Preventing Liver Cancer Consumption Of Balanced Diet Biology Essay

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The right upper quadrant of the abdomen consists of liver , biliary tree and gall bladder. The liver is concerned with many metabolic functions of the body which play critical role in maintaining body's homeostasis which include processing of dietary aminoacids , synthesis of plasma proteins, microbes and toxins removal , detoxification etc (Burtis, C.A et al,1999). As it is exposed to wide variety of functions , hepatic disorders can have hazardous consequences on the body of an individual. These hazardous consequences called the primary diseases of liver include viral hepatitis, alcoholic liver disease and hepatocellular carcinoma (Kuo.G et al,1989). Liver disease is a slow and gradual process in which the symptoms of liver decompensation can appear after weeks , months or even years after the occurrence of the injury (Burtis, C.A et al,1999). In most of the cases , there is a long time gap between occurence of the disease and its detection. Hence, individuals with liver problems often suffer from chronic liver disease.

3] Jaundice and cholestasis which can be analysed on the basis of laboratory evaluation of liver disease tests that consists of hepatocyte integrity tests , biliary excretion function tests and hepatocyte function tests. These tests aid in the diagnosis of the most disastrous consequence of the liver disease called 'hepatic failure' (Fausto et al,1999).

It is the endpoint of gradual , progressive damage to the liver which forms the part of chronic liver disease caused either due to destruction of hepatocytes or parenchymal damage. Thus , due to elevations in the serum aminotransferases with intervening normal or near normal periods the old man is diagnosed with chronic hepatitis C infection (Burtis, C.A et al,1999). This can be transmitted through blood transfusions , inoculations , sexual transmission (15%) hemodialysis patients and health workers (5%) (Fausto et al,1999).

Symptoms: Fever,tiredness,fatigue(cognitive and emotional dysfunction),pruritis,itching are the primary symptoms of cirrhosis (Newton ,J.La,2006).

Epidemiology:

The no.of cirrhosis cases have gone down in western countries but hepatitis Cinduced liver cirrhosis is a major concern worldwide due to unavailability of vaccine for hepatitis infection.The death rates with cirrhosis have a major relation with per capita consumption of alcohol.Females are at greater risk compared to males (Bailliére's,1993).HCV chronic infections will increase 2 -3 fold in next 20 - 30 years.It is rarely observed in children. Post transfusion risk is about 1: 2,000,000 (Bush,M.P,2003). 1.5-3 cirrhosis cases per year develop hepatocellular carcinoma (Burtis,C.A,2009). North America,Europe,Japan have maximum chances of developing HCC from HCV (Burtis,C.A,2009).

Hepatitis C therapeutics: current status and emerging strategies

Fig1. Method of replication of HCV in the body

Source :

Seng-Lai Tan, Arnim Pause, Yuguang Shi & Nahum Sonenberg, (November 2002),

Nature Reviews Drug Discovery 1, Nature publishing group, 867-881.

Available at : www.nature.com/.../v1/n11/fig_tab/nrd937_F2.html

F:\My Documents\damage of hepatocytes by HCV virus.GIF

Source :

SPENGLER.U , NATTERMANN.J, (2007), Immunopathogenesis in hepatitis C virus cirrhosis, Clinical Science 112, (Great Britain), (141-155)

Available at : www.clinsci.org/cs/112/0141/cs1120141.htm

Main Body

Parameter Normal range

Results Interpretation

Hb 13.2 - 16.2g/dl

9.8 g/dl low/ Anaemic

RBC 4.3 - 6.2x1012/L

3.22 x1012/L less

WBC 4.1 - 10.9x109/L

5.8 x 109/L normal

HCT 0.4 - 0.5

0.332 low

MCV 82 - 102fl

78fl low

PLT 140 - 150x109/L

68 x 109/L low

BILIRUBIN 5.1 - 17µmol/L(total)

1 - 5.1 µmol/L (direct)

175 µmol/L high

INR 0.8 - 1.2

1.8 high

APTTr 0.8 - 1.2

1.6 high

The person was subjected to drugs eg : ribavarin for the treatment of hepatitis C infection. Liver plays an important role in drug metabolism and as a result it is exposed to bioaccumulation of drugs (if drugs are given in excess) , leading to formation of toxic metabolic intermediates which can cause harmful effects on the body. Most of the drugs that are used for the treatment are lipophilic and hence , are easily absorbed into the small intestine and are transported to the liver by portal circulation (Burtis,C.A,2009). To eliminate these drugs from the body they should be converted to hydrophilic compounds so that they can be excreted into urine and bile by the process called biotransformation (Burtis,C.A,2009). Biotransformation occurs in two phases which protects the liver from accumulation of harmful substances (Chituri S,2000).

