Treatment Of Cirrhosis Portal Hypertension And Complications

Desired Outcomes

Recognizing and treating the cause of cirrhosis is paramount. Cirrhosis is irreversible; treatments are directed at limiting disease progression and minimizing1 complications. The immediate treatment goals are to stabilize acute complications such as variceal bleeding and prevent SBP. Once life-threatening conditions have stabilized, the focus shifts to preventing complications and preventing further liver damage. Complication prevention involves both primary and secondary prophylaxis. To determine appropriate prophylactic therapy, a careful analysis of patient characteristics and disease history is mandatory. The sections that follow concentrate on treatment and prevention of cirrhotic complications.

Nonpharmacologic Therapy

Lifestyle modifications can limit disease complications and slow further liver damage. Avoidance of additional hepatic insult is critical for successful cirrhosis treatment. The only proven treatment for alcoholic liver disease is the immediate cessation of alcohol consumption. Patients who have cirrhosis from etiologies other than alcoholic liver disease should also abstain from alcohol consumption to prevent further liver damage.

All patients with ascites require counseling on dietary sodium restriction. Salt intake should be limited to less than 800 mg sodium (2 g sodium chloride) per day. More stringent restriction may cause faster mobilization of ascitic fluid, but adherence to such strict limits is very difficult. Ascites usually responds well to sodium restric-

14 22 31 32

tion accompanied by diuretic therapy. ' ' ' The goal of therapy is to achieve ur-

inary sodium excretion of at least 78 mEq (78 mmol) per day. While a 24-hour urine collection will provide this information, a spot urine sodium:potassium ratio greater than 1 provides the same information and is much less cumbersome to perform.

Medication use must be monitored carefully for potential hepatotoxicity. Hepatic-ally metabolized medications have the potential to accumulate in patients with liver disease. Little guidance is available on drug dosing in hepatic impairment because these patients have historically been excluded from drug trials. Daily acetaminophen use should not exceed 2 g. Dietary supplements, herbal remedies, and nutraceuticals have not been well studied in hepatic impairment and cannot be recommended.

In patients with variceal bleeding, nasogastric (NG) suction reduces the risk of aspirating stomach contents. Aspiration pneumonia is a major cause of death in patients with variceal bleeding. NG suction is also helpful in decreasing vomiting during acute

33,34

episodes of variceal bleeding. ' Blood within the GI tract is very nauseating; removal of the blood can decrease vomiting.

Patient Encounter, Part 1

ES is a 44-year-old Hispanic man who presents to the emergency department with complaints of abdominal pain and fatigue.

Chief complaint: "My belly feels tight"

HPI: Increasing feelings of fullness and abdominal tightness that have become noticeable over the past 2 weeks, accompanied by nausea and decreased food intake, but without vomiting

PMH: Hypertension x 15 years, acute pancreatitis x 2 episodes PSH: No surgeries

SH: Married, currently separated; denies tobacco and illicit drug use; for the past 20 years typically drinks a 12-pack of beer daily and several shots of tequila; use has recently increased due to depression over marital separation

FH: Father with cirrhosis, died at age 45 from coronary disease; mother alive at age 62 with type 2 diabetes mellitus, hypertension, hyperlipidemia, and gastroesophageal reflux disease

Outpatient Meds: Chlorthalidone 25 mg daily

ROS: (+) Anorexia and nausea; denies vomiting, constipation, or diarrhea; patient reports moderate shortness of breath and dyspnea on exertion

VS: BP 125/75 mm Hg, P 84 bpm, T 37.3°C (99.1 °F), RR 18/min, oxygen saturation 98% on room air

HEENT: PERRL, EOMI, (+) sclera icterus CV: RRR, no murmurs, rubs, or gallops Chest: CTA bilaterally, no crackles or wheezes

Abd: Tense, distended abdomen that is tender to palpation, decreased bowel sounds, (+) hepatosplenomegaly

Ext: 2+ pedal pulses, 2+ pitting edema

What are this patient's risk factors for liver disease?

