Liver Cirrhosis And Hypertension Biology Essay

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Cirrhosis occurs where the liver stiffens which increases portal flow resistance and hypertension. Veins begin to form and blood will shunt away from these sites (Lee et al. 2009). Splanchnic vasodilation is the main factor inducing ascites. Nitric Oxide is produced where portal hypertension occurs to dilate the veins as part of the vasodilatory substances causing splanchnic vasodilation (Lee et al. 2009).

Chronic hepatitis C, alcohol abuse and fatty liver disease are the most common forms of liver damage which induce liver cirrhosis. Cirrhosis is a silent disease where patients are asymptomatic until pathology and liver decompensation occurs. In the US, 40% of patients discover cirrhosis incidentally during routine examination or autopsy (Heidelbaugh et al. 2006). As a complication of cirrhosis, ascites leads to a progressive worsening of the cirrhotic process in 50% of patients within 10 years (Lee et al. 2009). There are non-cirrhotic causes of ascites which are required to be diagnosed as the frequency of occurrence tends to increase in patients with compromised livers which includes malignancy, tuberculosis, and pancreatic ascites, however liver cirrhosis amounts to 85% of cases (Moore et al. 2003).

Overall general management of ascites always requires a follow up and health advice to reduce dietary sodium intake. Management strategies can be derived through a grading system. Grade 1 can be detected only by ultrasound and is regarded as mild. The management strategy requires reducing sodium intake (70-90mEq/d) and diuretic medication, most commonly, spironolactone (aldosterone antagonist) and furosemide (loop diuretic) (Lee et al. 2009).

Grade 2 is seen as moderate where it is detected by symmetrical abdominal distension (Moore et al. 2009). A paracentesis can drain fluid of 8g/L also with synthetic plasma expanders. A Large volume paracentesis (LVP) may be used which consist of any ascetic fluid volume drained over 5L. In combination with general sodium restriction, LVP is only required at most every 2 weeks allowing outpatient contact (Lee et al. 2009).

Grade 3 is a severe form of ascites and possesses a larger distension of the abdomen and requires the protocol of Grade 2 ascites. Transjugular intrahepatic portosystemic shunt (TIPS) can be used where paracentesis is greater than 3 times per month (Heidelbaugh et al. 2006), or if possible, a liver transplant should be performed(Lee et al. 2009). TIPS improves renal function and sodium excretion but has limited to no proven benefit for patient survival (Moore et al. 2003). TIPS is associated with hepatic encephalopathy in 30% of cases and stenosis in 70% by 1 year (Heidelbaugh et al. 2006). Refractory ascites demonstrates unresponsiveness to large doses of diuretics and involves complication as well as more frequent ascites reoccurrences. For refractory ascites to progress to liver failure, 80 â€" 90% of the liver parenchyma must be destroyed via impaired hepatic function or reorganisation of liver parenchyma (Heidelbaugh et al. 2006).

Spontaneous bacterial peritonitis (SBP) is a pathological process induced by ascites via poor clearance of bacteria overgrowth from the intestine. It is a serious complication with a mortality rate of 20-40%. Gram-negative bacteria are more efficient at relocating and are usually Escherichia coli or Klebsiella species. Antibiotic prophylaxis has decreased effectiveness as bacteria become resistant which demonstrates the requirement for other approaches of pathological control (Cholingitas et al. 2006). Child-Pugh scores and MELD are capable of being used to determine applicants for liver transplants in priority considering the mean survival times of patients. This has not been studied specifically considering ascites which could give a potential beneficial factor for this scoring process (Lee et al. 2009).

Propanolol, a non-selective beta blocker of the sympathetic nervous system, has a potential protective effect on SBP by lowering portal vein pressure and increasing bowel motility as shown in experimental rat tests (Perez-Paramo et al. 2000). A dose of 10mg/Kg a day was used at much higher concentrations than in normal clinical practice but that even higher doses may be required (Cholingitas et al. 2006). Intestinal motility leads to decreased systemic translocation of bacteria so it is expected that high dosages should be enough to regulate SBP. A study to define the link between SBP, ascites and cirrhosis was performed which defined a type II statistical error (poor statistical sensitivity). A more conclusive study needs to be performed to determine whether a type II error is masking benefits of propranolol (Cholongitas et al. 2006).

Aims and Approach

The aim is to determine the influence propranolol has on reducing portal vein pressure in cirrhotic patients with ascites and its effect on SBP.

Study participants information will be collected from patient admittance to hospital to be put in a double blind phase I trial. A sample of 300 is required to have enough power to have significance and avoid type II errors. Chi-squared test, t-test and Wilcoxon signed-rank test will be used to compare quantified data in a 95% confidence interval utilizing SPSS statistical software (Cholongitas et al. 2006).

The study will consist of 3 patient groups;

Group 1: Control group, receiving a placebo of 46 patients. Group 2, will contain 127 patients being given 10mg/Kg a day of propranolol. Group 3 will contain 127 patients will be taking 50mg/Kg a day of propranolol.

Each patient will have a baseline taken which consists of, ascitic fluid taken and analysed, a diagnostic paracentesis performed as well as a detailed patient history taken. The particulars of each patients details to be taken include; age, gender, weight, cirrhosis cause, hospital admission reasons, child class/score, complications of cirrhosis, ascitic fluid characteristics, platelet count, prothrombin time, creatinine, bilirubin, albumin, ascitic fluid content (protein, albumin, glucose, cholesterol) and particularly white blood cell counts and patients use of propranolol. SBP is the main criteria to be measured (Cholongitas et al. 2006).

Questions for patients will consist of the baseline criteria as mentioned in follow up questionnaires which will be taken in the first month once at the end of each week and complete reports will be generated by blood tests for liver and key function and ascites diagnostic paracentesis cultures. The patients will require follow ups to perform this same procedure in the 2nd month, 3rd month, 6th month, 9th month, 1 year later, 1year 6 months and 2 years.

Patients who are diagnosed with an SBP history or take antibiotics a week before trials commence are not valid participants. SBP is capable of being detected in ascitic fluid where polymorphonuclear leukocyte counts are above 250 neutrophilic cells/mm3 which will be checked in patients cultures (Cholongitas et al. 2006).

Significance

Spontaneous Bacterial Peritonitis is inherently associated with ascites and cirrhosis and requires significant advances in the current state of treatment due to the lack of liver transplantation availability which is the only definitive treatment. Antibiotic overuse has caused increasing prevalence of drug resistance in bacteria which has a mortality rate of up to 40% in bacterial peritonitis. Alternative treatments are required to control SBP.

This study will purport to find how propranolol can be useful in treatment of people with cirrhosis and ascites and prevention of the onset of SBP. Previous studies have shown negligible (low dose) or minor improvement but have been statistically low in significance to be validly relied on to interpret the results. This study will increase propranolol dosages to be able to resolve if at higher dosages in humans it is advantageous to preventing SBP as indicated by rat trials (Perez-Paramo et al. 2000). The study will also increase the size of the patient sample so that it would be the first human trial to investigate high dose propranolol in a statistical evaluation with enough statistical power to make conclusions on its efficacy in reducing SBP and its pathological processes.

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