CHAPTER 1

1.0 INTRODUCTION

Liver is the organ which is most important, and it plays a pivotal role in regulating various processes in the body, such as storage, metabolism and secretion. It has great capacity to detoxify toxic substances to nontoxic substances and synthesize useful principles (Shanmugasundaram et al 2006).

1.1 Anatomy of the Liver

The liver is a triangular organ that extends across the entire abdominal cavity inferior to diaphragm. Most of the liver’s mass is located on right side of body, where it descends inferiorly toward right kidney. The liver is madeup of very soft, pinkishbrown tissues encapsulated by connective tissue capsule. The capsule is covered and reinforced by the peritoneum of the abdominal cavity which protects liver and holds it in the place within abdomen.

Liver consists of four distinct lobes first the left lobe, second the right lobe, third caudate lobe, and last quadrate lobe. The left and right lobes are the large lobes and are separated by the falciform ligament. The right lobe is about five to six times larger than tapered left lobe. The small caudate lobe extends from posterior side of the right lobe and it wraps around the inferior vena cava. Small quadrate lobe is inferior to the caudate lobe and it extends from the posterior side of the right lobe and it wraps around the gallbladder.

Figure-1: Structure of liver.

1. Functions of liver:

• Production of bile that required for the digestion of foods.
• Storage of extra sugar or glucose into stored glycogen in liver cells of the body and then converts it back into glucose when the the body needs it for energy.
• Production of clotting factors.
• Production of amino acids that is building blocks for making proteins, that includes those used to help fight infection.
• The production and storage of iron which is necessary for production of red blood cells in the body.
• Manufacturing of cholesterol and other chemical substances that is required for fat transport.
• Conversion of waste products of the metabolism into urea that is excreted in urine.
• Metabolising medicines into their active form (ingredient) in the body.

1.2 Liver diseases

Liver disease is any disturbance in functions of the liver that cause illness. The liver is responsible for various critical functions in the body and when it becomes injured or diseased, loss of those functions can cause significant damage to body. Liver diseases are also referred as hepatic disease.

1.3 Types of liver diseases

• Alcoholic liver disease
• Primary liver cancer
• Cirrhosis
• Cysts
• Fatty liver disease
• Liver fibrosis
• Hepatitis
• Jaundice
• Primary sclerosing cholangitis

1.3.1 Alcoholic Liver Disease

In 2000, cirrhosis was 1 of the leading causes of death in U.S.A. (United States). Alcoholic liver disease usually develops after large amount of alcohol intake. The long period during which alcohol excessively consumed, larger the amount ingested, high the rate of developing alcoholic liver disease and other liver problems.

Signs and Symptoms:

• Confusion
• Excessive fluid between the membranes lining abdomen and abdominal organs
• Tenderness and abdominal pain
• Dry mouth
• Fever
• Fatigue
• Jaundice
• Weight gain
• Nausea
• Loss of appetite
• Abnormal dark or light skin
• Agitation
• Altered level of consciousness
• Breast development in males
• Difficulty concentrating
• Hallucinations
• Impaired judgment
• Paleness
• Redness on feet or hands

1.3.2 Primary Liver Cancer

Primary cancer of the liver which is a growing liver problem called primary liver cancer, it generally remains undetected until when this disease has reached the advanced stage because most people do not exhibit these symptoms early on.

Signs and Symptoms

• Jaundice that is yellow discoloration of skin.
• Abdominal pain (the upper right part of the abdomen)
• Swelling of abdomen
• An enlarged liver
• Fatigue
• General weakness
• Loss of appetite
• Nausea vomiting
• Weight loss

1.3.3 Liver Cirrhosis

Liver cirrhosis is generally considered to the fourth stage of the alcoholic liver disease, it is progressive condition which causes liver damage. chronic alcoholism is the most common cause of this disease. 40% of the 27000 people die from this disease. Cirrhosis is characterized by the replacement of normal healthy tissue by fibrous tissue, regenerative nodules and scarring of the liver that is liver scarring. The resulting hardening of the liver, hard liver interferes with the blood circulation in the body, it leads to irreversible damage to the liver and a completely loss of liver function.

