New Home Treatments for Fatty Liver
Despite its low natural abundance of 1.1 , 13C can be used to measure hepatic glycogen (Rothman et al. 1991 Gruetter et al. 1994). Healthy liver usually presents with a glycogen concentration in the range of 200-400 mmol l tissue. A large homogenous tissue volume close to the body surface can be well covered by an appropriate MR surface coil. Hepatocytes, which primarily account for glycogen metabolism, are distributed isotropically and represent 80 of the parenchymal volume of the liver. The rib cage, abdominal muscles and subcutaneous fat layers present anatomical obstacles that can lead to contamination of the MR signal. To overcome this, a suitable localisation technique has to be chosen. Traditionally, adapted one-dimensional inversion based or one-dimensional chemical shift imaging techniques, combined with use of surface MR probes, are applied to either suppress unwanted
Hepatotoxicity accounts for 15 among the toxicity profiles of drug candidates, second only to cardiovascular toxicity 1 . A plethora of assays have been used by investigators to study organ-specific toxicity mechanisms including hepatotoxicity. This can be conducted in an ex vivo fashion using cells from a specific target organ, followed by in vitro studies where cells from a specific target organ are treated by the toxic agents, and a series of measurements are made depending on the mechanism of interest. This typically falls into the investigative toxicological studies as opposed to the toxicological screening approaches listed above. The rationale for such a distinction is due to cost versus benefit (the cost of running all possible mechanistic assays for many compounds, as opposed to the benefit of having high confidence that a subset of such mechanisms is actually causal to the observed in vivo side effects). As an NCE enters the body and interacts with a variety of...
Lethal, toxicological interaction between Kepone (also known as chlordecone) and carbon tetrachloride (CCl4). Briefly, CCLt is a well-known hepatotoxin. Following free radical formation through the cytochrome P450 enzyme system, the toxicity of CCl4 is manifested through an accumulation of lipids (steatosis, fatty liver) and degenerative processes leading to liver cell death (necrosis). The toxicological interaction between Kepone and CCl4 was elucidated to be the Kepone-mediated impairment of the liver's regeneration process. These mechanistic studies were summarized in a number of publications 93-95 . Based on the described mechanism of interaction, El-Masri et al. 96 constructed a PBPD model, a conceptual version of which is shown in Figure 3.5. A computer implementation of this model was capable of providing time-course simulations of mitotic, injured, and pyknotic (dead) cells after treatment with CCl4 alone or with Kepone pretreatment. This implementation was further linked with...
Alcoholic liver disease (ALD) progresses to liver cirrhosis in less than 10 of heavy drinkers. This clinical variability, and disappointing results from studies of genes involved in alcohol metabolism, has led to considerations that cirrhosis, fatty liver and alcoholic hepatitis are determined to some degree by genetic factors which regulate the immune system. An immune hypothesis for alcoholic cirrhosis has been suggested, although there is some evidence for a dose response. Twin studies suggest that genes do play a role in determining progression beyond simple alcoholic steatohepatitis, and candidate associations have been sought either with HLA or with other immunoregulatory genes.
The progression to cell damage after the production of primary or secondary cyto-toxic mediators is not inevitable, nor is it irreversible. A battery of chemical and enzymic cytoprotectants prevails within the liver. These cytoprotectants combat the endogenous production of potential cytotoxins (such as reactive oxygen species ROS and cytokines) and reverse their adverse effects (by the repair of oxidized proteins, damaged membranes and methylated DNA). The cytoprotectants include the antioxidant vitamins A, C and D, reduced glutathione (GSH) and numerous chemicals, proteins and enzymes with complementary functions in maintaining redox status with its normal reductive bias. Particularly important are the enzymes detoxifying ROS, e.g. superoxide dismutase, catalase and the glutathione-depen-dent enzymes. The latter include glutathione peroxidase, which reduces hydrogen peroxide in mitochondria where catalase is absent, and the glutathione transferases which catalyse the detoxication of...
