Drug-induced liver injury (DILI) is a challenging and constantly changing field. The pathologist plays a key role in interpreting liver biopsies by classifying the pattern of injury, grading the severity of injury, and evaluating for other possible causes. Reports of iatrogenic liver injury are reviewed here with a focus on total parenteral nutrition (ie, intestinal failure-associated liver disease [IFALD]) and immune checkpoint inhibitors (ICIs). The hallmark features of IFALD are cholestasis and steatosis. Cholestasis is more common in infants, whereas steatosis and steatohepatitis are more commonly seen in older children and adults. Infants tend to have a faster progression to fibrosis and cirrhosis. Perivenular fibrosis and ductopenia may also be seen in IFALD. Although fish oil-based lipid emulsions can reverse cholestasis, recent studies have shown persistent or progressive fibrosis. ICI-induced liver injury usually presents as an acute hepatitis with features similar to those seen in idiopathic autoimmune hepatitis and drug-induced autoimmune hepatitis. However, it lacks a prominent plasma cell infiltrate and serological markers of autoimmune hepatitis. Other features such as fibrin ring granulomas and cholangitis have also been reported in association with ICIs. Treatment for ICI-induced liver injury includes corticosteroids and other immunosuppressants.

Total parenteral nutrition provides nutrition by infusion into the systemic circulation. Bypassing the intestine and processes associated with absorption can cause additional pathophysiological changes to occur. For example, in rats, normal gut and pancreatic cell function may change, absorptive capacity may be altered, and enzyme functional activity including drug metabolism may be affected. The objective of this study was to examine the effects of a control diet or a diet of total parenteral nutrition in the presence or absence of choline on urinary biomarkers and hepatic microsome functional activity from rats. Selective functional markers of cytochrome P-4502E1 (CYP2E1) and flavin-containing monooxygenase (FMO) were examined in vitro. The N-oxygenation of trimethylamine was used as an in vivo selective functional marker for FMO. After the administration of total parenteral nutrition plus choline for 5 days, the urinary excretion of trimethylamine and trimethylamine N-oxide declined approximately 7- and 3-fold, respectively, compared with rats treated with control diet. The concentration of urinary biogenic amines was also significantly affected by total parenteral nutrition. Compared with control animals, rats administered total parenteral nutrition plus choline for 5 days showed a decrease of approximately 5- and 2-fold in urinary dopamine and norepinephrine concentration, respectively. To examine a molecular basis for the influence of total parenteral nutrition +/- choline on monooxygenase regulation, hepatic microsomal activity of the FMO and CYP2E1 was examined. Compared with animals treated with a control diet, total parenteral nutrition plus choline in rats caused a 3-fold increase in hepatic microsomal FMO and a 2-fold increase in hepatic cytochrome CYP2E1 functional activity, respectively. Although the data did not reach statistical significance, selective immunoblot studies using hepatic microsomes from rats treated with total parenteral nutrition + choline showed that compared with controls, FMO1 protein was decreased 1.4-fold and FMO3 increased 1.3-fold, respectively. In hepatic microsomes from rats treated with total parenteral nutrition + choline, compared with control animals, FMO4 immunoreactivity was increased 1.6-fold. The data suggest that total parenteral nutrition has a detectable effect on modulating rat FMO3, FMO4, and CYP2E1 monooxygenase functional activity. The clinical relevance of these results is unknown but may be of significance for individuals receiving total parenteral nutrition and those afflicted with trimethylaminuria.

The main objective of this study was to evaluate the effect of switching from parenteral to enteral feeding on liver blood flow and propofol steady-state blood concentrations in patients in the intensive care unit (ICU).

Steady-state blood concentrations of propofol were measured in eight ICU patients before (on days D -3, D -2, and D -1) and after (on days D + 1, D + 2, and D + 3) switching from parenteral to enteral feeding (on day DO). All patients received a continuous intravenous infusion of propofol (4.5 mg x kg(-1) x h(-1)) from several days before the start of the study, continuing throughout the experimental period. Hepatic blood flow was estimated by measuring steady-state D-sorbitol hepatic clearance.