Signs and Symptoms

• Abdominal accumulation of fluid in abdominal cavity
• Abnormal pain
• Bleeding from engorged veins in esophagus
• Dark cola-colored urine
• Exhaustion
• Gallstone
• Fatigue
• Diabetes type 2
• Itchy hands and feet
• Loss of appetite
• Cancer of liver
• Liver failure
• Nausea and vomitting
• Malfunctioning of other systems such as impotence, kidney dysfunction and failure, and osteoporosis
• Hypertension
• Sensitivity to medications
• Spider-like small blood vessels under the skin
• Swelling of feet and hands from retained fluid
• Hepatic encephalopathy
• Weight loss
• Weakness
• jaundice

4. Liver cysts

Liver cyst also known as hepatic cyst, a simple liver cyst is a bubble (thin walled bubble), a fluid filled cavity in liver. A common liver problem, liver cyst can normal benign and pose no health risks. but in some cases, liver cyst may grow large enough to cause pain and discomfort in the abdomen, liver enlargement, infection of bile ducts, and bile ducts obstruction, that leads the cyst itself to become infected. In this case, it is necessary to drain and remove the cyst.

5. Fatty Liver Disease

Fatty Liver Diseases (steatosis) are generally considered to the first stage of Alcoholic Liver Disease. The exact causes of Non Alcoholic Fatty Liver Disease (NAFLD) are unclear. Many researchers, however, believe that the metabolic syndrome—a cluster of disorders that increase risk of diabetes, heart disease, and stroke—plays a crucial role in development of NAFLD.

NAFLD Levels of Severity

• Simple fatty liver (steatosis).
• NASH (Non-alcoholic steatohepatitis), it is the inflammation and signs of necrosis.
• Cirrhosis is characterized by scarring of liver, results in a hard liver which is un-able to function proper. so Cirrhosis can be fatal.

Signs and Symptoms

• Bleeding in esophagus from engorged veins
• Fatigue
• Fluid in the abdominal cavity
• Itching of feet and hands, and eventually entire body
• Loss of appetite
• Liver failure
• Lack of interest in sex
• Mentally confusion, such as forgetfulness and trouble concentrating
• Nausea and vomitting
• Small red spider veins under skin
• Swelling of feet and legs from retained fluid
• Weight loss
• Weakness
• Cola-colored urine
• Jaundice

1.3.6 Liver Fibrosis

Liver fibrosis is generally considered to the third stage of Alcoholic Liver Disease, liver fibrosis is a liver condition which is very progressive. Liver fibrosis is characterised by the formation of the fibrous tissue, regenerative nodules and scarring of liver, which interfere circulation of blood and lead to loss of functions of liver. caused by chronic alcoholism and hepatitis C, cirrhosis is a disease which is degenerative disease of liver.

Signs and Symptoms:

• Abdominal accumulation of fluids in abdomen
• Abnormal pain
• Bleeding from engorged veins in intestines or oesophagus
• Dark cola coloured urine
• Easy bruising
• Exhaustion
• Fatigue
• Itchy feet and hands
• Loss of appetite
• Lack of interest in sex
• Nausea and vomitting
• Swelling of feet and legs by retained fluid (edema)
• Enlargement of the liver
• Weakness
• Loss of weight
• Jaundice

1.3.7 Hepatitis

Hepatitis is gastroenterological disease, means inflammation of liver. Hepatitis is not 1, but many diseases hepatitis A to E in which inflammation of liver occurs and its cells are damaged and then inflammatory chemicals are released and being produced in the liver. in some cases hepatitis B infection increases person’s chance to development of liver cancer by 100 times.