Paracetamol (acetaminophen)-induced hepatotoxicity provides a useful illustration of the potential for toxicogenetic variants to determine outcome following overdose with a drug and these are currently under investigation in the author and colleagues' laboratories. Paracetamol is a safe and effective analgesic when used in the recommended doses (four X 1 g daily) but is considered the archetypal, predictable, iatrogenic hepatotoxin if excessive amounts are ingested 5 . Approximately 150 deaths from acute liver failure occur annually in the UK following paracetamol overdose. Considerable differences exist in the severity of liver damage, as well as in the outcome. For example, there are contrasting case reports of fatality after 6 g 6 , but an absence of toxicity with repeated daily doses of 20 g sustained for 5 years 7 . While liver transplantation offers a final treatment modality, the early and accurate prediction of patients requiring this expensive and limited resource are...
In a multivariate statistical analysis of more than 500 patients with ALF, aetiology was found to be the single most important independent predictor of outcome 4 . Fatality rates are invariably 100 in ALF due to Wilson's disease and may exceed 70 in cases due to hepatitis nonA-E and drug-induced liver failure without liver transplantation. In contrast, patients with ALF due to acute viral hepatitis A and B have survival rates of 40-70 . Females with acute fatty liver of pregnancy and patients with paracetamol-induced ALF are those with the best prognosis 3, 4 .
Levels of HGF are detected in patients with acute liver failure. In these cases, plasma HGF levels have an inverse relationship with patient survival. Under these circumstances, it is not possible to determine whether high HGF levels in these patients constitute a marker for proliferative activity in the liver or whether they are a consequence of liver damage.
Taurine protects the body from damage by toxic compounds in the environment and diet. Taurine binds to, detoxifies, and enhances excretion of chemicals, pesticides, and other toxins.1 Taurine helps prevent liver damage from chronic, heavy alcohol consumption.
Many prescription medications are processed by the liver, which converts drugs into a water-soluble compound that is more easily removed from the body. Liver-friendly (hepatic) herbs can help this process. The N.D. may suggest Chionanthus virginicus (fringe tree), gentian, Leptandra virginica (Culver's root), and Cynara scolymus (artichoke). Silybum (milk thistle) has been reported to prevent liver damage due to pheny-toin (Dilantin ) (8).
HDV is associated with acute (coinfection) and chronic hepatitis (superinfection) and can exacerbate pre-existing liver damage caused by HBV. The routes of transmission and at-risk groups are the same as for HBV. Staff victims in contact with a putative exposure and detainees with disease should be managed as for HBV. Interferon-a (e.g., Roferon) can be used to treat patients with chronic HBV and HDV (21), although it would not be practical to continue this treatment in the custodial setting.
Figure 13.4 Assessment of Liver Fat Accumulation by CT A) CT scan of normal liver. The liver is denser (brighter) than the spleen B) CT scan of a fatty liver. The liver is less dense (darker) than the spleen. Reproduced with permission from Joy D et al. (2003) Eur J Gastroenterol Hepatol 15 (5), 539-543. Figure 13.4 Assessment of Liver Fat Accumulation by CT A) CT scan of normal liver. The liver is denser (brighter) than the spleen B) CT scan of a fatty liver. The liver is less dense (darker) than the spleen. Reproduced with permission from Joy D et al. (2003) Eur J Gastroenterol Hepatol 15 (5), 539-543.
As in the skeletal muscle, the first studies were designed to find an association between hepatic fat content and features of insulin resistance in various populations. Increased hepatic fat content was found and associated with various measures of insulin resistance in T2DM (Figure 13.10) (Ryysy et al. 2000 Anderwald et al. 2002 Mayerson et al. 2002 Kelley et al. 2003 Krssak et al. 2004), in women with previous gestational diabetes (Seppala-Lindroos et al. 2002 Tiikkainen et al. 2002 Larson-Meyer et al. 2006a) as well as in insulin resistant lipodystrophic patients (Petersen et al. 2002 Sutinen et al. 2002). It was also linked with hepatic insulin resistance (Marchesini et al. 2001) and impaired whole-body reaction to oral glucose test challenge (Sargin et al. 2003) in non-alcoholic fatty liver disease.