Identify features of his presentation that are consistent with cirrhosis.

Endoscopic band ligation and sclerotherapy are both means to stop acutely bleeding varices. Endoscopic band ligation is the application of a stricture around the varix, whereas sclerotherapy involves injecting the varix with substances designed to decrease blood flow to the area and prevent rebleeding. Endoscopic band ligation has replaced sclerotherapy as the preferred endoscopic treatment and is effective in stopping acute variceal bleeding in up to 90% of patients.35 It is the standard of care for secondary prophylaxis of repeat bleeding in patients with a history of either esopha-

geal or gastric variceal bleeding. Endoscopic band ligation is best used in conjunction

36_38

with pharmacologic treatment.

Balloon tamponade involves the application of direct pressure to the area of bleeding with an inflatable balloon attached to an NG tube. It is an option for patients in whom drug therapy and band ligation fail to stop variceal bleeding. Balloon tamponade is used only when other methods have failed. Once the direct pressure of the balloon is removed, rebleeding often occurs, so balloon tamponade is only a temporary measure prior to more definitive treatment such as shunting.11

During episodes of acute HE, temporary protein restriction to decrease ammonia production can be a useful adjuvant to pharmacologic therapy. Long-term protein restriction in cirrhotic patients is not recommended. Cirrhotic patients are already in a nutritionally deficient state, and prolonged protein restriction will exacerbate the 20

problem.

Vaccination against hepatitis A and B is recommended in patients with underlying cirrhosis to prevent additional liver damage from an acute viral infection.39 Pneumococcal and influenza vaccination may also be appropriate and can reduce hospitalizations due to influenza or pneumonia.

Shunts are long-term solutions to decrease elevated portal pressure. Shunts divert blood flow either through or around the diseased liver, depending on the location and type of shunt employed. Transjugular intrahepatic portosystemic shunts (TIPS) create a communication pathway between the intrahepatic portal vein and the hepatic vein. TIPS procedures have an advantage over surgically inserted shunts because they are placed through the vascular system rather than through a more invasive surgical procedure, but they still carry a risk of bleeding and infection. TIPS placement is associated with an improvement in HRS but an increased incidence of HE.40 HE associated with TIPS placement results from decreased detoxification of nitrogenous waste products because the shunt allows blood to evade metabolic processing.

Pharmacologic Therapy

Drug therapy targeted to reduce portal hypertension and cirrhosis can alleviate symptoms and prevent complications but cannot reverse cirrhosis. Drug therapy is available to treat the complications of ascites, varices, SBP, HE, HRS, and coagulation abnormalities.

Portal Hypertension

^^ Nonselective ft-blockers such as propranolol and nadolol are first-line treatments to reduce portal hypertension. They reduce bleeding and decrease mortality in patients with known varices. Use of ft-b lockers for primary prevention of variceal formation is controversial.

Only nonselective P-blockers reduce bleeding complications in patients with known varices. Blockade of P1 receptors reduces cardiac output and splanchnic blood flow. P2-Adrenergic blockade prevents P2-receptor-mediated splanchnic vasodilation while allowing unopposed a-adrenergic effects; this enhances vasoconstriction of both the systemic and splanchnic vascular beds. The combination of P1 and P2 effects makes the nonselective P-blockers preferable to cardioselective agents in treating portal hypertension.1,35,41 Cardioselective P-blockers do lose their cardioselectiv-ity at higher doses, but most patients with cirrhosis cannot tolerate the high doses.

Because P-blockers decrease blood pressure and heart rate, they should be started at low doses to increase tolerability Propranolol is hepatically metabolized, and its half-life and pharmacologic effects are prolonged in portal hypertension. A reasonable starting dose of propranolol is 10 mg two to three times daily.

Doses should be titrated as tolerated with the goal of decreasing heart rate by 25%

1135

or to approximately 55 to 60 bpm. ' Heart rate is not an accurate marker for portal pressure reduction, but it is the acknowledged surrogate marker for effectiveness because there are no other acceptable alternatives.