Hepatic blood flow was high and was not affected by switching from parenteral to enteral feeding: 33 +/- 8 ml x min(-1) x kg(-1) (mean +/- SD) and 33 +/- 10 ml min(-1) x kg(-1) on D -3 and D -1, respectively, as compared to 37 +/- 11 ml x min(-1) kg(-1) and 34 +/- 8 ml x min(-1) x kg(-1) on days D + 1 and D + 3, respectively. Systemic clearance of propofol was much higher than liver blood flow with average values on the six observation days ranging from 74.0 to 81.2 ml x min(-1) x kg(-1) and was not affected by switching from parenteral to enteral feeding.

Liver blood flow and systemic clearance of propofol were not affected by switching from parenteral to enteral feeding in the eight ICU patients studied. Extrahepatic clearance accounted for at least two thirds of the overall systemic clearance of propofol.

NASH is an important form of chronic liver disease that is increasingly recognized. The diagnosis is secured by biopsy findings with similarities to alcoholic hepatitis in a patient with a confirmed history of abstinence. Obesity is a major risk factor, but the disease also occurs in the nonobese. In 20% to 40% of patients the disease can progress to various stages of fibrosis and ultimately cause cirrhosis and death from end-stage liver disease. For this reason, recognition of NASH is important, and establishing the diagnosis provides a further impetus for performing a liver biopsy as part of the evaluation of unexplained liver abnormalities. The mainstay of treatment is weight reduction in the obese. For those individuals who are not obese, continued observation is the only option currently available. Patients who develop decompensated cirrhosis should be considered for liver transplantation unless advanced age or other underlying medical illnesses are a problem. With the increasing knowledge about the pathophysiology of hepatic steatosis, it is hoped that better diagnostic tests for specific causes of NASH will be available and lead to efficacious therapy.

NASH is a form of chronic liver disease that is defined by biopsy findings and has the appearance of alcoholic hepatitis. Although this disease was once thought to be a problem of women, diabetics, and the obese, more recent studies have identified a significant proportion of patients who do not fit these risk factors. In a fraction of patients, the disease can progress to various stages of fibrosis leading ultimately to cirrhosis and death from end-stage liver disease. For this reason, recognition of NASH is important and provides a further impetus for performing a liver biopsy as part of the evaluation of unexplained liver biochemical abnormalities. The mainstay of treatment is weight reduction in the obese. For those individuals who are not obese, continued observation is the only available option at this point. With increasing knowledge about the pathophysiology of hepatic steatosis, perhaps more specific diagnostic tests for the cause of the disease in specific patients will be available and will guide appropriate therapy.

We investigated the effect of intravenous infusions of the therapeutically available amino acid solutions Moripron and Morihepamin (Roussel Morishita, Osaka, Japan) on gallbladder contraction and cholecystokinin (CCK) release in healthy male volunteers. Plasma CCK levels were measured by radioimmunoassay, using the antibody OAL-656, which is specific for the aminoterminus of CCK-8 and thus recognizes biologically active forms of all CCKs. The volume of the gallbladder was calculated by ultrasonographic measurements. Intravenous infusion of Moripron at the rate of 3.33 ml/min for 60 min, caused gallbladder contraction, with a peak response of 31.3 +/- 8.6% of the fasting volume at 45-60 min, and a significant increase in plasma CCK concentration, from 1.8 +/- 0.2 pmol/l to a peak of 9.9 +/- 1.5 pmol/l, at 30-45 min. The maximum gallbladder contraction and the peak CCK release during the Moripron infusion were not significantly different from findings after a test meal. There was a close relationship between the peak plasma CCK concentration and the maximal gallbladder contraction during the administration of Moripron, and this agent, even when infused at the rate of 1.67 ml/min, significantly increased plasma CCK levels and gallbladder contraction. Intravenous infusion of Morihepamin had no significant influence on gallbladder volume or plasma CCK levels. The discrepancy in responses appeared to be related to differences in composition between Moripron and Morihepamin, and not to the total dose of amino acid. Intravenous infusions of amino acids appear to have different effects on gallbladder contraction and plasma CCK secretion depending on the amino acids composition. Our findings suggest that an intravenous infusion of Moripron could be used for the prophylaxis of acute acalculous cholecystitis and sludge formation due to reduced biliary motility in patients on total parenteral nutrition.

