Issues in the end‐stage liver disease patient for which palliative care could be helpful

Watch a video presentation of this article

Watch the interview with the author

Abbreviations

BCAA

branched‐chain amino acid

ESLD

end‐stage liver disease

QoL

quality of life

End‐stage liver disease (ESLD) is often associated with multiple complications that have significant impact on function and quality of life (QoL).The palliative approach for patients with ESLD involves meticulous management of these complications, which in turn helps maintain levels of functioning and enhanced QoL for patients and families.

Ascites

Ascites is the most common of complication of ESLD. Ascites that is not responsive to medical therapy is associated with an increased risk of death within 6 months. Management of ascites includes sodium restriction of ≤ 2000 mg/daily and oral diuretics, which has been shown to reduce discomfort caused by ascites in 90% of patients1 (Table 1). Fluid restriction is not indicated unless serum sodium drops below 125 mmol/L. However, fluid restriction contributes to worsening QoL, which is an important consideration in palliative care.2

Table 1.

Palliative Management of Ascites

Diureticsa	Dosing	Recommendations
Potassium Sparing
Spironolactone	100‐400 mg daily	Increase every 3‐5 days by 100 mg to maximum dose of 400 mg
Amiloride	10‐40 mg	Increase every 3‐5 days by 10 mg to maximum dose of 40 mg
Loop Diuretics
Furosemide	40‐160 mg daily	Increase every 3‐5 days by 40 mg to maximum dose of 160 mg
SBP Prophylaxis
Norfloxacin	400 mg oral daily	Recommended if the ascitic fluid protein is <1.5 g/dL, along with creatinine ≥1.2, BUN ≥25 or serum Na ≤130) or Child score ≥9 and bilirubin ≥3.
Trimethoprim/ sulfamethasoxazole	DS oral daily or 5 days/week	Daily dosing is preferable
Ciprofloxacin	750 mg orally every 7 days
	Rationale
Shunts and Catheters
Transjugular intrahepatic portosystemic stent‐shunt (TIPS)	Multiple meta‐analyses have been published regarding TIPS. They all report better control of ascites but increased hepatic encephalopathy.	Can be considered for use in diet and diuretic refractory patients if cardiac ejection fraction is within normal range and if Model for End‐Stage Liver Disease (MELD) score is <18 and total bilirubin <4 with no other existing contraindications.
Peritoneovenous (Denver) shunt	Historic data has shown poor long‐term patency, excessive complications and required surgical placement. Newer data reports that placements can be done by Interventional radiologists making this a more viable option in palliative care.	Can be considered for use in diet and diuretic refractory patients that are not candidates for transplant, TIPS or intolerant to paracentesis
Pleural Catheters	These types of catheters when used for malignant ascites showed low infection rates of 5.9%. In nonmalignant ascites, higher infection rates of 16% were seen.	Can be considered for use in diet and diuretic refractory patients that are not candidates for transplant, TIPS or intolerant to paracentesis with prognosis of < 3‐6 months.

^aThese are given together and increased simultaneously

Refractory Ascites

If tense painful ascites is present and does not respond to sodium restriction and diuretics, then serial paracentesis with colloid replacement (6‐8 g per liter removed) for >5 L paracentesis should be initiated. Paracentesis can be done every 10‐14 days for patient comfort. Medications for spontaneous bacterial peritonitis prophylaxis should be initiated if indicated, and daily dosing should be preferentially used (Table 1). Because of lower blood pressures that occur with cirrhosis, increased circulatory effects of paracentesis, and prostaglandin inhibition effects on the renal system, concurrent use of angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers, nonsteroidal anti‐inflammatory drugs (NSAIDs), and beta blockers should be avoided. Blood products should not be given prior to paracentesis, because there is no reported increased bleeding risk with paracentesis.3

If more frequent paracentesis is required in the setting of quickly re‐accumulating ascites, then consideration should be given to using portosystemic shunts, peritoneovenous shunts, or pleural catheters (Table 1).

Hepatic Encephalopathy

Hepatic encephalopathy is one of the most debilitating symptoms of ESLD and manifests as subtle personality or sleep disturbances, to confusion or coma. Symptoms can be exacerbated by gastrointestinal hemorrhage, infections, renal and electrolyte imbalances, constipation, and medications, in particular, opioids and benzodiazepines. Initial treatment involves correction of underlying causes, along with nonabsorbable disaccharides, and antibiotics aimed at decreasing intestinal toxins, particularly ammonia (Table 2). Blood‐ammonia levels do not need to be routinely checked because they provide little diagnostic or prognostic value. Protein restriction can be harmful due to increased protein requirements in ESLD patients, and thus is not recommended.4

Table 2.

Managing Hepatic Encephalopathy

Nonadsorbable Disaccharides	Dosing
Lactulose or Lactilol First‐line treatment	Initial treatment: 25 mL every 1‐2 hours until 2 soft or loose bowel movements daily are produced. Then titrate dose down to maintain 2‐3 bowel movements daily.
Antibiotics
Rifaximin First‐line treatment in refractory symptoms	Used in conjunction with Lactulose for refractory symptoms at a dose of 550 mg twice daily. No solid data to support use alone.
Neomycin12 Second‐line treatment in refractory symptoms	Used in conjunction with Lactulose for refractory symptoms at a dose of 1‐2 g daily
Metronidazole13 Second‐line treatment in refractory symptoms	Used in conjunction with Lactulose for refractory symptoms at a dose of 250 mg two to four times a day. Long‐term use associated with ototoxicity, nephrotoxicity, and neurotoxicity.