Nitrates have been suggested in patients who do not achieve therapeutic goals (heart rate reduction) with P-blocker therapy alone. Trials to evaluate the effects of nitrates (e.g., isosorbide mononitrate) on portal pressure, both alone and in combination with P-blockers, show enhanced reduction of portal pressure; however, there is an increase in mortality when nitrates are used alone. Adverse effects are significantly higher in patients treated with the combination of nonselective P-blockers and nitrates as opposed to P-blocker monotherapy.42,43 The current evidence only supports use of the combination to prevent rebleeding, not for primary prophylaxis. Unfortunately, P-blockers either alone or in combination may be intolerable for many patients with cirrhosis.

Ascites

The goals of treating ascites are to minimize acute discomfort, reequilibrate ascitic fluid, and prevent SBP. Treatment should modify the underlying disease pathology; without directed therapy, fluid will rapidly reaccumulate.

In the case of tense ascites, relief of acute discomfort may be accomplished by therapeutic paracentesis. Often the removal of just 1 to 2 L of ascitic fluid provides relief from pain and fullness. When removing 5 L or more of fluid at one time, volume resuscitation with 8 to 10 g of albumin given IV should be provided for each liter of fluid removed. Large-volume paracentesis without albumin administration is a known precipitant of HRS, secondary to decreased perfusion. If less than 5 L of fluid

is removed in a hemodynamically stable patient, albumin use is not warranted. Diuretics

Diuretics are often required in addition to sodium restriction (see Nonpharmacologic

Therapy). Spironolactone andfurosemide form the basis of pharmacologic therapy for ascites. Spironolactone is an aldosterone antagonist and counteracts the effects of activation of the RAAS. In hepatic disease, not only is aldosterone production increased, but the half-life is prolonged because of decreased hepatic metabolism. Spironolactone also acts to conserve the potassium that would otherwise be excreted because of elevated aldosterone levels.

Patient Encounter, Part 2

In the emergency department, a chest x-ray was normal. The following laboratory test results were obtained:

Sodium 128 mEq/L (mmol/L)

Potassium 3.1 mEq/L (mmol/L)

Chloride 106 mEq/L (mmol/L)

Bicarbonate 24 mEq/L (mmol/L)

Glucose 145 mg/dL (8.0 mmol/L)

Hematocrit 38% (0.38)

Platelets 118 x 103/mm3 (x 109L)

Total bilirubin 2.3 mg/dL (39.3 p,mol/L)

Alkphos 177 IU/L (2.95 pKat/L)

INR 1.6

GGT 185 IU/L (3.1 iKat/L) LDH 203 IU/L (3 .38 iKat/L) PT 29 seconds

Which of these values are consistent with the diagnosis of cirrhosis?

What (if anything) in the current presentation implies the underlying cause of the disease?

Which of the laboratory results are suggestive of complications related to cirrhosis?

ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, y-glutamyl transferase; INR, International Normalized Ratio; IU, international units; LDH, lactate dehydrogenase; PT, prothrombin time.

Spironolactone is usually used in combination with a loop diuretic (e.g., furosemi-de) for more potent diuresis. A ratio of 40 mg furosemide (the most commonly used loop diuretic) to each 100 mg spironolactone can usually maintain serum potassium concentrations within the normal range. Therapy is commonly initiated with oral spironolactone 100 mg and furosemide 40 mg/day.

Doses should be titrated at intervals no more frequent than every 2 to 3 days. Because spironolactone is used for its antialdosterone effects, much higher doses (up to 400 mg/day) are needed than those used when treating hypertension. If intolerable side effects such as gynecomastia occur with spironolactone, other potassium-sparing

diuretics may be used, but clinical trials have not shown equivalent efficacy.

