Pathophysiology Of Variceal Haemorrhage Biology Essay

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Varices are dilated portosystemic collaterals with thin cell walls and located in the lamina propria of the distal oesophagus, fundus and gastric curves of the stomach 1,2,3. Variceal bleeding occurs when these varices rupture due to excessive pressure exerted on them. Patients experience massive blood loss, often going into shock and can bleed to death (mortality rate of 30%-50% within 2 years)2,4. 25% of developed varices haemorrhage within 2 years 2,3.Oesophageal varices are more common than gastric varices in cirrotic patients. (50% versus 5-33%)1,4. Oesophageal variceal bleeding is more common than gastric variceal bleeding (90% versus 8%)1. Oesophageal varices have a first 6 weeks mortality rate of around 30-40%, lowered to 20% with proper haemostatic treatment 2,4,5.Rebleeding is common within the 6 weeks of initial bleeding, with a tendency towards the first 5 days after treatment (40.5% of early rebleeding)5 The rebleeding rate within 6 weeks ranging around 32% to 84% in untreated patients, 30-40% in treated patients and a mean late rebleeding rate (rebleeding after 6 weeks) of 59%2,5,6.

Variceal haemorrhage is the major complication of chronic liver disease associated with portal hypertension, marked by an increased Hepatic Venous Portal Gradient (HVPG) 2,3,6.Variceal development and variceal haemorrhage typically only occurs when HVPG exceeds 11-12 mm Hg (normally 3-5 mmHg),with rebleeding mortality and treatment failure rates significantly increasing when HVPG exceeds 20 mmHg. 2,3,5,6 This changes result in increased diameter of varices and decreased wall thickness to lower portal pressure2.3. Thus, the variceal wall is weakened and ruptures when the exerted wall pressure exceeds the variceal wall tension, typically causing massive haemorrhage2,3,5 .It contributes 60-70 % of upper gastrointestional bleeding in chirrosis.3

The prognosis of patients mortality and rebleeding is dependent on the liver disease severity and size of the varices seen via endoscopy. Chronic liver disease severity is accessed via a Child Pugh Score system, and is categorised into 3 classes, Class A, Class B and Class C. Class A represents mild liver failure, B moderate and C severe liver failure. Class A patients have fever oesophageal varices than Class C patients (40% versus 85%) 5 Mortality from variceal bleeding is higher in Class C (79%) patients than Class B (46%) and Class A patients(32%) 1. Large varices that exceed 5mm diameter are more prone to rebeeding (15% versus 5%) and red varices that indicate thin and weak variceal walls 2,5.

. Chronically damaged liver has an increased resistance towards portal bloodflow mainly due to the development of fibrous cells and ascites in chirrosis, as well as development of myofibroblasts and 'modified' contracting stellate cells.3 Intrahepatic resistance is also increased due to reduced nitric oxide and elevated vasoconstrictors (endothelin) in the liver 2,3 The increased portal pressure promotes release of endogenous nitric oxide seen in chirrosis and reduced vasoconstrictors production, lowering systemic blood pressure3. However, this leads to a compensatory homeostatic response via the release of atrial nartiuretic peptide (ANP) and the rennin-angiotensin pathway that increase plasma volume via water retention and increased cardiac output, triggering a hyperdynamic circulatory state that increases portal inflow and HVPG 2,3.

Review of Treatment Regiments for Variceal Haemorrhage

A reduction in HVPG baseline levels measured immediately after haemorrhage to lower than 10 to 12 mmHg or 20 % reduction of that baseline HVPG will lower rebleeding rates to 10-15% 2, ,5,6 Prompt haemostatic treatment is given to stop the variceal bleeding and lower HVPG, followed by secondary rebleeding prophylaxis due to the high rebleeding risks and mortality rate 1,2,5,6. Treatment regiment remains the same regardless of patients liver failure, varices size and past treatment history for variceal bleeding 1,2,5,6.