The liver produces bile, which eliminates medications from the body. Vitamin B6 deficiency can cause cholestasis (reduction of bile flow) choline, methionine, and dandelion increase bile flow. Lecithin (choline in concentrated form), L-taurine, and L-methionine (sulphur-containing amino acids) promote bile circulation and increase estrogen excretion from the liver (15). Increasing fiber and using supplements to increase bile flow will increase estrogen excretion into the feces and bile, thereby decreasing estrogen levels (30). Using diet, supplements, and lifestyle changes aids the bowel and liver in hormone metabolism. Liver health is a priority in seizure disorders that are related to hormonal imbalance, because the liver is responsible for the effective excretion of estrogen.
It is estimated that about 3 of the world's population carries this virus, but they are unaware of it because there are often no symptoms until the liver damage is severe. However, people who donate blood may find out that they have the disease before it causes serious damage, since blood banks
Improved methods for detecting the hepatocellular damage associated with allo-graft rejection may be a more pragmatic option and objective evidence that the earlier detection and treatment of acute rejection can influence subsequent clinical outcome has emerged from longitudinal studies of a-glutathione S-transferase (a-GST) monitoring. This enzyme has a much shorter in vivo plasma half-life than conventional transaminases and can provide a more accurate indication of ongoing liver damage. In probably the first randomized controlled trial of a laboratory diagnostic test, the author and colleagues found that increases in a-GST occurred at a median of 1 day earlier than transaminases before rejection in 60 de novo liver transplant recipients 11 . Monitoring a-GST improved survival and halved the risk of graft loss during the first 3 postoperative months. It also reduced hospital-ization, requirements for biopsy, the severity of rejection and the incidence of infection. One practical...
The most common cause of autosomal recessive SCID is deficiency of an enzyme called adenosine deaminase (ADA) due to mutations in the ADA gene. ADA functions in the salvage pathway of purine synthesis and catalyzes the irreversible deamination of adenosine and 2'-deoxy-adenosine to inosine and 2'-deoxyinosine, respectively. Deficiency of the enzyme leads to the accumulation of deoxyadenosine and its precursors S-adenosyl-homocysteine and deoxyadenosine triphosphate (dATP). These byproducts have many toxic effects, including inhibition of DNA synthesis. Although ADA is present in most cells, developing lymphocytes are less efficient than most other cell types at degrading dATP into 2'-deoxy-adenosine, and therefore lymphocyte maturation is particularly sensitive to ADA deficiency. Other features of the disease can include deafness, costochondral abnormalities, liver damage, and behavioral problems. ADA deficiency leads to reduced numbers of B and T cells lymphocyte cell numbers are...
Discussion Pollutants, cigarette smoke, and infections increase PMNs and macrophages in the lung and thus produce a number of proteolytic enzymes. Damage to lung tissue due to these einzymes is controlled by the globulin ( -antitrypsin, which inhibits trypsin, neutrophil, elastase, and collagenase. A deficiency of this enzyme causes excessive lung tissue destruction and panacinar emphysema (cigarette smoking is associated with the centrilobular type). Patients may also develop liver damage.
Impaired judgment, slurred speech, unsteady gait, slower reaction times, uncontrollable emotions. Chronic alcohol abuse leads to loss of intellectual ability and liver damage. Alcohol kills nerve cells that cannot be regenerated. As nerve cells die, the brain actually gets smaller. The frontal lobes, where judgment, thought, and reason are centered, are the first to die.
If you're taking a statin, your blood should be tested for signs of liver damage at regular intervals if liver tests become abnormal (at least twice the upper limit of normal), withdrawal of the offending drug and its replacement by another of the same class often is effective, and no clinical liver toxicity results.
Oil of pennyroyal contains pulegone, a very toxic compound that can cause death in humans at an oral dose of as low as one tablespoon. At lower doses it can cause abortion, liver damage, and renal failure. Although the dermal toxicity of pennyroyal is fairly low, cats are sometimes victims of poisoning after applications of pennyroyal to their coats, presumably because they ingest it as a result of grooming.