The target in treating ascites is to cause a fluid loss of approximately 0.5 L/day. Because ascites equilibrates with vascular fluid at a much slower rate than does peripheral edema, aggressive diuresis is associated with intravascular volume depletion and should be avoided unless patients have concomitant peripheral edema. Patients with peripheral edema in addition to ascites may require increasing furosemide doses

until euvolemia is achieved; IV diuretics are often necessary. Diuretic therapy in cirrhosis is typically lifelong.

Varices

Unfortunately, variceal bleeding is common in cirrhotic patients; it accounts for between 10% and 30% of all cases of upper GI hemorrhage. During acute variceal hemorrhage, it is crucial to control bleeding, prevent rebleeding, and avoid acute complications such as SBP; mortality from first bleeding episode is up to 55%, and patients must be treated aggressively. A treatment algorithm for acute variceal bleeding is depicted in Figure 22-4.

Patient Encounter, Part 3

ES is found to have ascites. Therapeutic paracentesis is ordered to relieve shortness of breath and abdominal pain; 4 L of ascitic fluid is removed.

What are the goals for treating ascites in this patient?

What lifestyle modifications should the patient make that may decrease his risk of hospitalization and death from cirrhosis?

What pharmacologic options are available to treat ascites in this patient?

Octreotide

Octreotide is a synthetic analogue of somatostatin; it causes selective vasoconstriction of the splanchnic bed, decreasing portal venous pressure with few serious side effects. Vasopressin has also been used to achieve this effect, but since vasopressin causes nonselective vasoconstriction, it carries the risk of systemic consequences, which limits its usefulness.

The recommended octreotide dose is a 50- to 100-mcg IV loading dose followed by a continuous IV infusion of 25 to 50 mcg/hour. Therapy should continue for at least 24 to 72 hours after bleeding has stopped. Some clinicians continue octreotide for a full 5 days since this is the time frame during which the risk of rebleeding is highest. Octreotide combined with endoscopic therapy results in decreased rebleeding

rates and transfusion needs when compared to endoscopic treatment alone. Spontaneous Bacterial Peritonitis

Initiation of prophylactic antibiotic therapy to prevent SBP is recommended during acute variceal bleeding; this is typically initiated with a fluoroquinolone (e.g., ciprofloxacin 500 mg twice daily for 7 days) or an IV third-generation cepha-losporin. Some institutions would not use a fluoroquinolone antibiotic in patients who have been on long-term prophylactic therapy with that class of drugs. Prophylactic antibiotic therapy reduces in-hospital infections and mortality in patients hospitalized for variceal bleeding.44

If the presence of SBP is suspected, empiric antibiotic therapy with a broad-spectrum anti-infective agent should be initiated after ascitic fluid collection, pending cultures and susceptibilities (Fig. 22-5)45,46 In the setting of presumed infection, delaying treatment while awaiting laboratory confirmation is inappropriate and may result in death. The initial antibiotic should be an IV third-generation cephalosporin (e.g., cefotaxime 2 g every 8 hours, ceftriaxone 1 g every 24 hours), an IV extended-spectrum penicillin (e.g., piperacillin-tazobactam 3.375 g every 6 hours or 4.5 g every 8 hours), or a fluoroquinolone (e.g., ciprofloxacin 400 mg IV every 12 hours), because these agents cover the most common gram-negative and gram-positive agents implicated in SBP. Third-generation cephalosporins are usually recommended as first-line therapy. Fluoroquinolones may be used if resistant (extended-spectrum P-lactamase positive) organisms are suspected based on local susceptibility patterns or patient history. Once an infectious agent has been identified, antibiotic coverage can be narrowed to an agent that is highly active against that particular organism.

SBP has been identified as a cause of HRS. The risk of renal failure is lessened with IV albumin therapy, dosed at 1.5 g/kg of body weight initially, followed by 1

g/kg of body weight on day 3 of SBP therapy.

Portal Hypertension Treatment

FIGURE 22-4. Treatment algorithm for active Gl bleeding resulting from portal hypertension. (Adapted from Schiano TD, Bodenheimer HC. Complications of chronic liver disease. In: Friedman SL, McQuaid KR, Grendell JH, eds. Current Diagnosis and Treatment in Gastroenterology, 2nd ed. New York: McGraw-Hill, 2003, p. 649, with permission).