The purpose of this study was to determine whether IV chenodeoxycholate (CDC) could prevent total parenteral nutrition (TPN)-associated pigmented gallstones in the prairie dog.

Twelve prairie dogs were divided into two equal groups, each receiving an identical TPN regimen. Each animal received 92 kcal/d with 61% of the calories from carbohydrate. The total volume of infusate delivered to each animal was 59 mL/d. Animals in one group, termed the TPN + CDC group, received a daily bolus injection of CDC at a dose of 15 mg/kg. Prairie dogs in the second group, termed the TPN group, received water (vehicle carrier) 1 mL/kg/d. The TPN and TPN + CDC groups received TPN for 40.3 +/- 1.3 and 42.5 +/- 0.6 days, respectively.

There was no statistical difference in the initial and final weights between the two groups. None of the TPN + CDC-treated animals had gallstones or calcium bilirubinate crystals. In contrast, all of the TPN-treated animals had calcium bilirubinate crystals (p = .002), and five of six had macroscopic black pigmented gallstones (p = .015). Cholesterol crystals were not observed in either group of animals. The amount of biliary bilirubin and ionized calcium was significantly greater in the TPN group (both p < .001); however, both groups had a similar total biliary calcium concentration.

IV CDC is effective in preventing TPN-associated gallstones in the prairie dog.

Total parenteral nutrition provides nutrition support in patients who are unable to eat. Long-term parenteral nutrition is accompanied by alterations in gut and liver function including changes in drug metabolism. This study examined the effects of lipid-free total parenteral nutrition in rats on (1) the overall elimination pharmacokinetics of acetaminophen, (2) changes in sulfation and glucuronidation pathways during acetaminophen elimination, and (3) hepatic drug metabolizing enzyme activities determined in vitro.

Chronic indwelling catheters were implanted in the aorta, inferior vena cava, and portal vein of adult male Sprague-Dawley rats. Total parenteral nutrition, consisting of 25% dextrose, 5% amino acids, electrolytes, and vitamins, was infused via the portal vein for up to 14 days. Acetaminophen pharmacokinetics were characterized in vivo and selected drug metabolizing enzyme activities were determined in vitro.

Parenteral nutrition for 10 days decreased the total clearance of acetaminophen by 23% (from 11.5 +/- 1.4 to 8.9 +/- 1.4 mL/min per kg; p < .05) and decreased the formation clearance to acetaminophen sulfate (from 6.2 +/- 0.4 to 3.9 +/- 0.5 mL/min per kg; p < .05). Parenteral nutrition decreased microsomal cytochrome P450 concentration (47%), p-nitroanisole demethylase activity (68%) and p-nitrophenol UDP-glucuronosyltransferase activity (58%). Cytosolic glutathione-S-transferase activity towards 1-chloro-2,4-dinitrobenzene decreased 29%. Sulfotransferase activity towards p-nitrophenol and acetaminophen was decreased 48% and 25%, respectively.

Lipid-free, total parenteral nutrition depresses drug conjugative metabolism in rats. The magnitude of this effect in humans remains to be investigated.

Small bowel transplantation (SBT) is thought to be the only radical treatment for short bowel syndrome in childhood. It is very important that the length of the graft and the type of intestine be chosen carefully because this will determine the outcome of transplantation. This model of short bowel syndrome in the rat confirms that total intestinal resection results in malnutrition and failure to gain weight. After 10 cm of ileum was transplanted orthotopically in a syngeneic combination in rats with total intestinal resection, the animals gained weight. The authors determined that 10 cm of terminal ileum is the minimum length required for survival. Second, the immunologic basis of lethal graft-versus-host reaction (GVHR) as it relates to the intestinal graft length was also evaluated. Ileal grafts of 10 cm from LEW (RT1l) rats were implanted heterotopically into (LEW x BN)F1 rats. Ileal grafts of 10 or 40 cm were implanted from BN(RT1n) rats into (LEW x BN)F1 animals. A lethal GVHR always occurred after grafting a 10 cm ileum in the LEW/F1 combination, whereas only 17% of the BN/F1 recipients died of typical GVHR. However, in the latter combination, 67% lethal GVHR was induced when 40 cm of the intestinal graft was implanted. These results indicate that mesenteric lymph nodes are a major source of lethal GVHR, but gut-associated lymphoid tissue can also induce this.