The metabolic basis of paracetamol hepatotoxicity was elucidated over 25 years ago 5 . Figure 17.2 illustrates the kinetic changes in paracetamol disposition that underlie the development of liver damage. These principally involve the rate and extent of production of a reactive metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), in amounts that exceed the capacity for detoxication by conjugation with GSH. The formation of paracetamol sulphate and glucuronide conjugates represent pathways that compete with paracetamol intoxication to NAPQI. GSH availability limits the arylation of protein sulphydryl groups with NAPQI and the metabolic sequelae which culminate in hepatic necrosis that also include secondary toxicity e.g. via Kupffer cell activation and TNF release. Toxicogenetic biomarkers of paracetamol-induced liver damage might include (i) those which accentuate intoxication (e.g. production of NAPQI via high activity CYP1A2, 2E1 and 3A4 variants, and mediators of an exaggerated...
Alcohol is absorbed through the stomach and duodenum. Absorption depends on many factors, including sex and weight of the individual, duration of drinking, nature of the drink, and presence of food in the stomach. Alcohol dehydrogenase in the gastric mucosa may contribute substantially to alcohol metabolism (gastric first-pass metabolism), but this effect is generally only evident with low doses and after eating. Studies of alcohol dehydrogenase activity in gastric biopsies of women suggest a significant decrease in activity in women compared with men, which could explain why women have higher peak blood alcohol levels and are more susceptible to liver damage after consumption of smaller quantities of alcohol when compared with men (16). Further details of alcohol metabolism are given in Chapter 10.
Which is a cytochrome P450-dependent oxidation step. Excessive formation of NAPQI in the liver can cause depletion of glutathione and may result in cell death and hepatotoxicity due to covalent binding to essential cellular macro-molecules and or other mechanisms such as oxidative stress. It has been shown in animal models that activators of PXR (PCN) or CAR (PB) can enhance the hepatotoxicity of APAP by the increased formation of NAPQI 87,88 . Notably, increased liver damage is not observed in CAR- or PXR-knockout animals, suggesting that receptor activation and enzyme induction play critical roles in the hepatotoxicity of APAP. In humans, several hormone nuclear receptors that are activated by many drugs and steroids play major roles in the induced expression of CYPs and other drug-metabolizing enzymes that are involved in APAP elimination and toxicity. For example, PXR plays a key role in the regulation of CYP3A4, CYP2C9, CYP2B6, and UGT1A1 as well as transporters such as MDR1....
Cystic fibrosis is a chronic, fatal disease characterised by mutations in the CFTR gene, which codes for a cAMP-activated chloride channel, the most common mutation being a deletion of the phenylalanine at position 508. The disease is characterised by an increase in the concentration of secreted fluids on the surface of epithelia in the lung, pancreas and elsewhere. Patients become very susceptible to bacterial infections in the lung and damage to the pancreas can result in diabetes, a common complication. Liver damage is also common. Annexin 1 has been found to be down-regulated or differentially expressed in nasal cells of CF patients with a number of CFTR mutations and in cells from intestinal crypts, the lungs and pancreas (all cells known to express the CFTR) in the CFTR knock out mouse (Bensalem et al., 2005). Full-length annexin 1 can be detected in bronchoalveolar lavage (BAL) fluids from healthy individuals but in CF patients, in which neutrophils are often present in the BAL...
After absorption from foods or production in the skin, vitamin D is stored as 25-OH-vitamin D in the liver. When needed by the body, it is subsequently activated to 1,25 -OH-vitamin D by the kidney.1 Thus, a healthy liver and kidneys are essential for optimum vitamin D status. (1 jig vitamin D 40 IU vitamin D.)
Recovery from ALF has always been considered to be dependent on adequate liver regeneration with functional recovery being more important than morphological recovery. This may be the result of the balance between endogenous factors promoting, and factors inhibitory to, regeneration (Figure 19.2), although toxic metabolites accumulating in ALF probably have negative effects. Thus, the influence of bioartificial liver support systems on this balance may be of considerable clinical importance. Hepatocyte growth factor (HGF) is one of the most potent mitogens for hepatocyte DNA synthesis. Plasma levels of HGF determined by ELISA are greatly increased (over 50-fold) in ALF, but this is considered to be due more to a lack of clearance rather than the presence of a powerful regenerative stimulus, particularly as it correlates with the degree of liver damage. When plasma levels of HGF were determined in the ELAD study, there was a further 3-fold increase in the first 6 hours of treatment...