Phase I reactions consist of oxidation or demethylation that are dependent on cytochrome P450 enzymes which are composed of heme and unique apoprotein that bring about aliphatic or aromatic hydroxylation (Burtis,C.A,2009),(Stedman.C,2002).

The hydroxyl group form the important component for phase II reaction in which a large polar group is attached by the process of glucuronidation or sulfation to the hydroxyl oxygen. This process makes the drug water soluble thus eliminating it through bile or urine. This biotransformation process normally protects the body , but sometimes it can lead to accumulation of toxic substances(Burtis,C.A,2009),(Stedman.C,2002). These toxic substances can be eliminated from the body by conjugation with glutathione which forms the third phase in this process(Burtis,C.A,1999). There is limited supply of glutathione in the body , if it gets depleted the toxic substances accumulate causing drug induced injury. It gets depleted by intake of alcohol or fasting. Excess of drug ingestion causes accumulation of toxic electrophiles which interact with cellular proteins causing cellular injury through necrosis or apoptosis(Goodman.Z,2002).

Stable metabolites , excretion

Drug

PhaseI Detoxification

Cell damage

Non - immune mechanism

Immune mechanism

REACTIVE METABOLITE P450 activation

Source :Burtis, C.A et al,(1999),Tietz textbook of clinical chemistry,(3),W.B Saunders company,Pg no: 1159.

This necrosis results in obstruction to the portal flow leading to portal hypertension. This obstruction can be either presinusoidal, sinusoidal or postsinusoidal. Presinusoidal portal syndrome leading to obstruction of hepatic veins which ultimately causes hepatomegaly, abdominal pain, ascites , jaundice leading to portal hypertension, liver failure (Burtis, C.A et al,1999) . Increase in the portal pressure, causes dilation of portal venous system and results in the formation of collateral connections with the systemic venous flow which causes decrease in portal flow and ultimately causing the liver to be more dependent on arterial flow from the hepatic artery leading to shrinkage of liver due to lack of hepatotrophic factors that originate from the pancreas (Myers.R et al,2002). This portal shunting leads to decreased hepatocyte perfusion causing hypoalbuminemia which predisposes to ascites formation and hypoprothrombinemia which predisposes to bleeding and also loss of thrombolytic factors which predisposes to hypercoagulability(Burtis, C.A et al,2009). The most disastrous effects of portal hypertension are GI bleed and ascites formation(Burtis, C.A et al,2009). Ascites is the accumulation of serous fluid in the cavity of the abdomen which makes the person uncomfortable and compromises respiration. The important pathogenesis of ascites include:

1) Increase in the pressure of venous system due to scarring of the liver

2) Decreased intravascular pressure (hypoalbuminemia)