The acute bleeding of oesophageal varices is usually stopped by concomitant usage of the vasoconstricting drugs somatostatin ,terlipressin or octreotide with Emergency Endoscopic Variceal Ligation (EVL) or Endoscopic Sclerotherapy (EST) 1,2,4,5,6 This combination induces haemostasis 90% of the time and prevents early rebleeding by around 85%2. There was a significant combination effect at stopping bleeding (Odds Ratio(OR): 1.12, 95 %CI 1.02-1.23 NNT=8) and preventing early rebleeding (OR:1.28, 95% CI : 1.18-1.39 NNT=5) versus either EVL or EST 1,8 The drugs were administered prior to endoscopy to lower risk of variceal bleeding during endoscopic treatment (50% to 20-25%) 2.4, These drugs constrict the splanchic arterial blood vessels, lowering portal inflow and pressure, thus stopping variceal haemorrhaging. 5These drugs have similar haemostatic activity, rebleeding prophylaxis, mortality rates and fewer side effects. (Relative Risk (RR) = 0.14 ) versus endoscopic therapy alone 1,2,,3 EVL is more effective at preventing rebleeding compared to EST (OR=0.52, 95%CI 0.37-0.74) and at lowering mortality rates (OR = 0.67, 95%CI = 0.46-0.98), along with fever incidences of side effects (OR=0.10 95%CI 0.03-0.29) 1. Finally, combination therapy of EVL and EST is not recommended for acute treatment or secondary prophylaxis since combination treatment has similar rebleeding risk (Relative Risk = 1.05, 95%CI of 0.67-1.64) or mortality (Relative Risk of 0.99, 95%CI of 0.68-1.44) and is associated with higher oesophageal stricture formation 9.

. EVL involves the insertion of rubber bands over the varices using a specialised ligation device fixed to an endoscope6. This bands cause haemostasis and formation of scar tissue at the previous site of the varices, thus eliminating them 6. Newer methods allow EVL to be performed during a haemorrhage and multiple bands to be placed in one session, thus stopping acute variceal bleeding 5. EST involves injecting 1-5 ml of surfactants into the lower oesophagus in multiple sessions 6. EST works like EVL eradicating varices via induced thrombosis and subsequent fibrosis, 6. EST is an alternative should the hospital lack the facilities to perform EVL. Both EVL and EST cause ulceration, with ulcerations from EVL being smaller, thus heals better than EST ulcerations 6. EST elevates HVPG, unlike EVL , thus increasing rebleeding and mortality risks11.Furthermore, EST can cause necrosis, allergic reactions to surfactant, pain with injection of surfactant,pulmonary embolism and Deep Vein Thrombosis.(DVT) 10.

Somatostatin and it's analogue, octreotide, work by lowering the release of glucagon and other vasodilatory peptides2,12. They are actually used for treating neuroendocrine tumours and acromegaly 13.Somatostatin infusions maintain a lower HVPG, whereas bolus injection produces a large drop in HVPG 2. An initial bolus dose of 250µg is administered, followed with an infusion of 250-500 µ/hour afterwards 10. However, the higher dosing regiment of 750µg bolus followed with a 500µg/hour is more effective than the lower dose regiement in initial haemostasis (82% versus 60%) ,in preventing rebleeding, reducing HVPG (13% versus 6% HVPG reduction).with higher survival rates (93% versus 70%) 1 . Somatostatin suppresses the production of glucagon and potientating protein kinase C vasoconstrictors, thus preventing postprandial hyperemia 2,5,12. Somatostatin also lowers intrinsic hepatic resisitance in cirrhosis 2,12. Somatostatin has typically mild side effects, such as nausea and vomiting (25% patients) and hyperglycaemia in 2-4% of patients 10. However, only octreotide, and not somatostatin is available in the UK 11. Vaperotide ,another somatostatin analog also treats variceal bleeding but is not well documented unlike octreotide/somatostatin.

Octreotide works by a non-glucagon dependent mechanism, via potentiating the Protein Kinase C dependent vasoconstrictors, thus more effective in cirrhosis 10. Maximum effect was observed with a 50 µg bolus dose, followed with a 25-50 µg/h infusion rate11. Octreotide has a longer half life (2 h) compared to somatostatin (2 minutes) and more potent than somatostatin 12,14. Octreotide and somatostatin also prevents and reduces postprandial hyperemia 2,12, However, it is unlicensed for treating variceal bleeding in the UK11. The HVPG reducing effect of octreotide is shortlived (around 15 minutes long13, Tolerance develops towards octreotide, with subsequent bolus injections having half the HVPG reducing effect as the initial dose13. Octreotide induces severe tachyphylaxis as well as biliary cholic upon acute withdrawal,12,14.

