Liver Disease: Causes, Symptoms, Effects and Treatments

Evaluation of hepatoprotective activity of polyherbal formulation against CCl4 induced hepatic damage in rats

CHAPTER 1

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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.

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
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.

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
Causes of liver disease
Viral hepatitis
Obesity
Alcohol
Genetics
Autoimmune disorders
Drugs
Toxins
Cancer

Table-1 Types of hepatobiliary injury or damage

Types of hepatobiliary injury or damage

Representative toxins

Fatty liver

CCl4, ethanol, fialuridine, valproic acid.

Hepatocyte death

Acetaminophen, cu, dimethylformamide, ethanol, Ecstasy

Immune mediated response

diclofenac, ethanol, halothane, tienilic acid.

Canalicular cholestasis

Chlorpromazine, cyclosporine A, 1,1 dichloroethylene, estrogens,Mn, phalloidin.

Bile duct damage

Amoxicillin, ANIT, methylene dianiline, sporidesmin.

Sinusoidal disorders

Anabolic steroids, cyclophosphamide, microcystin, pyrrolidine alkaloids.

Fibrosis and cirrhosis

Arsenic, ethanol, vitamin A, vinyl chloride.

Tumors

Aflatoxin, androgens, thorium dioxide, vinyl chloride.

1.5 Mechanism of hepatotoxicity

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.

S.N

Name of the plant

Family

Part tested

1.

Andrographis paniculata

Acanthaceae

Leaves

2.

Veronica amygdalina

Compositae

Leaves

3.

Boerhavia diffusa

Nyctaginaceae

Leaves

4.

Carissa carandas

Apocynaceae

Root

5.

Silybum marianum

Asteraceae

Ripe fruit

6.

Swertia chirata

Gentianceae

Whole plant

7.

Cinnamomum zeylanicum

Lauraceae

Bark

8.

Azadirachta indica

Meliaceae

Leaf

9.

Careya arborea

Myrtaceae

Bark

10.

Eclipta Alba

Asteraceae

Leaves

11.

Solanum nigrum

Solanaceae

Whole plant

12.

Wedelia calendulacea L

Asteraceae

Leaves

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