Mack C Mitchell

University of Texas Southwestern Medical Center | UT Southwestern · Department of Internal Medicine

Diagnostic challenges continue to impede development of effective therapies for successful management of alcohol-associated hepatitis (AH), creating an unmet need to identify noninvasive biomarkers for AH. In murine models, complement contributes to ethanol-induced liver injury. Therefore, we hypothesized that complement proteins could be rational...

Background Brief alcohol interventions use patient-provider communication to promote alcohol cessation. We characterized the receipt of this intervention in chronic liver disease (CLD). Methods We surveyed patients with CLD for weekly drinking patterns and examined associations with patient-provider communication receipt. Results Among 840 partic...

Background Alcohol-associated liver disease (ALD), encompassing alcohol-associated hepatitis and alcohol-associated cirrhosis, is rising in the United States. Racial and ethnic disparities are evident within ALD; however, the precise nature of these disparities is poorly defined. Methods We conducted a search of the PubMed/MEDLINE and EMBASE datab...

Background Severe alcoholic hepatitis (AH) has a high short-term mortality rate. The MELD assesses disease severity and mortality; however, it is not specific for AH. We screened plasma samples from patients with severe AH for biomarkers of multiple pathological processes and identified predictors of short-term mortality. Methods Plasma was collec...

Background Chronic alcohol consumption impairs gut barrier function and perturbs the gut microbiome. Although shifts in bacterial communities in patients with alcohol-associated liver disease (ALD) have been characterized, less is known about the interactions between host metabolism and circulating microbe-derived metabolites during the progression...

Introduction: We investigated the effect of daily oral Lactobacillus rhamnosus GG (LGG) in reducing liver injury/severity and drinking in patients with alcohol use disorder (AUD) and moderately severe alcohol-associated hepatitis (mAH). Patients/Methods: Forty-six males and females with AUD and mAH (12<MELD<20, aged 21-67) received either LGG (n=...

Background: This study is to evaluate safety and pharmacokinetics (PK) of larsucosterol (DUR-928 or 25HC3S) in subjects with alcohol-associated hepatitis (AH), a devastating acute illness without FDA-approved therapies. Method: This Phase 2a, multicenter, open-label, dose escalation study evaluated safety, PK, and efficacy signals of larsucoster...

Background aims: Prolonged systemic inflammation contributes to poor clinical outcomes in severe alcohol-associated hepatitis (AH) even after cessation of alcohol use. However, mechanisms leading to this persistent inflammation remain to be understood. Approach results: We show that while chronic alcohol induces NLRP3 inflammasome activation in...

Narrative session. Symposia 23. Alcohol: Clinical and Experimental Research Vol. 75 (S1), pp. 19A.

It is still sometimes difficult to differentiate alcohol-associated hepatitis (AH) from other liver problems. In this edition of AJG, Atkinson et al. showed that keratin-18 (intermediate filament protein) is a promising biomarker for predicting histological severity of AH, defining the type of hepatocyte death (necrosis vs apoptosis), predicting 90...

Background/aims Despite high mortality of alcohol-associaed hepatitis, there has been limited advancement in treatment strategies. Defeat Alcoholic Steatohepatitis (DASH) is a multicenter, randomized, double-blind controlled trial whose primary objective was to evaluate the safety and efficacy of a novel combination of 3 drugs targeting different p...

Purpose of review: Alcohol consumption is increasing globally, as are complications of alcohol-related liver disease, including the most severe manifestation, alcoholic hepatitis. Despite the increased prevalence, many patients hospitalized with alcoholic hepatitis are either not diagnosed or inadequately treated leading to significant morbidity a...

The purpose of this clinical practice update is to review diagnostic criteria for severe acute alcoholic hepatitis and to determine the current best practices for this life-threatening condition. The best practices in this review are based on clinical trials, systematic reviews including meta-analysis and expert opinion to develop an approach to di...

Background Alcoholic hepatitis (AH) is an inflammatory disorder of the liver characterized clinically by jaundice, hepatomegaly, and abdominal pain, and histologically by macrovesicular steatosis and necroinflammation. Methods This clinical review will cover what is known about the pathogenesis, clinical presentation, current treatments, and novel...