Total parenteral nutrition (TPN) may affect bone metabolism in a variety of ways. These may include potential indirect effects such as on gastrointestinal hormone secretion, liver function, especially cytochrome P450 isoenzymes, metabolic biorhythms where established, and the continuous compared with the intermittent supply of nutrients. More substantial evidence exists for the reduction of bone formation, parathyroid hormone secretion, and calcitriol production in TPN patients along with high urinary calcium excretion. This review considers both aluminum loading and vitamin D sensitivity as etiologic factors and suggests that aluminum may have played a primary role in the pathogenesis of these abnormalities in bone and mineral metabolism, but that vitamin D may have potentiated the deleterious actions of aluminum. While the sources of aluminum contamination of TPN solutions have been identified and efforts are under way to reduce its contamination of TPN solutions, the persistence of low bone mass measurement in TPN patients is a problem that has been identified repeatedly, does not have a current explanation, and requires further study.

Prolonged bowel rest and total parenteral nutrition lead to gastrointestinal mucosal atrophy. The possibility that enteral diets of varying composition could have a beneficial effect in reversing total parenteral nutrition-associated gut atrophy was investigated. A group of male Sprague-Dawley rats were randomized to receive TPN for 10 days, followed by 10 days of elemental or regular food. The effects of these diets on body mass, gastro-intestinal index (intestinal weight divided by body weight), mucosal incorporation of titrated thymidine, and intestinal villi length were compared. Significant gut villi atrophy and use of gut weight occurred in rats receiving TPN and bowel rest compared with the fed control group. These changes were significantly reversed by elemental diets, but not by rat food diets. We conclude that elemental diets may enhance gut recovery after prolonged TPN and bowel rest in a rat model.

Severe depletion of body protein stores can result from prolonged starvation or from hormonal and cytokine-mediated effects during critical illness. Recent advances in the understanding of cytokine actions have substantially refined the interpretation of the nutritional assessment of critically ill patients. In addition, the design of nutritional programs for hospitalized patients has changed considerably during the past decade. Although nutritional support of critically ill patients will not lead to positive nitrogen balance, nutrition can increase protein synthesis, enhance immune function, and beneficially modify the body's response to an illness.

Parenteral nutrition (PN)-related bone disease remains a problem in patients of all ages. Understanding of the pathogenesis of PN-related bone disease is complicated by the effect of underlying illnesses, therapeutic interventions, and pre-existing nutrition deficiencies before the initiation of PN therapy. Interrelation of various nutrients, for example, calcium, phosphorus, and vitamin D, in their effects on bone mineralization, demands simultaneous assessment of the role of multiple nutrients and increases the difficulty in defining the role of a single nutrient in the development of bone disease. However, recent reports indicate that there exist a number of factors important in the development of PN-related bone disease and some factors such as increased mineral requirement are unique to growing infants whereas other factors such as aluminum toxicity may be common to both adult and pediatric populations. Nonnutritional factors, including chronic use of potent loop diuretics and altered acid-base status, can affect urine mineral loss, cell metabolism, and bone mineralization, particularly in small, preterm infants. Current evidence indicates that the cause of PN-related bone disease is multifactorial, and the prevention of PN-related bone disease awaits better delineation of the exact sequence of pathogenic events.

To explore HBV infection status in a group of serologic HBV markers-negative or HBsAg-negative patients with chronic hepatitis, in situ hybridization to hepatocellular HBVDNA was carried out in combination with detection of HBsAg and HBcAg in the liver tissues. It was found that prevalence of intrahepatic HBVDNA, HBsAg and HBcAg was 43%, 39% and 17% respectively, and 15 out of 23 cases studied were sure to bear one or more positive marker(s) of intrahepatic HBVDNA, HBsAg and HBcAg. These findings suggest that more than half of the patients with chronic hepatitis were still undergoing HBV infection, despite serologic HBV markers or HBsAg negative. Furthermore, we found that hepatocytes containing HBVDNA or surface or core antigen were often close to hepatic necrosis foci, indicating that HBV replication and its antigen(s) expression in hepatocytes could account for chronic, active and necrotic inflammation occurring in the liver of the patients mentioned above.

