Evaluation and management of insomnia, muscle cramps, fatigue, and itching in cirrhotic patients

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Abbreviations

HCV

hepatitis C virus

OSA

obstructive sleep apnea

PBC

primary biliary cirrhosis/cholangitis

Cirrhosis is associated with overt and proximately causal complications such as ascites, hepatic encephalopathy, and esophageal varices for which management is well defined and broadly implemented. However, there remain many symptoms whose etiology, morbidity, and treatment continue to be poorly understood.1 This concise review discusses the symptoms of (1) insomnia, (2) muscle cramps, (3) fatigue, and (4) itching.

Insomnia

Insomnia is a common and burdensome problem in cirrhotic patients. It is recognized by daytime sleepiness and/or early awakenings and difficulty with sleep initiation and/or continuity. It is contained within a larger framework of sleep/wake abnormalities that also include hypersomnia (excessive, inappropriately timed sleepiness) and sleep‐associated behaviors.1, 2 The molecular mechanisms underlying insomnia have both circadian (periodic) and homeostatic (aggregating) properties.2 Successful management can improve quality of life and can also alter the patient's disease progression. Obstructive sleep apnea (OSA), which is common in patients with fatty liver disease, is a paradigm of this: The prolonged hypoxemia of OSA is correlated with steatohepatitis and fibrosis; thus, good treatment can have long‐term benefits to the lung and liver.3

In evaluating insomnia, the use of a sleep diary and metrics, for example, the Epworth Sleepiness Scale,4 can better quantify this burden. Insomnia can be broadly classified by careful assessment of the following (see Table 1): (1) secondary causes (i.e., insomnia as a sequelae), (2) offending ingestions/medications, and (3) disruptive behaviors to sleep continuity. Despite the numerous hypnotics used in cirrhotic patients, formal evidence is limited regarding dosage, duration, efficacy, and safety.1 Indeed, many of these medications may alter the waking/attentive state, and thus predispose to or mimic other issues, for example, hepatic encephalopathy. Refractoriness to the earlier measures should prompt a sleep service referral.

Table 1.

Causes and Confounding Issues in Insomnia With Corrective Actions

Parameter	Comment and Associated Risk	Correction Actions
Hepatic encephalopathy	Bowel movement frequency	Bowel cathartics, e.g., lactulose
Depression and anxiety	Change in mood, eating, and so on	Referral for therapy; medications
Ingestions:	Ingestions:	Ingestions:
Caffeine/Nicotine	A stimulant	Avoid or decrease amount
Alcohol	Altered sleep/wake states; liver toxicity	Avoid entirely
Medication: cause/treatment	Medications: necessary?	Medications:
Antihistamines (e.g., hydroxyzine)	Alter sleep/wake states; encephalopathy; constipation	Controlled use; monitoring; lower dosing
Benzodiazepines (e.g., clonazepam)	Alter sleep/wake states; encephalopathy; delayed metabolism; addictive potential	Controlled use; monitoring; lower dosing
Zolpidem	Memory issues; encephalopathy	Controlled use; monitoring
Trazodone	Priapism	Monitor for side effects
Melatonin	Limited studies; unregulated dosing	Likely not harmful; benefits?
Diuretics	Nocturia (twice‐daily dosing?)	Morning dosage to limit nocturia
Sleep‐associated disorders:
Obstructive sleep apnea	Elicit history of snoring; weight gain	Pulmonology referral; weight loss
Restless leg syndrome	Directed questioning; ask partner	Iron studies and iron replacement
Sleep hygiene	Elicit day and bedtime rituals	Ordered sleep/wake schedule

Muscle Cramps

Muscle cramps are involuntary and usually brief (seconds to minutes) small‐muscle‐group contractions (e.g., hands and calf muscles). They affect a majority of cirrhotic patients at one time or another, and although benign can significantly impair quality of life.5, 6 Muscle cramps should be quickly differentiated from myalgias, myositis, and rhabdomyositis with, for example, serum creatine kinase and serum aldolase. Muscle cramps are found less commonly in noncirrhotic chronic liver disease patients, as well as other conditions (see Table 2). The cause of muscles cramps is generally understood to involve dysregulation in three domains: (1) nerve function, (2) energy metabolism, and (3) plasma volume and electrolytes.5

Table 2.