FIGURE 22-4. Treatment algorithm for active Gl bleeding resulting from portal hypertension. (Adapted from Schiano TD, Bodenheimer HC. Complications of chronic liver disease. In: Friedman SL, McQuaid KR, Grendell JH, eds. Current Diagnosis and Treatment in Gastroenterology, 2nd ed. New York: McGraw-Hill, 2003, p. 649, with permission).

Initial Evaluation; Identify Precipilants and Correct if Possible

Diagnostic paracentesis: Cell count

Cullure and Gram slain Albumin (serum albumin)'

Large volume paracentesis albumin) Initial com roi

Maintenance

Ne restriction (less than 2 g/day) (lluiu restriction il Na less than 120 meq/L)

Inadequate

Spironolactone 100 mg/day

± furosernide 40 mg/day (escalaie up to 400 mg/day and 160 mg/day)

inadequate

If Gram st,nn positive or PMN greater than 250,'iill Presumptive diagnosis of SBP

Begin antibiotic (e.g.. cefotaxime 2 g IV q 8-12 hours lor 5-10 days)

(Change coverage according to culture result]

inadequate

1

Consider: TIPS

Perltoneovenous shunt Liver transplantation

Monitor aeium and urine electrolytes, SUN. creatinine

Add furosemide or hydrochlorothiazide

FIGURE 22-5. Approach to the patient with ascites and spontaneous bacterial peritonitis (SBP). (BUN, blood urea nitrogen; Na, sodium; PMN polymorphonuclear leukocyte; TIPS, transjugular intrahepatic portosystemic shunt.) (From Chung RT, Podolsky DK. Cirrhosis and its complications. In: Kasper DL, Braunwald E, Fauci AS, et al., eds. Harrison's Principles of Internal Medicine, 17th ed. New York: McGraw-Hill, 2005: 1858-1869, with permission.) *lf PMN is greater than 250/^L but culture is negative (culture-negative neutrocytic ascites) begin empiric antibiotics and retap after 48 hours. If culture is positive but PMN less than 250/^L, treat as if PMN greater than 250/^L (presumed SBP). If polymicrobial infection exists, exclude SBP.

Patient Encounter, Part 4

ES is brought to the emergency department by ambulance 2 months after the initial presentation.

Chief Complaint: "I've been vomiting black stuff and I'm really tired."

HPI: Hematemesis for the past 2 days, worsening today and accompanied by profound weakness; patient is continuing to drink alcohol at the same rate as he was at his first visit.

Outpatient Meds: Spironolactone 100 mg daily; furosemide 40 mg daily

ROS: (+) Nausea, coffee-ground emesis, and melena; denies constipation or diarrhea; (+) bilateral lower extremity edema

VS: BP 98/60 mm Hg, P 122 bpm, T 37.1°C (98.8°F), RR 21/min, oxygen saturation 91% on room air

CV: Tachycardia; no murmurs, rubs, or gallops Chest: CTA bilaterally

Abd: Mildly distended, tender to deep palpation, decreased bowel sounds, (+) hepato-splenomegaly and fecal occult blood test

Ext: Decreased pedal pulses, 3+ pitting edema

What are the immediate treatment goals for ES? How will these goals be achieved?

Does this presentation warrant prophylaxis to prevent further disease complications? If so, what therapy is appropriate for this patient?

