LIVER CIRRHOSIS: A REVIEW

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ABOUT AUTHORS:
Kambham Venkateswarlu1*, N.Devann2, R.Venu Priya3, P.Bharath Rathna Kumar4
1M.Pharm Scholar, Department Of PharmaCEUTICS,
2Director Of JNTUA-Otri,
3Faculty Of Pharmacy, Department Of Pharmaceutics,
4Faculty Of Pharmacy, Department Of Pharmaceutical Chemistry,
JNTUA-Oil Technological Research Institute,
Beside Collector Office, Anantapur, Anantapur District, Andhra Pradesh, India.
Pin Code: 515001

ABSTRACT:
Cirrhosis is defined as the histological development of regenerative nodules of liver parenchyma surrounded by fibrous septa in response to chronic liver injury. Chronic liver diseases represent a significant health problem across the globe with liver cirrhosis,an end stage consequence of fibrosis, being the major medical emergency with significant morbidity and mortality.
The exact prevalence of this life threatening disease worldwide is unknown as clinical spectrum of cirrhosis ranges from indolent, asymptomatic to complete hepatic decompensation. The progression of fibrosis to cirrhosis is lower in women than men due tothe protection offered by oestrogens. The ultimate curative option for liver cirrhosis currently is liver transplantation, which poses significant risk to the patient.

REFERENCE ID: PHARMATUTOR-ART-2088

1. INTRODUCTION:
Liver fibrosis or scaring of liver is a complex,dynamic perpetuation of normal wound healing response to a variety of fibrogenic stimuli leading to activation and trans differentiation of hepatic stellate cells (HSC) to myofibroblasts leading to excessive synthesis and deposition of ECM components mainly type I and type III collagen accompanied by distortion of normal hepatic vasculature, hepatocyte dysfunction and eventually leading to irreversible liver damage, subsequent complications and possible death.[1]

2. ETIOLOGY:
1. Autoimmune
a. Autoimmune hepatitis

2. Viral/infectious
a.Hepatitis B
b.Hepatitis C
c.Schistosomiasis

3. Metabolic
a. Alcohol
b. Toxins, medications
c.Hereditary hemochromatosis
d.Wilson’s disease
e.Nonalcoholicsteatohepatitis
f.Insulin resistance

4. Cholestatic
a. Primary biliary cirrhosis
b.Primarysclerosing cholangitis
c.Biliary atresia
d.Secondary biliary cirrhosis

5. Vascular
a.Right heart failure
b.Budd–Chiari syndrome
c.Alpha-1-antitrypsin deficiency
d.Sarcoidosis
e.Cystic fibrosis[2]

3. COMPLICATIONS OF CIRRHOSIS:
1. Impaired metabolic and endocrine functions: Jaundice occurs due to compromised hepatocyte excretory function.
2. Spider angiomata due to decreased oestradiol degradation in liver.
3. Splenomegaly due to portal hypertension.
4. Hematological derangements such as thrombocytopenia.
5. Ascites a severe complication due to portal hypertension.
6. Hyponatremia.
7. Gastrointestinal varices.
8. Spontaneous bacterial peritonitis.
9. Hepatic encephalopathy.
10. Hepatorenal syndrome.
11. Hepatocelluar carcinoma.[2]

4. DIAGNOSIS:
1.Serological: AST, ALT, ALP, Gamma-glutamyl transpeptidase, bilirubin, albumin, prothrombin time, immunoglobulins mainly IgG, sodium.

2.Histological: Liver biopsy which is considered as the gold standard for diagnosis and sequential histological grading of fibrosis.

3.Radiodiagnosis: Ultrasonography, CT and MRI.

4.Transientelastography[2]

5. ANIMAL MODELS OF LIVER FIBROSIS:
Several approaches to induce liver fibrosis in animal are described according to their stimulus from inciting injury. Liver fibrosis models are associated with
1) Toxic damage: (hepatocyte toxicity induced by: CCl4,dimethylnitrosamine(DMN), galactosamine and bileduct epithelial cell toxicity by thioacetamide(TAA).
2) Immunologically induced damage (heterologous serum (porcine) and experimental schistosomiasis)
3) Biliary damage (common bile duct ligation or occlusion)
4) Alcohol induced damage
5) Fatty liver disease in particular the malignant inflammatory form non alcoholicsteatohepatitis (NASH), can progress to liver fibrosis and cirrhosis.