Pain

Pain is a significant problem in patients with ESLD and it adversely affects their QoL. Pharmacologic treatment of pain is complicated because: 1) most analgesics are metabolized through the liver; 2) opioid analgesics have been associated with exacerbating hepatic encephalopathy which makes choosing and dosing these medications difficult; and 3) there are no evidence‐based guidelines on the use of analgesia in patients with ESLD.

Aspirin and NSAIDs should not be used in patients with ESLD due to increased risks of renal dysfunction, antiplatelet effects, and mucosal bleeding. Acetaminophen can be used at doses of ≤2 g daily. Morphine, oxycodone, and hydromorphone have decreased clearance in patients with ESLD, so should be given in reduced doses and increased intervals. Both fentanyl and methadone have not shown altered pharmacokinetics in patients with cirrhosis, and could be used, although they have not directly been studied in patients with ESLD. Precise dosing strategies of opioids for pain in those with ESLD is a topic of current debate in the literature. An individualized approach based on patient factors is warranted.5 In addition, some nonpharmacologic approaches such as acupuncture and mindfulness have shown to be useful in controlling pain and improving QoL and should be considered as adjunct therapy.6, 7

Pruritus

Pruritus is common in chronic liver disease, and is described as “an itch that comes from inside and cannot be scratched”. It can be mild to severe and dramatically reduces QoL. The pathogenesis of itching is not fully understood but is felt to be related to accumulation of bile salts, bile acids, and bilirubin in the circulation and tissues along with elevated endogenous opioids.8 The pruritus is generalized, intermittent, often occurring at night, and disturbs regular sleep and limits activities of daily living. Systemic treatments using bile acid resins, serotonin and norepinephrine inhibitors, tricyclic antidepressants, sedating antihistamines, and Mu‐opioid antagonists are preferred over topical treatments (Table 3).

Table 3.

Management of Pruritis in ESLD

Medication	Dose Range	Notes
Bile acid resins	Cholestyramine up to 4 g given four times a day	Alternate time intervals with intake of other oral medications
Opioid Antagonist	Naltrexone 25‐50 mg daily	Contraindicated with concurrent opioid use
Antidepressants
SSRI	Sertraline 75‐100 mg daily
SNRI	Mirtazepine 7.5‐15 mg at bedtime	Useful in nighttime pruritus
Tricyclic	Doxepin 10‐25 mg at bedtime can be increased to 100‐150 mg daily	Useful in nighttime pruritus
Antihistamines		In general, antihistamines have shown limited relief of pruritus caused by cholestasis
	Hydroxyzine 25 mg at bedtime or divided doses can be increased to 100‐200 mg daily	Can be useful in nighttime pruritus

Muscle Cramps

Up to 88% of patients with ESLD experience painful muscle cramps that result in sleep deprivation and decreased QoL. Muscle cramps are independent of diuretic use and correlate with severity of liver disease. Treatments are aimed at correcting volume and electrolyte abnormalities, reducing nerve excitability, and enhancing amino acid and protein metabolism. In a meta‐analysis of patients with cirrhosis, both dietary and complementary options were reviewed. There was no strong evidence to support the use of any one particular intervention over the other9, 10 (Table 4).

Table 4.

Management of Muscle Cramps

Medications	Dose	Notes
Vitamin E	200 mg three times a day	No side effects reported should use with caution in cirrhosis
Quinine sulfate	200‐300 mg at bedtime	No longer available over the counter due to significant adverse effects. Should only be used after failure of all other options
Taurine	3 g daily	No side effects reported
Branched‐chain amino acids (BCAA)	4 g granules three times a day	No side effects reported. More expensive
Zinc	220 mg twice a day	Mild diarrhea
Magnesium	400 mg 1‐2 times a day	Mild diarrhea. Used widely clinically, no data in ESLD
Vitamin B complex	1 tablet daily	Most helpful in nocturnal leg cramps
Gabapentin	600‐900 mg daily	Has been helpful in patients with neurologic disease and muscle cramps, no data in ESLD

Malnutrition

Malnutrition and its associated loss of muscle mass and reduced energy is present in 95% of those with ESLD. Because malnutrition is implicated in worsening ascites, hepatic encephalopathy, functional ability, and QoL, attempts should be made to correct it. Contributing factors to malnutrition are inadequate dietary intake due to poor appetite, impaired digestion and absorption due to significant portal hypertension, and altered metabolism. Treatment of malnutrition currently focuses on adequate caloric intake, protein in particular, and vitamin replacement if deficient (Table 5). Total parenteral and enteral nutrition should be limited to special situations. Studies of branched‐chain amino acids (BCAAs) and probiotics have shown promise in correcting malnutrition, but due to poor tolerance and expensive formulations of BCAAs and limited data with probiotics they are not currently recommended in ESLD.11

Table 5.

Management of Malnutrition in ESLD

Recommendations
Total caloric intake: 25‐35 kcal/kg/day
Protein intake: 1.2‐1.5 g/kg/day
Sodium intake: If edema and/or ascites present <2 g daily
Daily multivitamin
Fat‐soluble vitamin levels may be checked if clinical deficiency is suspected. Replacement recommended if deficiency is present of vitamins A, D, E, K. Zinc should be checked and replaced if deficient in those with hepatic encephalopathy
4‐6 smaller meals daily with high‐protein bedtime snack to help prevent hypoglycemia, protein deficiency, and promote gastric emptying