Development of liver damage and cirrhosis (ALD) related to alcohol consumption is complex. Studies have reported a threshold of drinking 20–30 g daily for women compared to 40–50 g daily for men. However, the absolute risk of ALD related to heavy drinking is relatively low, ranging from 6 to 15 %, so the majority of drinkers do not develop signific...

Background Both the amount and the rate of absorption of ethanol (EtOH) from alcoholic beverages are key determinants of the peak blood alcohol concentration (BAC) and exposure of organs other than gut and liver. Previous studies suggest EtOH is absorbed more rapidly in the fasting than in the postprandial state. The concentration of EtOH and the t...

We performed the first multiple dose study of remimazolam designed to assess both the feasibility of maintaining suitable sedation during colonoscopy and reversing the sedative effects of remimazolam with flumazenil. Healthy volunteers received fentanyl followed by remimazolam for sedation during colonoscopy. Three dose groups of 15 volunteers each...

Background & aims: Weight regain or insufficient loss after Roux-en-Y gastric bypass (RYGB) is common. This is partially attributable to dilatation of the gastrojejunostomy (GJ), which diminishes the restrictive capacity of RYGB. Endoluminal interventions for GJ reduction are being explored as alternatives to revision surgery. We performed a rando...

Naltrexone (Revia, Vivitrol) is recognized as having the potential for hepatotoxicity. We evaluated the safety of intramuscular extended-release naltrexone (XR-NTX) in a cohort of patients with a high prevalence of chronic hepatitis C virus (HC V) and HIV infection undergoing treatment for opioid dependence. A total of 250 (88% male) opioid-depende...

Glutathione (GSH), the most abundant nonprotein thiol in cells, plays a pivotal role in protecting cells against damage from reactive drug metabolites, free radicals, peroxides, and other toxic oxygen species. Within the last decade, there has been substantial progress in understanding the metabolism of glutathione, its functions in cellular detoxi...

The recent proposal to dissolve the National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse and create a new institute for substance use, abuse, and addiction will require significant effort by the staff of both institutes, the Advisory Councils, and outside experts to overcome complex challenges that could threaten...

The effects of oral contraceptive steroids (OCS) on the disposition and elimination of lorazepam, oxazepam, and chlordiazepoxide were examined. Lorazepam and oxazepam are metabolized via glucuronidation while chlordiazepoxide is metabolized by oxidation in the liver. The disposition and elimination of lorazepam, oxazepam, and chlordiazepoxide was s...

In patients with chronic hepatitis B, brief lamivudine therapy suppresses hepatitis B virus (HBV) DNA but results infrequently in sustained losses of virus replication posttreatment. We evaluated treatment response and its posttreatment durability during up to 18 months of lamivudine therapy (100 mg/d) in 24 patients who had hepatitis B e antigen (...

The effect of parenteral amino acid administration on nutritional state, liver function and mortality was assessed in patients with severe alcoholic hepatitis. Twenty-eight patients received 2 l/day of a solution of dextrose (65 gm/L) and amino acids (25.8 gm/L) for 1 mo, whereas 26 received only the dextrose solution. All patients were allowed to...

Ethanol effects in the brain appear to be mediated at least in part by an alteration in receptor-effector coupling via guanine nucleotide-binding regulatory proteins (G proteins). To test the hypothesis that a similar pathway participates in the cardiotoxic effects of ethanol, we assessed the effects of chronic ethanol on two commonly used experime...

The effect of parenteral amino acid administration on nutritional state, liver function and mortality was assessed in patients with severe alcoholic hepatitis. Twenty-eight patients received 2 1/day of a solution of dextrose (65 gm/L) and amino acids (25.8 gm/L) for 1 mo, whereas 26 received only the dextrose solution. All patients were allowed to...

Over a 4-yr period that began October 1, 1986, 103 orthotopic liver transplants were performed on 91 patients at the Johns Hopkins Hospital. Biliary reconstruction at the time of transplantation was performed in standard fashion by an appropriately trained member of the surgical team. Six (7%) patients developed biliary complications, which include...

Vasopressor hormones alter efflux of glutathione (GSH) and increase permeability of tight junctions in perfused rat liver. Infusions of 10 nM angiotensin II, 10 microM phenylephrine, and 10 nM vasopressin significantly increased efflux of GSH into perfusate by 32-41% and decreased biliary efflux by 31-57%. Direct modulation of protein kinase C (PKC...