BDL and CCl4 are the most widely used rodent models in liver fibrosis to assess the effectivity of experimental drugs on the pathogenesis, because these models represent features of human pathogenesis and are best characterised with respect to histological, biochemical, molecular changes associated with fibrosis.[5]

5.1. Acute and chronic models with carbon Tetrachloride (CCl4)
The damage to hepatocytes by CCl4 is reflected by high plasma alanine tranaminase(ALT) and aspartate transaminase(AST) levels after CCl4 administration. CCl4 also causes fatty changes in the hepatocytes.This initial damage is followed by hepatic stellate cell activation and tissue fibrosis.

The CCl4 model is associated with tremendous inflammation, a feature that is also seen in livers of patient with liver fibrosis. In animal models, CCl4 treatment is used to obtain different stages of the fibrotic process,ranging from early damage and HSC activation until advanced cirrhosis.

CCl4 is administered to the animals via i.p., s.c., oral administration, or by inhalation. Fori.p injections, CCl4 is diluted in olive oil and given in doses of 0.5-1.0ml/kg to rats and mice Often supplementation of phenobarbital in drinking water is used to get more reproducible fibrosis development and to accelerate the speed of fibrosis development.

Disadvantages of this model are the variations obtain in disease induction in animals and relatively high rate of mortality after CCl4 administration.[5]

5.2. Galactosamine induced hepatotoxicity
D-Galactosamine (400 mg/kg, i.p) produces diffuse type of liver injury simulating viral hepatitis. It presumably disrupts the synthesis of essential uridylate nucleotides resulting in organelle injury and ultimately cell death. Depletion of those nucleotides would impede the normal synthesis of RNA and consequently would produce a decline in protein synthesis. This mechanism of toxicity brings about an increase in cell membrane permeability leading to enzyme leakage and eventually cell death. The cholestasis caused by galactosamine may be from its damaging effects on bile ducts or ductules or canalicular membrane of hepatocytes  Galactosamine decrease the bile flow and it’s content i.e. bile salts, cholic acid and deoxycholic acid. Galactosamine reduces the number of viable hepatocytes as well as rate of oxygen consumption.

Dose of D-Galactosamine: 400 mg/kg, I.P.[3, 4]

5.3.Thioacetamide induced hepatotoxicity
Thioacetamide (100 mg/kg,s.c) e interferes with the movement of RNA from the nucleus to cytoplasm which may cause membrane injury. A metabolite of thioacetamide (perhaps s-oxide) is responsible for hepatic injury. Thioacetamide reduce the number of viable hepatocytes as well as rate of oxygen consumption. It also decreases the volume of bile and it’s content i.e. bile salts, cholic acid and deoxycholic acid. Dose of thioacetamide: 100 mg/kg, S.C.[3]

5.4. Alcohol induced hepatotoxicity
Liver is among the organs most susceptible to the toxic effects of ethanol. Alcohol consumption is known to cause fatty infiltration, hepatitis and cirrhosis. Hepatitis and cirrhosis may occur because of enhanced lipid peroxidative reaction during the microsomal metabolism of ethanol. Among the mechanisms responsible for effects of alcohol, an increase in hepatic lipid peroxidation leads to alteration in membrane phospholipid composition.The peroxidation of membrane lipids results in loss of membrane structure and integrity.[5]

This result in elevated levels of ¡-glutamyltranspeptidase, a membrane bound enzyme in serum. The decrease in activity of antioxidant enzymes superoxide dismutase, glutathione peroxidase are speculated to be due to the damaging effects of free radicals produced following ethanol exposure or alternatively could be due to a direct effect of acetaldehyde, formed by oxidation of ethanol.[5]

Alcohol pre-treatment stimulates the toxicity of CCl4 due to increased production of toxic reactive metabolites of CCl4 ,namelytrichloro-methyl radical by the microsomal mixed function oxidative system. This activated radical binds covalently to the macromolecules and induces peoxidative degradation of membrane lipids of endoplasmic reticulum rich in polyunsaturated fatty acids. This lipid peroxidative degradation of bio membranes is the principle cause of hepatotoxity.[5]

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