Terlipressin (triglycyl-lysine vasopressin) also has a similar effect in lowering portal pressure and causing vasoconstriction of the varices 2. Terlipressin is more potent than octreotide and somatostatin at postprandial hyperemia 2. As a synthetic analogue of vasopressin, terlipressin is slowly converted into vasopressin in the body 2,5. Terlipressin exerts a localised vasoconstrictive effect on the splanchic blood vessels, thus reducing HVPG 2,5,13. Terlipressin also lowers the intravariceal pressure (16.3mmHg versus 20.9mHg) and the estimated variceal wall tension (59 mmHg versus 78 mmHg) in portal hypertension patients compared to placebo within 60 minutes of administration 14. It reduces mortality compared to placebo treatments (Risk Ratio RR of 0.66, 95%CI of 0.49 to 0.88), lowers risk of haemostatic failure ( RR of 0.66, 95%CI of 0.53 to 0.82) and fewer subsequent treatments (RR of 0.72, 95%CI of 0.55 to 0.93) 13. Terlipressin is given as a bolus dose (1-2 mg every 4-6 hours) with similar efficacy as high dose somatostatin treatment in haemostasis and preventing rebleeding 2.5,11. Terlipressin also treats subsequent uncontrolled bleeding (Odds Ratio of 0.52, P=0.092) more effectively compared to placebo treatment with a Numbers Needed to treat of 8.3 1,13. Terlipressin should also be used cautiously in patients that have cardiovascular diseases, hypertension, oedema and in renal impairment 11, Vasopressin is not recommended due to its non-localised vasoconstricting effects resulting in a high rate of systemic side effects (25% of patients) 2,5.

These drugs are given intravenously and concomitantly administered with antibiotics to prevent rebleeding induced by secondary infection, typically by Gram Negative microbes in the enteric tract, like Escherichia Coli 1,2 4,17. Patients with uncontrolled bleeding and chronic lever disease are more prone to systemic infection that trigger release of endothelin and nitric oxide which indirectly increases portal pressure and trigger rebleeding 17, Infections occur in 33% of patients and may cause treament failure and early death 5,17Antibiotic prophlaxis lowers mortality rate from variceal bleeding (OR: 0.73, 95%CI :0.55 to 0.95) 5 Typically, oral norfloxacin or intravenous floroquinolones when the oral pathway is inaccessible are used over seven days, along with terlipressin for 2 days or somatostatin/octreotide for 3-5 days 1. Intravenous ceftriaxone in used in advanced liver dysfunction, due to lower risks of sepsis and encephalopathy1,5,17. Plasma expanders and 8g/DL haemoglobin are administered cautiously to restore blood volume, preventing hypervoluemia which elevates HVPG and increases rebleeding and mortality rate 2,5,6,

Octreotide is better than Vasopressin/Terlipressin for variceal haemostasis (Relative Risk (RR) of 0.58, CI of 0.42-0.81), secondary rebleeding prophylaxis (RR of 0.89) and mortality (RR of 0.8) versus and a similar efficacy to immediate sclerotherapy 18 .It has lower frequency of majorside effects versus terlipressin (RR =0.31, 95%). However, octreotide is unlicensed in the UK for treating variceal bleeding and lacks a standardised treatment regiment for variceal haemostasis 12,13,18. Furthermore, it is a very costly drug regiment, compared to terlipressin. (approximately £410 versus roughly £155-310 for the respective treatment regiments)13.Thus, though more effective it's not recommended to treat variceal bleeding, as it's expensive, may induce severe tachyphylaxis and the undefined dosing regiments makes using octreotide somewhat risky .