Signs and Symptoms of Hepatitis:

• Diarrhea
• Dark urine
• Abdominal pain
• Enlarged liver
• Fever
• Fatigue
• General achiness
• Jaundice

1.3.8 Primary Sclerosing Cholangitis

Cholangitis is inflammation of bile ducts of liver. Sclerosing is inflammation leads to the excessive formation of scar and fibrous tissue. In primary sclerosing cholangitis PSC, the bile ducts of the liver have become inflamed and scarred.

1.3.9 Jaundice

It is not directly the disease of liver but rather symptom that can occur as result of variety of diseases. Jaundice appears a yellow discoloration of skin and white of the eyes caused by the abnormal formation of bilirubin in the blood. Orange yellowish pigment bilirubin, bilirubin is the part of bile, it forms in the liver as a byproduct of old cells of blood. When there are many blood cells (RBC) dying for liver to cope with yellowish pigment forms in the body resulting in jaundice, it is visible sign of liver problems.

Jaundice is an indicator that a person is suffering from 1 of a many diseases including,

• Paracetamol toxicity
• Alcoholic liver diseases
• Autoimmune hepatitis
• An abnormal narrowing of the bile duct
• Blocked bile ducts caused by stones, infection, and tumors
• Chronic hepatitis
• Drug induced cholestasis, bile pools in the gallbladder as a result of certain drugs
• Drug induced hepatitis
• Fatty liver disease
• Hemolytic anemia
• Intra-hepatic cholestasis of pregnancy, bile pools in the gallbladder because of the pressure in the abdomen during pregnancy.
• Ischemic hepatocellular jaundice
• Pancreatic cancer
• Primary biliary cirrhosis
• Primary liver cancer
• Viral hepatitis
• Malaria

4. Causes of liver disease

• Viral hepatitis
• Obesity
• Alcohol
• Genetics
• Autoimmune disorders
• Drugs
• Toxins
• Cancer

Table-1 Types of hepatobiliary injury or damage

1.5 Mechanism of hepatotoxicity

1. Distruption of cytoskeleton: phalloidin and microcystin disrupts the integrity of hepatocyte cytoskeleton by affecting proteins that are vital to its dynamic nature. (Phillips et al, 1986)

• Cholastasis: Bile formation is vulnerable to toxicant effects on the functional integrity of sinusoidal transporters, canalicular exporters, cytoskeleton dependent processes for transcytosis, and the contractile closure of the canalicular lumen.changes that weaken the junctions that form the structural barrier between the blood and the canalicular lumen allow solutes to leak out of the canalicular lumen. An immunosuppressive drug frequently reported to cause elevated level of serum bile salts and bilirubin as well as a reduction in bile flow.

• Mitochondrial damage: Preferential injury to mitochondrial DNA, as opposed to nuclear DNA, is a plausible mechanistic basis for structural and functional alterations to hepatic mitochondria associated with nucleoside analog therapy for hepatitis B and AIDS infections and with alcohol abuse.

1.6 Hepatotoxic agents

• Abacavir
• Acetaminophen
• Acitretin
• Alcohol
• Aldesleukin
• Amiodarone
• Amsacrine
• Anabolic steroids
• Androgens
• Asparaginase
• Bexarotene
• Carbamazepine
• Carmustine
• Cytarabine
• Dantrolene
• Dapsone
• Daunorubicin
• Disulfiram
• Divalproex
• Epirubicin
• Erythromycins
• Estrogens
• Ethionamide
• Etretinate
• Felbamate
• Fluconazole
• Flutamide
• Gold compounds
• Halothane
• HMG-CoA reductase inhibitors
• Imatinib
• Iron (overdose)
• Isoniazid
• Itraconazole
• Ketoconazole
• Labetalol
• Mercaptopurine
• Methimazole
• Methotrexate
• Methyldopa
• Metronidazole
• Naltrexone
• Nevirapine
• Niacin
• Nilutamide
• Nitrofurans
• Pemoline
• Phenothiazines
• Phenytoin
• Plicamycin
• Propylthiouracil
• Rifampin
• Rosiglitazone
• Sulfamethoxazole
• Sulfonamides
• Tacrine
• Tenofovir
• Tizanidine
• Tolcapone
• Toremifene
• Tretinoin
• Troleandomycin
• Valproic acid
• Vitamin A
• Zidovudine
• Lamivudine