To evaluate the role of energy state in pulmonary vascular responses to hypoxia, we exposed isolated pig lungs to decreases in inspired PO2 or increases in perfusate NaCN concentration. Lung energy state was assessed by 31P nuclear magnetic resonance spectroscopy or measurement of adenine nucleotides by high-pressure liquid chromatography in freeze...

Hypoprothrombinemia is a serious adverse effect of antimicrobial therapy that occurs after administration of some second- and third-generation cephalosporins which contain the methyltetrazole-thiol (MTT) group. Previous studies have shown that in vitro MTT directly inhibits microsomal gamma-carboxylation of a synthetic pentapeptide. Since MTT is a...

Plasma tumor necrosis factor alpha (TNF alpha), interleukin 1 alpha (IL-1 alpha), and interleukin 1 beta (IL-1 beta) were measured in plasma samples obtained from 23 patients with severe alcoholic hepatitis on admission and after 30 days of hospitalization. Over a 2-year follow-up period, 14 patients died at a mean time of 8 months following discha...

Plasma tumor necrosis factor α (TNF α), interleukin 1 α (IL-1α), and interleukin 1 β (IL-1β) were measured in plasma samples obtained from 23 patients with severe alcoholic hepatitis on admission and after 30 days of hospitalization. Over a 2-year follow-up period, 14 patients died at a mean time of 8 months following discharge. The presence of ele...

An isocratic reverse-phase high-performance liquid chromatography method for the separation and quantitation of total pyridine dinucleotides in hepatocyte cultures is described. Cells are extracted with cold 3 M perchloric acid or 0.5 N sodium hydroxide containing 50% (v/v) ethanol and 35% cesium chloride for the determination of the oxidized or re...

1. The lobular distribution of paracetamol conjugation was studied using antegrade and retrograde perfusion of isolated rat liver. After addition of 25 mg of paracetamol, recovery of sulphate from antegrade perfusions was greater than from retrograde perfusions indicating periportal predominance of this metabolic pathway. 2. Recovery of sulphate wa...

Chronic ethanol feeding has been shown to enhance hepatic microsomal drug oxidation in humans and in laboratory animals. However, the effects of chronic ethanol administration on drug conjugation are less conclusive. We have studied the effects of chronic ethanol feeding on (a) the conjugation and elimination of p-nitrophenol (PNP) by the isolated...

To determine the possible role of prostacyclin (PGI2) as a mediator of the splanchnic hyperemia seen with portal hypertension, the portal and mesenteric hemodynamics in normal and portal hypertensive rabbits were studied before and after cyclo-oxygenase blockade. Three weeks after partial portal vein ligation, splenic pulp pressure was elevated fro...

It has been proposed that administration of adenine nucleotide precursors might accelerate replenishment of myocardial ATP and "free" ADP, thus improving recovery of depressed contractility of postischemic hearts. To test this hypothesis, Langendorff-perfused rabbit hearts were subjected to 20 min of global ischemia and reperfused for 2 h with norm...

Alcohol and dietary intake were determined in alcoholic patients with chronic pancreatitis and alcoholic liver disease. Patients with chronic pancreatitis, alcoholic hepatitis, and cirrhosis ingested approximately 50% of their calories as alcohol, and all had low mean intakes of protein, carbohydrate, and fat as compared with control subjects. Pati...

Chronic ethanol feeding increases hepatic turnover and sinusoidal efflux of glutathione in rats. The present study was performed to determine whether the observed increase in glutathione efflux was due to increased extrahepatic requirements for glutathione. The concentration and disposition of plasma glutathione were determined in rats fed liquid d...

Plasma amino acid profiles of alcoholic subjects without clinically apparent liver disease, alcoholic patients with biopsy-proven alcoholic hepatitis, and nonalcoholic controls were compared. Differences in the plasma aminograms of alcoholic subjects with and without liver disease appear to be due predominantly to differences in liver function wher...

Chronic ethanol feeding increases hepatotoxicity of drugs, such as acetaminophen, which form electrophilic metabolites. Availability of glutathione (GSH) is important in preventing liver damage from reactive metabolites. Chronic ethanol feeding has been reported to increase turnover of hepatic GSH in rats. The results of the present study show that...