Terlipressin lowers mortality rate from variceal haemorrhage2,15 Terlipressin has similar effectiveness as somatostatin in initial haemostasis (failure rate Relative Risk of 1.05, CI 0.67-1.63) preventing rebleeding episodes (Relative Risk: 1.20, CI of 0.80-1.81) as well as mortality rate (Relative Risk : 0.95, CI of 0.62-1.48), as well as octreotide2,12 . Terlipressin also directly and rapidly lowers pressure at the variceal bed, thus prompting cessation of bleeding 16. Terlipressin has similar efficacy as sclerotherapy at initial haemostasis( RD : -0.02, CI:-0.12-0.09) and preventing rebleeding (RD: 0.02, CI:-0.14-0.11) 7.Terlipressin is as effective as the 'last resort' balloon tamponade treatment in initial haemostasis (relative risk of failure 1.48, CI 0.73-2.98) preventing rebleeding (Relative Risk: 0.84, CI 0.46-1.55) and mortality (Relative Risk : 0.94, CI 0.50-1.77)12. The SIGN guidelines recommend the use of terlipressin in treating acute variceal bleeding 1. Terlipressin is also favoured as it is given as a bolus dose and shorter treatment course. Furthermore, it also inhibits of postprandial hyperemia and has similar potency to high dose somatostatin 2,15. Thus, terlipressin is the drug of choice to treat acute oesophageal variceal bleeding as it is easy to use, cheap and highly effective.

The balloon tamponade is the temporary salvage treatment for variceal haemmorage uncontrolled by pharmacotherapy and endoscopic treatment 4,5,19. The balloon tamponade is inserted into the patients oesophagus and into the stomach 19. Then, the gastric balloon is inflated and clamped to the gastroesphageal junction followed by the oesophageal balloon when the bleeding still persists. The balloon is left inflated for 24-48 hours 19. Balloon tamponade is effective in stopping initial bleeding (89.5%), but not at stopping subsequent rebleeding (40% rebleeding rate) following balloon deflation 19.. Baloon tamponade is an invasive procedure performed by trained doctors and requires endotracheal intubation to prevent pulmonary aspiration 18 . However,it causes discomfort with it's presence in the oesophagus and stomach. Furthermore, there is a high rate of complications (20-40%) and high mortality rate (20-30) % 2,5,19. Treatment failure is common due to improper inflation and clamping of the gastric balloon in the stomach 17. Furthermore, it has serious side effects such as pulmonary aspiration, alar necrosis, oesophageal rupture and cardiac arrest 17.

The main secondary prophylaxis against variceal rebleeding is using non-selective β-blockers like propanolol, carvidelol and nandolol after terlipressin or somatistatin or octreotede and EVL/EST treatment stops variceal haemmorage. 1,2,5,6,. This therapy is recommended in patients without contraindications against B blockers 1,2,5, The use of non selective Β blockers (propanolol) lower the cardiac output via inbibition of β1 andrenoreceptors and prevent the vasodilatory effect mediated by β2 andrenoceptors 2. Thus,β-blockers lower portal inflow, subsequently reducing HVPG.The reduction in HVPG and Heart rate are not correlated, thus the dosing of β-blockers are slowly titrated upwards to minimise systemic effects 2,. β blockers alone lower the risk of rebleeding form 63% to approximately 42% and safer than sclerotherapy(50-55%) for rebleeding prophylaxis 2. Carvedilol is most potent at preventing rebleeding (55% versus 30-40%), but should not used in this patient due the risk of postural hypotension associated with it's partial α-andrenoceptor blocking effect2. Nadolol is recommended for this patient as it does not affect sleep patterns, since it does not cross the blood brain barrier 2. Furthermore, the patient must be continued on β-blockers after treatment is started, since rebleeding occurs when β-blockers are stopped. Furthermore, EVL and B-blockers combination are more potent than EVL/EST or β-blocker monotherapy at preventing rebleeding episodes (OR=0.44, CI 0.21-0.94) with a similar mortality outcome (OR =0.95, CI 0.33-2.75) in high risk patients 2. This combination is recommended should patient have no contraindications to β-blockers 1,2,5,6. EVL and EST remains the alternative prophylaxis method for patients when β-blocker use is contraindicated (exampled: asthma, heart block) 1,2,13 However, the old patient may not respond well to β-blocker therapy 2.