1.7 Mechanisms of liver injury by some hepatotoxic substances

1.7.1 Mechanism of liver injury by CCl₄

CCl₄ converts into CCl₃ and CCl₃OO free radicals in the presence of enzyme CYP2E1, these free radicals then activate the inflammatory and profibrogenic mediators, inflammatory mediators cause lipid peroxidation and profibrogenic mediators cause liver fibrosis which are responsible for the liver injury. CCl₄ also acstivates Tissue inhibitor of metalloproteinase 1 (TIMP-1), Tissue inhibitor of metalloproteinase 2 (TIMP-2), Matrix metalloproteinase 2 (MMP-2) and MMP-9 these expressions also activate profibrogenic mediators which cause liver fibrosis.

Fig-2: Mechanism of liver injury by CCl₄

1.7.2 Mechanism of liver injury by acetaminophen

In therapeutic dose acetaminophen metabolises by glucuronyl transferases and sulfotransferases to stable metabolites which excreted throughout the body but in over dose acetaminophen metabolises by CYP2E1,CYP3A4 and CYP1A2 to toxic metabolite NAPQI(N-acetyl parabenzo quinine immine). this toxic metabolite covalently binds with the hepatocyte and causes damage to hepatocyte.

After binding of NAPQI to hepatocyte there are two possibility, first is stimulation of CD44 receptor expression on T cell which recovers hepatocyte and second is the reduced expression of CD44 receptor on T cell causes hepatocyte apoptosis which is fatal condition to liver.

Fig-3: (a)Liver injury by acetaminophen (b) Hepatocyte recovery and apoptosis process.

1.7.3 Mechanism of liver injury by alcohol

Fig-4 : Pathways through which alcohol (ethanol) can contribute to apoptosis.

1.8 Hepatoprotection

Hepatoprotection is the ability to prevent damage to the liver.

One medicine of hepatoprotection is silymarin, derived from Milk Thistle which selectively inhibits formation of leukotrienes by Kupffer cells.

1.8.1 List of Herbs have potentially hepatoprotective constituents (Jia et al, 2011)

• Almond oil
• Ganoderma lucidum
• Glycyrrhiza glabra
• Arctium lappa
• Halenia elliptica
• Astragalus membranaceus
• Murraya koenigii
• Nymphaea stellata
• Ocimum sanctum
• Paeonia lactiflora
• Pergularia daemia
• Picrorhiza kurrooa
• Phyllanthus amarus
• Plumbago zeylanica
• Silybum marianum
• Scoparia dulcis
• Salvia miltiorrhiza
• Amomum xanthoides
• Astragalus membranaceus
• Cichorium intybus
• Curcuma longa
• Cajanus indicus,
• Centella asiatica
• Coccinia indica
• Brassica,
• Eclipta
• Flickingeria fimbriata
• Flickingeria fimbriata
• Ganoderma lucidum
• Glycyrrhiza glabra
• Halenia elliptica
• Murraya koenigii
• Nymphaea stellata
• Ocimum sanctum
• Paeonia lactiflora
• Pergularia daemia
• Picrorhiza kurrooa
• Phyllanthus amarus
• Plumbago zeylanica
• Silybum marianum
• Scoparia dulcis
• Salvia miltiorrhiza
• Scutellaria baicalensis
• Schisandra chinensis

Table2: Plant tested in animal models for their hepatoprotective activity and found to be active.

SBS PGI Balawala, DehradunPage 1