3) Increased intraperitoneal pressure(Kapnias.D et al,1996). These pressures ultimately cause shrinkage of the central blood volume and cause sodium retention and water absorption causing ascites and edema(Burtis, C.A et al,2009). It can also lead to bacterial peritonitis which causes abdominal pain, fever or leukocytosis(Burtis, C.A et al,2009). DIC is another condition that can be caused due to tissue destruction, malignancy, sepsis etc. Disseminated intravascular coagulation is the abnormal activation of blood clotting mechanisms that are produced due to prevalence of various diseases in the body. This results in the formation of small clots in the blood vessels(Ziv Ben-Ari,1999). These clots consume coagulation proteins and platelets thereby causing disturbance for normal coagulation process leading to abnormal bleeding from the site where the blood samples were collected etc. These small clots can also obstruct the normal blood flow to various organs like liver, kidney causing their malfunction that can ultimately lead to multiple organ failure which can be fatal(Ziv Ben-Ari,1999). In homeostatic condition, there is a balance between coagulation and fibrinolysis(Ziv Ben-Ari,1999). When the coagulation cascade is activated, thrombin is produced which converts fibrinogen to fibrin which is the stable endproduct of hemostasis. In fibrinolysis, there is breakdown of fibrinogen and fibrin. When this system is activated, plasmin is produced in the presence of thrombin which aids in fibrin clot lysis (Barbara,J.B et al,2003). This breakdown of fibrinogen and fibrin results in formation of polypeptides called fibrin degradation products or fibrin split products. In DIC, coagulation and fibrinolysis are disrupted resulting in clotting of blood all over the body leading to bleeding. The release of transmembrane glycoprotein called tissue factor (TF) is the most critical step in DIC. Many cell types like monocytes, macrophages, endothelial cells consist of TF on their surface which is not normally present in general circulation (Davidson et al,2002).It is released into the circulation after vascular damage. Eg : cytokine stimulation.When it is activated, it binds to the coagulation factors triggering the intrinsic and extrinsic pathways of coagulation. Excess of thrombin is produced due to excess activation of coagulation pathway (in malignancies). This thrombin causes breakdown of fibrinogen to fibrin clots which accumulate in the blood (Abbas,2002). The clots that are present in excess trap platelets making them larger in size and the lodging of these clots in microcirculation in the large vessels or organs leads to ischemia and ultimately organ failure (if in liver will lead to liver failure) (Robbins et al,1999).This process also consumes the coagulation inhibitors which results in increased blood clot formation and there is development of such a feedback system that increase in blood clotting leads to more clotting and simultaneously thrombocytopenia is also caused which consumes all the platelets(BarbaraJ.B et al,2003) . Clotting factors are consumed in the process of formation of clots which results in bleeding. Simultaneously the circulating thrombin converts plasminogen to plasmin causing fibrinolysis. This breaking of clots releases FDPs which are powerful anticoagulants that cause hemorrhage or purpura(BarbaraJ.B et al,2003).

Coagulation cascade

Source: Barbara,J.B et al,(2003),A-Z of haematology,(1),Blackwell publication,Pg no:77,78.

Pathophysiology of cirrhosis

Endothelial injury

Sepsis

Massive tissue destruction

Release of tissue actor

Platelet aggregation

Widespread microvascular thrombosis Widespread microvascular thrombosis

Activation of plasmin

Microangiopathic hemolytic anaemia

Vascular occlusion

Consumption of clotting factors and platelets

Ischemic tissue damage

Proteolysis of clotting factors

Fibrinolysis

Fibrin split products

Bleeding

Inhibition of thrombin, platelet aggregation, and fibrin polymerization

Source : Fausto et al,(1999),Robbins and Cotran Pathologic basis of disease,(7),Elsevier Inc.

The first and foremost important and convenient technique of diagnosis is liver biopsy.This is associated with certain problems and hence, it is done in only in patients who are not confirmed of cirrhosis infection. Confirmation of cirrhosis can be suggested by patients history, routine testing, physical examination (Floch,M.H et al,2008). On the basis of this further tests can be done to evaluate the complication caused by cirrhosis and its severity. A history of intravenous drug abuse and hepatitis suggest the possibility of cirrhosis.

http://www.netterimages.com/images/vpv/000/000/006/6830-0550x0475.jpg

Source :Floch,M.H et al,(2008),Netter's Gastroentrology,(illustrated),Icon learning systems,Pgno:715.

Available at: www.netterimages.com/.../226-715.htm

Source: Agarwal.M et al,(2009),Anesthesia and intensive care medicine,volume(10),Stanford,pg no:326-327.