The β-blockers are more effective when given concomitantly with Isosorbide Mononitrate (ISMN) 2,5,6. However, this combination is mainly reserved for patients whose HVPG does not drop with β-blocker monotherapy. It is as effective as EVL at preventing subsequent rebleeding (35% versus 42%),1,2 A study with ISMN and propanol reduces the rebleeding rate from 41% to 33% compared to propanolol alone 4. The nitrates exert a vasodilatory effect that lowers portosystemic and increased hepatic resistance observed in cirrhotic patients that elevates HVPG 2,4,5. Furthermore, this reduces tolerance towards HVPG reduction mediated by β-blockers 2.

Transjugular Intrahepatic Portosystemic Shunt (TIPS) is recommended therapy for variceal bleeding uncontrolled by endoscopy and pharmaceutical treatment 2,5,18 TIPS is recommended in this elderly patient over other portosystemic shunts as TIPS dose not involve surgery 2,19. TIPS involves placing a shunt from the portal vein to the hepatic vein using a stent and an angioplastic balloon via a catheter inserted from the jugular vein 19. The shunts are monitored frequently to treat shunt stenosis and prevent shunt failure 19. TIPS is contraindicated if the patient has high pulmonary artery blood pressure (>20mmHg), central hepatoma and polysystic liver disease 19. Although risky, other portosystemic shunts are used in TIPS contraindications 5,6,18. TIPS is a relatively safe procedure (5% adverse effects) with a high success rate at lowering HVPG (> 90%) and lower incidences of variceal rebleeding compared to endoscopy (19% versus 41%)6,19. TIPS has a mortality rate of around 20%, 6,18. Preferably, a coated stent is used when TIPS is preformed, to lower the increased risk of encephalopathy (34% versus 19% in EVL/EST) 2.

Treatment regiment for Gastric Variceal (GOV) bleeding depends on the exact location of the gastric varices. Varices located near the lesser curvature of the stomach are treated like oesophageal varices. Varices near the fundus are treated with tissue adhesives (eg:butly-cyanoacrylate), and followed up with TIPS performed concomitantly with balloon tamponade should haemmoraging persist 1,5,20.The cyanoacrylate injections had a lower rebleeding rate (31% versus 51%, p=0..001) ,a higher rate of stopping bleeding (87% versus 45%) and fewer treatment induced ulcers (7% versus 28%) and fewer blood transfusion versus EVL, thus is preferred over EVL1,20. Ectopic variceal bleeding from other sites are treated like gastric varices, with cyanoacrylate injection for haemostasis and TIPS as salvage treatment (90% haemostasis success)1,2,5,6.

Treatment Regiment for this patient

The patient's haemorrhage is stopped with 1-2 g IV of terlipressin. The terlipressin regiment is 2mg at first, then reduced to 1g IV when bleeding has stopped and maintained for 2-3 days with oral norfloxacin (400 mg BD) / intravenous ceftriaxone antibiotics administered for 7 days to initiate haemostasis, prevent rebleeding, prevent infections and eradicate varices, 1,2,5,16 Plasma expanders and 8g/DL haemoglobin were carefully given to restore lost blood volume 2. Alternatively, somatostatin (750µg bolus followed by 500µg/hour) or octreotide in the UK (50µg bolus dose followed with a 25-50 µg/h infusion) is used when terlipressin is unavailable .1,2,5,,12,13. The balloon tamponade remains the 'rescue treatment' in haemostasis failure, before resuming conventional treatment 15. Endoscopic diagnosis is performed to determine location of the haemorrhaging varices. Oesophageal varices are treated with non-selective β-blocker, preferably nandolol is used, combined with EVL or EST for rebleeding prophylaxis1,2,5,6,8. Patients HVPG levels are monitored, with ISMN added should HVPG levels not drop with β-blocker treatment. EVL/EST is used alone if β-blocker use is contraindicated. The patients must undergo endoscopic review once every year or two years. Finally, TIPS is used as emergency rescue treatment or rebleeding prophylaxis should pharmacothreapy and endoscopic combination prove not effective 19. TIPS stent are reviewed every six months to control and treat stenosis 18. Portocaval shunt is used when TIPS is contraindicated. Gastric Variceal bleeding or ectopic variceal bleeding is treated with 0.5-1 mg butyl-cyanoacryate injection, with emergency TIPS and balloon tamponade as the emergency rescue treatment for uncontrolled bleeding. 1,20.