Alcoholic beverages contribute an appreciable percentage (4-6%) to the total caloric intake in Western societies. The caloric value of ethanol as fuel may be dose-related. Most evidence suggests that at moderate intake levels of less than 45 g/day (3 drinks) ethanol is efficiently utilized as a fuel by the liver. At high intakes, ethanol calories m...

Cimetidine protects against acetaminophen hepatotoxicity in the rat as evidenced by improved survival, lower serum aminotransferases, improved liver histology, decreased in vivo and in vitro covalent binding of acetaminophen to liver protein and decreased rate of glutathione depletion. This protection is best explained by inhibition of acetaminophe...

Several points emerge from the large body of data on the effects of alcohol on CNS function. First, the degree of impairment is dose related, but not identical or strictly linear for all behaviors. Alcohol-related impairment of behavioral skills involved in driving is greatest for those tasks that require cognitive functioning; simple perception al...

Glutathione (GSH) is important in protection of cells against electrophilic drug injury and against reactive oxygen species. Both steady-state concentrations and turnover of GSH are important determinants of susceptibility of the hepatocyte to injury. Chronic ethanol administration is known to enhance susceptibility to electrophilic drug injury. We...

Acetaminophen-induced hepatotoxicity results from hepatic enzymatic oxidation of acetaminophen to a toxic, electrophilic intermediate. Acetaminophen is ordinarily eliminated after conjugation with glucuronic acid and sulfate to nontoxic derivatives. Cimetidine has been shown to inhibit the hepatic oxidation of a number of drugs and to protect rats...

Plasma acetaminophen elimination was examined in women taking low-dose estrogen oral contraceptive (OC) steroids and in age-matched control women. Fractional rates of elimination and fractional clearances were calculated for each of the metabolic pathways, including oxidation, sulfation, and glucuronidation. The cysteine adduct and mercapturic acid...

Short-term ethanol ingestion has been shown to inhibit the metabolism of a number of drugs metabolized by cytochrome P-450 in both man and laboratory animals. However, the effects of short-term ethanol administration on the metabolism of cytochrome P-448-dependent drugs in man is unknown. Caffeine is a commonly used drug that is metabolized predomi...

Hepatic venous thrombosis (the Budd-Chiari syndrome) is a rare disorder characterized by right upper quadrant abdominal pain, hepatomegaly and ascites. In the past 10 years we have evaluated 12 patients with this syndrome. Most patients have an acute onset of symptoms but occasionally the disorder appears insidiously over a long period of time. The...

The effects of chronic ethanol feeding on cytochrome P-448- and P-450-mediated drug metabolism have been studied both in vivo and in vitro in the rat, using caffeine, phenacetin, antipyrine and aminopyrine as test substrates. N-Demethylation of aminopyrine (P-450 mediated) was increased both in vivo and in vitro in rats after chronic ethanol feedin...

Cimetidine has been demonstrated to impair microsomal oxidative drug metabolism in a dose-dependent manner in an animal model. The inhibition has also been shown to be rapid, occurring after a single dose. In the present study we demonstrate that recovery from inhibition after cimetidine withdrawal is also rapid, occurring within 24 h. Furthermore,...

Acetaminophen hepatotoxicity is believed to result from the metabolic conversion of acetaminophen to a highly reactive intermediate by cytochrome P450. Cimetidine has been shown to be a potent inhibitor of cytochrome P450-mediated drug metabolism in humans and in laboratory animals, both in vivo and in vitro. Therefore, this study was undertaken to...

Granulomatous hepatitis developed in two patients while they were receiving carbamazepine (Tegretol®). Both patients had evidence of hepatitis within one month of beginning the drug therapy and had a rapid and complete resolution once the agent was discontinued. In both, the liver biopsy contained granulomas in addition to acute portal inflammation...

The effect of chronic ethanol consumption and variations in dietary protein content on microsomal drug metabolism were studied in rats pair-fed liquid diets containing 10, 20, ro 30% dietary protein with or without ethanol. In vitro drug metabolism was measured by aminopyrine breath tests and aminopyrine blood elimination kinetics. In vitro drug me...