Patients who have previously experienced SBP and those with low-protein ascites (ascitic fluid albumin less than 1 g/dL [less than 10 g/L]) are candidates for long-term prophylactic antibiotic therapy. Recommended regimens include either a single trimethoprim-sulfamethoxazole double-strength tablet 5 days per week (Monday through Friday) or ciprofloxacin 750 mg once weekly.19,46

Encephalopathy Lactulose

© Lactulose is the foundation of pharmacologic therapy to prevent and treat HE. It is a nondigestible synthetic disaccharide laxative that is hydrolyzed in the gut to an osmotically active compound that draws water into the colon and stimulates defecation. Lactulose lowers colonic pH, which favors the conversion of ammonia (NH3 to ammonium (NH4 ). Ammonium is ionic and cannot cross back into systemic circulation; it is eliminated in the feces. Lactulose is usually initiated at 15 to 30 mL two to three times per day and titrated to a therapeutic goal of two to four soft bowel movements daily.^49,50

Antibiotic Therapy

Prior to the introduction of lactulose, neomycin was the only treatment available for HE. Neomycin exerts its antibiotic action in the gut, thereby eliminating urease-pro-ducing bacteria. Elimination of these organisms decreases ammonia production. Although neomycin is classified as a nonabsorbable antibiotic, patients with cirrhosis have been shown to have detectable plasma concentrations. This is thought to be due to decreased integrity of the intestinal mucosa and may lead to nephrotoxicity. Neo-mycin is given orally in doses of 3 to 6 g daily.

Rifaximin is another nonabsorbable antibiotic that is used extensively in Europe as first-line therapy for HE. Rifaximin therapy has been shown to be both efficacious and well tolerated, but the expense in the United States (where it is not licensed for HE) may be prohibitive for long-term use. Rifaximin given at the typical dose of 1,200 mg/day costs approximately tenfold more than lactulose.

Flumazenil

Evidence for the false transmitter theory as the cause of encephalopathy is demonstrated by the fact that administration of flumazenil (a benzodiazepine antagonist) has resulted in functional improvement. Unfortunately, long-term benefit has not been shown, and since flumazenil can only be administered parenterally, it is not an appropriate choice for clinical use. Its use is limited to the research setting.

Hepatorenal Syndrome

HRS is a life-threatening complication of cirrhosis. Targeted treatment increases volume within the central venous system. Peripheral vasoconstriction redistributes fluid from the periphery to the venous system, and the fluid is contained thereby increases in oncotic pressure from albumin administration. The ultimate goal is to increase renal perfusion.

A common regimen involves administration of albumin 1 g/kg on day one, followed by 20 to 40 g on subsequent treatment days. This regimen is used in combina tion with midodrine (an a-agonist) and octreotide. Midodrine is typically initiated at 7.5 mg three times daily, and octreotide is administered subcutaneously (as opposed to IV during variceal bleeding) 100 mcg three times daily. Both of these regimens can be titrated as tolerated to achieve increases in mean arterial pressure of 15 mm Hg or greater.

Terlipressin, a vasopressin analog available in Europe, has been used with success in patients with HRS, but it is not currently available in the United States.

Coagulation Abnormalities

Vitamin K is essential for the production of coagulation factors within the liver. Elevated clotting times from decreased protein synthesis are indistinguishable from those produced by low vitamin K levels resulting from malnutrition or poor intestinal absorption. Vitamin Ki (phytonadione) 10 mg given subcutaneously daily for 3 days can help to establish whether the prolonged bleeding time results from loss of synthetic function in the liver or vitamin K deficiency. It is unusual to completely reverse clotting abnormalities, but most patients experience a decrease in international normalized ratio (INR), conferring a decreased risk of bleeding.

Patient Encounter, Part 5

During the hospital stay, ES had endoscopic band ligation to treat esophageal and gastric varices. Propranolol 20 mg three times a day was initiated; IV furosemide 60 mg twice daily resolved the pedal edema. Prescriptions for spironolactone 200 mg daily and furosemide 40 mg twice daily were provided at discharge. Three weeks later, ES is brought to clinic by his daughter who states that he is confused and "hasn't been himself." She is unsure if he has been taking his medication but says he continues to drink and has been eating poorly. Patient will only speak to staff in Spanish.

What are the presenting signs and symptoms of hepatic encephalopathy (HE)?

What factors could contribute to HE in this patient?

What is the prognosis for this patient who has developed ascites, variceal bleeding, and HE within 3 months?

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