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Low Haemoglobin and Low Mean Cell Volume - microcytic anaemia

ï‚· Iron deficiency anaemia

ï‚· Thalssaemia - esp. if MCV too low for level of anaemia

Low Haemoglobin and High Mean Cell Volume - macrocytic anaemia

ï‚· Vitamin B12 deficiency - including pernicious anaemia

ï‚· Folate deficiency

ï‚· Haemolytic anaemia

ï‚· Alcohol

ï‚· Liver disease

ï‚· Antifolate drugs (phenytoin)

Low Haemoglobin and Normal Mean Cell Volume - normocytic anaemia

ï‚· Anaemia of chronic disease

ï‚· Pregnancy

ï‚· Bone marrow failure

ï‚· Renal failure

ï‚· Haemolytic anaemia

Note - haemolytic anaemia falls into macrocytic and normocytic

Source: Agarwal.M et al,(2009),Anesthesia and intensive care medicine,volume(10),Stanford,pg no:326-327.

CLOTTING PROFILE

ELEMENT

INR

NORMAL VALUES

0.8 - 1.2

ABNORMALITIES

Raised INR

CAUSES

Warfarin

Liver disease

DIC

APTTr

0.8 - 1.2

Raised APTTr

Heparin

Haemophilia

Von Willebrand disease

DIC

Warfarin

Source: Krier.M et al,(2009),Clinics in liver disease,Volume(13),Stanford, Pg no: 167-177.

LIVER FUNCTION TESTS

ELEMENT

NORMAL VALUES

ABNORMALITIES

CAUSES

High albumin

Dehydration

Albumin

35 - 50 g/l

Low albumin

Inflammation

Cirrhosis

Malnutrition

Bilirubin

3 - 17 µmol/l

High Bilirubin

Jaundice

Biliary obstruction Haemolysis

Alkaline phosphatase (ALP)

40 - 120 u/l

High ALP

Liver disease

Alcohol

Cholestasis

Bone disease (Paget's disease)

Aspartate Aminotransferase (AST)

10 - 40 u/l

High AST

Liver cell damage

Alcohol

Skeletal muscle damage

Myocardial infarction

Alanine Aminotransferase (ALT)

3 - 35 u/l

High ALT

Liver cell damage

Alcohol

Congestive cardiac failure

Gamma Glutamyl transferase (GGT)

10 - 55 u/l

High GGT

Alcohol

Hepatic inflammation

Source: Burke,D.M et al,(2002),Clinics in laboratory medicine,Volume(22),Newyork, Pg no:377-390.

α - fetoprotein is the confirmatory test to distinguish between hepatocellular carcinoma and hepatocellular disease.It is mildly elevated in hepatocellular disease like cirrhosis and highly elevated in hepatocellular carcinoma. In this case, it should be mildly elevated as person is cirrhotic (Burtis, C.A et al, 1999).The examination and testing of accumulated fluid in the abdomen can be done by suction of fluid with the use of long needle which can aid in diagnosis of cirrhosis.CTscan and MRI of the abdomen is used to diagnose hepatocellular carcinoma which is advanced stage of cirrhosis(Marks ,J.W,1996).

Abnormal liver function tests

AST>3xURL AST<3xURL

ALP<2xURL ALP>2xURL

Hepatocellular disease Cholestatic disease

Normal albumin Decreased albumin Normal albumin Decreased albumin

Acute hepatitis Chronic hepatitis Acute cholestasis Chronic cholestasis

Ultrasound or percutaneous

cholangiography

Intrahepatic cholestasis Extrahepatic cholestasis

Source : Burtis, C.A et al, (1999), Tietz textbook of clinical chemistry,(3), W.B Saunders company, Pg no: 1168.

Increased alkaline phosphatase

Confirm with 5' nucleotidase or GGT

Not increased Increased

Consider bone disease Obstructive liver disease

Ultrasound or computed tomography

Dilated ducts Non dilated

ducts

Consider stones or Consider biliary

Space occupying lesions cirrhosis.

If diagnosis is uncertain negative positive

Perform percutaneous cholangiography Primary biliary

to diagnose stones, sclerosing cholangitis cirrhosis

Source : Burtis, C.A et al, (1999), Tietz textbook of clinical chemistry,(3), W.B Saunders company, Pg no: 1168.

Conclusion - As this person has low Hb, hematocrit, less RBC's, low mean cellular volume, normal WBC's it is suggestive of haemolytic anaemia (drug induced) and moreover , low platelet count, prolonged APTTr and INR indicating DIC caused due to necrosed liver tissue (cirrhosis).

