward the experimentally or clinically induced CD, and to shed more light on the implicated (and probably interrelated) mechanisms responsible for the observed hepatocellular modifications and/or carcinogenesis.     

Hepatic Injury Due to Combined Choline-Deprivation and Thioacetamide Administration: An Experimental Approach to Liver Diseases

Background

The induction of prolonged choline-deprivation (CD) in rats receiving thioacetamide (TAA) is an experimental approach of mild hepatotoxicity that could resemble commonly presented cases in clinical practice (in which states of malnutrition and/or alcoholism are complicated by the development of other liver-associated diseases).

Aim

The present study aimed to investigate the time-dependent effects of a 30-, a 60- and a 90-day dietary CD and/or TAA administration on the adult rat liver histopathology and the serum markers of hepatic functional integrity.

Methods

Rats were divided into four main groups: (a) control, (b) CD, (c) TAA and (d) CD?+?TAA. Dietary CD was provoked through the administration of choline-deficient diet, while TAA administration was performed ad libitum through the drinking water (300?mg/l of drinking water).

Results

Histological examination of the CD?+?TAA liver sections revealed micro- and macro-vesicular steatosis with degeneration and primary fibrosis at day 30, to extensive steatosis and fibrosis at day 90. Steatosis was mostly of the macrovesicular type, involving all zones of the lobule, while inflammatory infiltrate consisted of foci of acute and chronic inflammatory cells randomly distributed in the lobule. These changes were accompanied by gradually increasing mitotic activity, as well as by a constantly high alpha-smooth muscle actin immunohistochemical staining. The determination of hepatocellular injury markers such as the serum enzyme levels?? of alanine aminotransferase and aspartate aminotransferase demonstrated a decrease at day 30 (they returned to control levels at days 60 and 90). However, the determination of those serum enzymes used for the assessment of cholestatic liver injury (gamma-glutamyltransferase, alkaline phosphatase) revealed a constant (time-independent) statistically-significant increase versus control values.

Conclusions

Long-term combined dietary CD and TAA administration could be a more realistic experimental approach to human liver diseases involving severe steatosis, fibrosis, stellate cell activation and significant regenerative hepatocellular response.     

Preemptive opioid analgesia does not influence pain after abdominal hysterectomy

Opioid administration before surgical stimulus may reduce or prevent subsequent pain. We studiied the effect of timing of opioid administration on the pain-related behaviour after abdominal hysterectomy. Eighty-five patients scheduled for abdominal hysterectomy were blindly randomized to receive fentanyl 10 μg· kg^?1 before induction of anaesthesia (FA), after peritoneal incision (FB) or after removal of the uterus (FC), or sufentanil 1 μg· kg^?1 before induction of anaesthesia (SA) or after peritoneal incision (SB) respectively. All patients received a standard postoperative analgesic regimen. The time from skin closure to the first analgesic request was recorded. Pain was assessed using the VAS and a verbal rating score (VSR 1 =no pain to 6 = intolerable pain) every 30 min until patients asked for the first analgesic, and 24 hr postoperatively. The times from skin closure to the first analgesic request did not differ among the five groups. The VAS scores using the two-way ANOVA with repeated measurements differed among the five groups (F = 4.046, df = 4, 213, P < 0.005). The VAS scores with one-way ANOVA differed among the five groups 30 min postoperatively (F = 4.542, df = 4, 58, P < 0.003), being higher in the FA (6.5 ± 1.8) and SA (5.9 ± 2.1) groups than in the FC (3.2 ± 2.5) group, and at 120 min postoperatively (F = 3.217, df= 4, 18, P < 0.05), being higher in the FA than in the FB group (6.1 ± 7.5 and 2.6 ± 1.9 respectively). The VRS scores did not differ among the FA, FB, FC, SA and SB groups at any time. This study failed to demonstrate a preemptive effect of systemic administration of fentanyl or sufentanil in the doses tested.     

Brief periods of hypoxia can produce hepatic injury in rats

To determine whether brief periods of hypoxia could produce hepatic injury, we pretreated Sprague-Dawley rats with phenobarbital, deprived them of food for 24 hr, and then exposed them to various hypoxic mixtures of nitrogen and oxygen for various lengths of time. Rats exposed to 6% oxygen for 15 or more minutes had centrilobular injury, the severity of which was directly related to the length of exposure (r = 0.71). Extrapolation of these data indicated that no injury would occur if exposures were less than 5 min. Experiments using lower concentrations of oxygen did not reveal hepatic injury, probably because death of the animals occurred before the appearance of detectable injury of the liver. Feeding animals before imposition of hypoxia markedly decreased the risk of hepatic injury. Whether patients who are deprived of food preoperatively and whose liver enzymes are induced incur an increased risk of hepatic injury from brief periods of hypoxia remains to be determined.