Fat accumulation in the liver is assessed from the bright echo appearance and the loss of the typical liver structure in the image (Quinn & Gosink 1985). Qualitative staging was introduced by Saadeh et al. (2002), leaving fat amount assessment to pattern recognition by the operator rather than specific quantitative measurement. But clear diagnosis of fatty liver is hampered by the fact that fibrosis, often associated with fat accumulation, has a similar bright echo appearance (Needleman et al. 1986 Celle et al. 1988). Nevertheless, despite its
Ited, allowing higher levels of cocaine to remain in the body. A portion of this cocaine undergoes hepatic microsomal transesterification and is converted to cocaethylene (Andrews, 1997 Jatlow et al., 1991). Cocaethylene has very similar behavioral and toxicological effects to cocaine, but these effects last much longer (cocaethylene's plasma half-life is three to five times that of cocaine Jatlow et al., 1991). Cocaethylene causes significant sustained increases in heart rate and blood pressure, myocardial infarctions, arrhythmias, and decreases in heart functioning, possibly due its inhibitory effects on potassium channels in the heart (O'Leary, 2002). In addition, cocaethylene is associated with seizures, liver damage, and immune compromise in adults (Andrews, 1997). Additional toxicological aspects, such as the effects on the exocrine pancreas, remain unexplored (Jatlow et al., 1991).
Hyperbilirubinemia may result from hemolytic anemia due to incompatibility of RH groups failure of bilirubin conjugation due to liver damage congenital enzyme (glucuronyl transferase) deficiency and certain drugs. Unconjugated bilirubin crosses the blood-brain barrier to injure selected neuronal groups.
Further lowers nutrient absorption from foods. The liver is particularly vulnerable to alcohol - more than three drinks a day causes inflammation and accumulation of fat in the liver. This impairs liver function, reducing the ability to detoxify chemicals and drugs. Because the liver is important for blood sugar control, alcohol-induced liver damage can produce hypoglycemia, leading to fatigue, irritability, and concentration difficulties. Alcohol increases urinary losses of many minerals, including zinc, calcium, and magne-sium.5 Because of these effects, a diet rich in fresh fruits and vegetables, whole grains, lean meats, and low-fat milk products should be carefully chosen.
Herbs, although natural, can have significant side effects. In addition, because they are not closely regulated, many side effects may not be reported. There has been concern over kava potentially causing liver damage (8). Twenty-five cases were reported in other countries,
Severely compromised synthesis of coagulation factors is both characteristic of ALF and closely related to the severity of the liver damage. Absolute and serial measurements of factor VII were an early candidate for prognostic outcome, either alone or in conjunction with coma grade. More recently, factor V measurements have been favoured, e.g. in cases with ALF due to hepatitis B 2 . However, there was a significant overlap of factor V levels in survivors and nonsurvivors of a paracetamol overdose 15, 16 .
Liver injury is the unique and most clinically significant drug-related toxicity observed in the preapproval clinical trials and in postapproval studies (24,30,31). Grade 3 or 4 elevations in liver transaminases (AST and ALT) or in total bilirubin occurred in 16 and 26 of patients, respectively. These signs of liver injury were delayed, with maximal abnormalities 1 to 2 wk after therapy. A fraction of patients (2 in the phase II trials and up to 11 of some combination therapy studies) also developed a veno-occlusive disease (VOD)-like syndrome with liver tenderness and enlargement, jaundice, and fluid retention. The incidence of liver damage was increased by previous bone marrow transplantation (both autologous and allogeneic). Co-administration of other cytotoxic drugs and cytokines (such as interleukin-11) may also predispose patients to the liver lesion (31). Ultrasound, computed tomography scan, and magnetic resonance imaging may show reversal of portal flow consistent with portal...
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