ACUTE LIVER FAILURE

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Introduction

The liver is an essential body organ that forms an important barrier between the gastrointestinal blood, which contains large amounts of toxins and antigens, and the body. Around 60% of the liver is formed by liver cells, hepatocytes, which are radially grouped into thick unicellular layers around the terminal hepatic veins, forming the smaller anatomic units of the liver, the classic lobes.

It is responsible for the production of bile which is stored in the gallbladder and released when required for the digestion of fats. The liver stores glucose in the form of glycogen which is converted back to glucose again when needed for energy. It also plays an important role in the metabolism of protein and fats.It stores the vitamins A, D, K, B12 and folate and synthesizes blood clotting factors.Another important role is as a detoxifier, breaking down or transforming substances like ammonia, metabolic waste, drugs, alcohol and chemicals, so that they can be excreted. These may also be referred to as xenobiotic chemicals.

ALF

Acute liver failure is a complex and devastating consequence of acute liver injury. It is characterized by hepatic encephalopathy, jaundice, coagulopathy and high mortality rates.Emergency liver transplantation is currently the only effective treatment for those patients who are unlikely to spontaneously recover. Donor shortages however remain a serious problem as the number of patients requiring orthotropic liver transplantation has far outpaced the number of donor livers and many patients die before a suitable organ is identified. This has generated interest in designing devices that would support or replace normal liver function until a donor liver became available for liver transplantation, or the patients own liver recovered.

The most common approaches used to induce experimental ALF include surgical strategies, hepatotoxic drugs such as paracetamol, carbon tetra chloride and D-Galactose, and viral models. Among surgical approaches, many strategies have been developed: total hepatectomy , partial hepatectomy , complete hepatic devascularization (a portacaval anastomosis followed by ligation of the hepatic artery, and combined surgical/hepatotoxic models . The development of an ideal model of ALF has been remarkably difficult to achieve. The reproducibility of surgical models relies extensively on the availability of appropriate surgical expertise; hepatotoxins have been used extensively in the development of animal models of ALF.

As most hepatoxins are taken orally the liver is the portal to the tissues for such compounds following absorption from the gastrointestinal tract. The liver is, therefore a vulnerable organ, being exposed to both the parent drug carried from the G.I. tract via the portal vein and to any metabolites produced which then enter the systemic circulation via the hepatic vein. However, despite this vulnerability, the liver is not the major target for adverse drug reactions, only about 9.5% of these involve the liver ). Although drug-induced hepatic damage may not be particularly common in general patient populations the case fatality rate is often high, and the severity of drug-induced hepatic injury is such that drugs are a major cause of hepatic failure . Several hepatotoxins have been used over the last 30 years in particular; D-Galactosamine (D-Gal), acetaminophen (paracetamol/APAP), carbon tetrachloride (CCl 4 ) and thioacetamide (TAA), and more recently, Concanavalin A (Con A) and lipopolysaccharide (LPS) have been investigated.As compared with other pharmacological agents D- Galactosamine works more effectively to induce liver damage.

D-Galactosamine is a hepatotoxin that induces liver damage in vivo, similar to human viral hepatitis, via depletion of uridine nucleotides and subsequently diminishes the synthesis of RNA and plasma membrane proteins . Oxidative tissue damage triggered by D-galactosamine is believed to be due to the formation of highly reactive hydroxyl radical which are the initiators of lipid peroxidation chain reaction which subsequently provokes inflammatory reaction and hence destruction and damage to cell membrane  .

Renal failure is often associated with end stage of liver damage and also reported that kidney injury induced by D-Gal along with liver damage.