Avoiding further liver damage Avoiding further damage to liver

Treatment of liver complications

Liver transplantation

t Treatment

Preventing liver cancer

Consumption of balanced diet and of multivitamin on daily basis may aid in improvement of the condition. Abstinence from alcohol and drugs are major factors aiding in recovery from cirrhosis and slowing the progression of the disease(Marks,J.W et al.1996)Hepatitis C infection should be eliminated by administrating the patient with antiviral drugs like ribavarin, interferon etc(BurtisC.A et al.2009). This administration depends on individuals capacity to tolerate drug dosage. Some individuals experience side effects like haemolytic anaemia due to excess intake of drugs.Blood removal from patients suffering from hemochromatosis and also using medicines that aid in excretion of copper in urine to avoid further liver damage.Drugs like ursodeoxycholic acid, help to reduce portal hypertension and colchicine and methotrexate help in preventing damage due to primary biliary cirrhosis(BurtisC.A et al ,2009).Edema and Ascites - Salt (2g/day) and fluid (1.2L/day) intake is restricted to decrease ascites and edema. Various combination of diuretics are given like spironolactone and furosemide aid in elimination of ascites and edema(Marks,J.W et al,1996). Elevated levels of blood urea nitrogen and creatinine indicate excessive usage of diuretics that can cause kidney dysfunction. When these diuretics fail to work, abdominal fluid is withdrawn by process called abdominal paracentesis and tested and examined (Marks,J.W et al,1996). Another method to treat ascites is transjugular intravenous portosystemic shunting.Bleeding from varices:This treatment aims to decrease the pressure in the portal vein and also destruction of varices. These include use of propranolol that reduces the pressure in the portal vein and prevents bleeding, if only Propranolol doesnot produce the desired effect then Isordil is administered(Marks,J.W et al,1996).Sandostatin can also be used.Patients who fail to produce the desired response to beta blockers can be treated with TIPS to decrease the portal hypertension. In this procedure, a tube is inserted through the neck vein down into the inferior vena cava and into the hepatic vein in the liver. This tube is placed in a high pressure portal region and down into the low pressure hepatic vein. This causes overall distribution of tension throughout the liver thereby relieving the portal hypertension. This procedure can lead to hepatic encephalopathy, narrowing of tube inserted and thereby reccurence of portal hypertension(Marks,J.W et al,1996). DSRS (Distal splenorenal shunt) is another surgical method used to treat portal hypertension. In this method, splenic vein which is attached to portal vein is removed and attached to renal vein. This causes decrease in the pressure of portal vein thereby preventing bleeding from varices(Marks,J.W et al,1996). Hypersplenism:Spleen is an organ which is responsible for blood filtration.Enlarged spleen filtration causes mild anemia, in some cases leukopenia,thrombocytopenia. Anaemia in severe form needs treatment with blood transfusion or erythropoietin.Bacterial peritonitis:It is treated with administration of various antibiotics with ampicillin, gentamycin, cephalosporin. Not all the individuals are prescribed for antibiotics but individuals with weakened immune system,GI bleeding,low protein levels in ascitic fluid have maximum chances of developing bacterial peritonitis(BurtisC.A et al ,2009). Hence, are administered with antibiotics. Patients that are exposed to cirrhosis due to HBV and HCV are recommended for screening tests every six months or year.50% of screening tests detect cancer at the stage that can be treated, most of tests detect it in the last stage which is difficult to treat. In these tests, ultrasound examination of abdomen is done and also level of cancer producing proteins is evaluated. Eg: α- fetoprotein.Inspite of cirrhosis being screened and treated, it is still irreversible and the condition worsens. Hence, liver transplantation is the most reliable and unique method to treat cirrhosis(Marks,J.W et al,1996),.Recent developments in medicine and transplants have prevented rejections and infections of liver transplantation(BurtisC.A et al,2009). 80% of the individuals who have undergone transplantation are alive 5 years after the transplantation is done.There is shortage of livers for transplant to be done and hence, it is essential to prevent the progression of disease and treat its complications by some medications or procedures(Marks,J.W etal,1996)

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