This study was undertaken to determine whether refeeding through the native small intestine or through a small bowel transplant would reverse hepatic steatosis induced by total parenteral nutrition (TPN), and of what influence a coexisting short-gut syndrome is. Three short-gut syndromes of different severity were established in Lewis rats (short-gut I, mild; short-gut II, moderate; short-gut III, severe). TPN was administered for 10 days and the animals were refed for 20 days. A liver biopsy after the TPN period confirmed a mild to moderate fatty infiltration of the liver in all groups. After the refeeding period a second liver biopsy was obtained and no evidence of hepatic steatosis was observed in Groups 1, 2, 3, and 4 (normal Lewis rat, short-gut I, II, and III). The animals in group 5 (short-gut I) received a syngeneic small bowel transplant after discontinuation of TPN. After the refeeding period the liver biopsies showed no evidence of fatty infiltration. The intestinal graft also reversed the nutritional deficiencies which were observed in the animals with short-gut and showed normal body weight gain and nitrogen and fat uptake in comparison to the normal animals (Group 1). These data show that a small bowel graft is capable of reversing the deleterious sequelae of short-gut syndrome as well as the TPN-related hepatic steatosis.

Advances in long-term venous access devices and in parenteral nutrition solutions have made it possible for patients with severe short bowel syndrome to survive and to live in our society. The spectrum of this disease is such that some patients may be able to lessen their dependence or even become free from parenteral therapy. This review will discuss the role of nutrition support in the patient with short bowel syndrome.

1. This study examines the efficacy of infused sodium chenodeoxycholate to prevent cholesterol gallstone formation in the prairie dog when fed a high cholesterol diet. 2. Three experimental groups were designed to examine this. The first group (N = 5) was fed a normal rat chow diet, the second group (N = 5) was fed a high cholesterol diet (0.4% cholesterol by weight), and the third group (N = 5) was fed a high cholesterol diet plus given a daily injection of intravenous sodium chenodeoxycholate (15 mg/kg). 3. All of the animals in the second group had cholesterol crystals and cholesterol gallstones. In the third group, none of the animals had gallstones, and all but one lacked cholesterol crystals. 4. Statistical analysis showed that the first and third groups were statistically identical in their lithogenic indices and biliary lipid composition. 5. We concluded that infused sodium chenodeoxycholate is effective in preventing cholesterol gallstone formation in the prairie dog when fed a high cholesterol diet.

Triacetin, the water-soluble triglyceride of acetate, was infused in mongrel dogs at isocaloric (N = 6) or hypercaloric (approximately 1.5 REE, N = 7) rates in mongrel dogs for 3 hr. Ketone body and glucose production rates were quantified with [13C2] acetoacetate and [3H]glucose, respectively. Four additional animals were infused with glycerol to serve as controls for the hypercaloric triacetin infusion. Energy expenditure was determined in the isocaloric experiments.

no evidence of acute toxicity was observed during triacetin infusion at either rate. Plasma acetate concentrations increased from basal levels to approximately 1 and approximately 13 mmol/liter in the isocaloric and hypercaloric experiments, respectively. Plasma lactate and pyruvate concentrations decreased dramatically after 30 min of both isocaloric and hypercaloric triacetin infusions. Glucose production rates did not increase in either group, but glucose clearance decreased significantly in both groups (p less than 0.05) over the last hour of triacetin infusion. Plasma ketone body concentrations increased from 1.4 to 3.5 and 1.8 to 13.5 mumol/kg.min, respectively, during isocaloric and hypercaloric triacetin infusion. Resting energy expenditure increased from 3.0 +/- 0.3 to 4.0 +/- 0.5 kcal/kg.hr during isocaloric triacetin infusion (p less than 0.05). These studies indicate that triacetin can be administered to dogs at high rates without overt toxicity. The decrease in glucose clearance may represent competition between carbohydrate (glucose) and lipid (acetate). Triacetin infusion resulted in significant increases in ketone body production and concentration. These preliminary data indicate that triacetin may have a future role as a parenteral nutrient, and that further studies of its use are warranted.