Pharmacological agents induced hepatotoxicity

Analgesics:

Acetaminophen (paracetamol) is among the most commonly used analgesics. It effectively reduces fever and mild to moderate pain, and is regarded, in general, as a very safe drug. Hepatic injury with acetaminophen is not only associated with overdose or use of high doses; rather, it can be encountered with chronic use at lower doses (<4g/ day), particularly in the presence of other predisposing factors, such as chronic alcohol consumption (Rao RR. et  al.,1977  ). Damage to the liver following acetaminophen ingestion is not due to the drug itself, but due to a toxic metabolite that is generated through the cytochrome P450 group of enzymes in the liver. This metabolite is usually rendered harmless through an interaction with the endogenous antioxidant, glutathione. However, when there is overproduction of the acetaminophen metabolite, glutathione stores in the liver become depleted, and the metabolite begins to accumulate and cause tissue injury. Hepatic injury can be limited through administration of N-acetylcysteine, which replenishes liver levels of glutathione. In the United Kingdom acetaminophen or paracetamol poisoning is the most common cause of AHF.

Acetaminophen-induced animal models of AHF are widely used to improve our insight into the metabolic and physiological derangements of AHF and to facilitate the development of new therapeutic modalities.

Carbon tetrachloride

The hepatotoxic effects of CCl4 have been known for a long time . It was used extensively in animal models of AHF in the seventies and early eighties but it was found to be poorly reproducible and also species variation was significant . It has been used in the development of cirrhosis animal models following its gastric and intraperitoneal administration.

Clinically the syndrome of AHF is poorly reproduced by CCl4intoxication with little encephalopathy and late stage hepatic coma. This model is infrequently used to represent AHF.

Anti-hyperlipidemics:

The anti-hyperlipidemic drug with the highest potential for hepatic injury is the sustained-release formulation of niacin. HMG CoA reductase inhibitors, otherwise known as statins, very rarely cause clinically significant liver injury, although asymptomatic elevation in aminotransferases is common.

Anaesthetic Agents:

Halothane, the most widely used anaesthetic is now accepted as causing hepatic injury. Multiple exposures are a major factor which may predispose the patient to liver injury, particularly if re-exposure occurs within 3 months. Obese patients and females seem more susceptible but children and young adults less so.

D-Galactosamine

It is an amino sugar and is metabolized in the liver leading to depletion of uridine nucleotides and hepatic transcriptional blockade. Depression of protein synthesis cannot explain d-Gal induced hepatic failure and it was suggested that d-Gal sensitized the liver towards other stimuli in part reflecting the role of uridine-containing compounds in hepatic biotransformation.

D-galactosamine is a hepatotoxic agent, which induces diffuse injury of liver tissue followed by the regeneration process. D-galactosamine (GalN) is known for inducing the features of acute hepatitis in rats. The toxic effect of GalN is connected with an insufficiency of UDP-glucose and UDP-galactose and the loss of intracellular calcium homeostasis. These changes affect cell membranes and organelles and the synthesis of proteins and nucleic acids. After GalN application, the location of proteoglycans is changed in the rat liver . GalN also inhibits the energy metabolism of hepatocytes.

Laboratory Tests to Perform in the Initial Evaluation of Acute Liver Failure

Laboratory tests to assess the ALF include a complete blood count, complete metabolic panel with serum chemistries and liver-associated enzymes, arterial blood gases, and lactate.

Enzymes that detect Liver failure

The liver contains thousands of enzymes, some of which are also present in serum in very low concentrations. These enzymes have no known function in serum and behave like other serum proteins. They are distributed in plasma and intestinal fluid and have characteristic half lives of disappearance, usually measured in days. The elevation of a given enzyme activity in serum is thought to primarily reflect its increased rate of entrance into serum from damaged liver cells. Serum enzyme tests can be grouped into two categories: enzymes whose elevation in serum reflects generalized damage to hepatocytes and enzymes whose elevation in serum primarily reflects cholestasis.

  1. Serum glutamate pyruvate transaminase (SGPT) or ALT
  2. Serum glutamate oxaloacetate transaminase (SGOT) or AST
  3. Serum alkaline phosphatase (ALP)
  4. Serum direct bilirubin
  5. Serum total bilirubin
  6. Total protein
  7. Total albumin
  8. Glucose.

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