Scenarios Associated With Muscle Cramps

System	Subtype
Idiopathic
Neurological	Peripheral neuropathy Amyotrophic lateral sclerosis Spinal cord disease
Renal (advanced disease)	Renal replacement therapy
Liver	Noncirrhotic (diuretic use?) Cirrhotic (diuretic use?)
Medications	Beta and calcium channel blockers Estrogens Naproxen Diuretics Statins
Cardiac disease	Peripheral vascular disease
Physiological	Exercise Pregnancy Malignancy

Adapted with permission from Clinical Gastroenterology and Hepatology.5 Copyright 2013, AGA Institute.

The treatment for muscle cramps is not standardized5: governed by much anecdote and a paucity of robust trials. Regarding nerve function, vitamin E (200 mg tid; no side effects) and eperisone (150‐300 mg/day; side effects: dizziness and GI upset) have been attempted. Quinine, a common component of tonic water, is associated with infrequent but broad toxicities, for example, thrombocytopenia, dysrhythmias, and liver injury.6 Although still used by many patients, the US Food and Drug Administration does recommend against quinine for this off‐label use. Taurine (3 g/day; no side effects) and branched chain amino acids (4 granules tid; no side effects) have been attempted to optimize energy metabolism.5 Concerning plasma volume and electrolyte replacement, both albumin (25%; no side effects) and zinc (220 mg bid; side effect: diarrhea) have been used.5 Given the earlier limitations, a sensible approach includes correcting biochemical abnormalities (in many cases, limiting diuretics) and considering medications based on nutritional benefits and minimal harms.

Fatigue

Fatigue represents a sense of excessive tiredness with impairment of work function that is also not relieved in its absence. Although fatigue is noted in multiple liver diseases, it has a high prevalence in primary biliary cirrhosis/cholangitis (PBC) and chronic hepatitis C virus (HCV) infection.1, 7, 8 The severity of fatigue is not correlated with the degree of liver dysfunction. Moreover, fatigue is a common complaint in the general population. The association with depression (which should be assessed) can represent a cause or consequence of fatigue, or remain parallel to it. Fatigue pathophysiology is poorly described but is thought to involve dysregulation in (1) central and autonomic nervous systems, (2) peripheral muscle groups, and (3) inflammatory cytokines and hormones (e.g., progesterones).1, 7

The management of fatigue is rather difficult because there are no standardized treatments for it. In PBC, wherein fatigue has been most heavily studied, numerous small trials involving nalmefene, antioxidants (vitamin A, vitamin E, and ubiquinone), fluoxetine, ursodeoxycholic acid, and modafinil have all been tested, with no compelling results.7, 8 Importantly, a differential diagnosis should be assessed for which perhaps there are treatments with meaningful benefits; for example, anemia‐associated fatigue with ribavirin may be temporary, celiac disease may respond to dietary alteration, and hypothyroidism will respond to replacement therapy (see Table 3).1 In particular, patients with HCV who achieve viral cure are reported to have significant improvement in fatigue.

Table 3.

Causes of Fatigue

Cause	Comment
Primary biliary cirrhosis/cholangitis	Ursodiol as primary treatment; there are limited data for fatigue
Anemia	May require transfusion; temporary symptoms if medication associated (e.g., ribavirin)
Fibromyalgia and rheumatological disorders	Rheumatological evaluation and behavioral therapy
Multiple sclerosis	Neurological evaluation
Diabetes	Endocrine evaluation, diet/weight/exercise modification
Celiac disease	Endoscopy evaluation; treatment with dietary alteration
Depression	Directed questioning; psychiatric evaluation

Itching

Itching (pruritus) is a common and burdensome symptom in cirrhosis, with special attention to cholestatic patients.9, 10 Cholestasis can arise in multiple disease states: parenchymal (e.g., pregnancy, drug or stress/infectious toxin, chronic HCV infection), cholangiolar (e.g., PBC, primary sclerosing cholangitis, sarcoidosis), or macroscopic obstruction (e.g., gallstones, biliary atresia, pancreatobiliary cancers).9, 10 Pruritus tends to exhibit diurnal variation (worse at night), affect distal extremities (although it can be global), and can lead to physical (e.g., excoriations, but absent rash) and psychological (e.g., anxiety, insomnia, depression) complications. Pruritus is thought to involve these processes: (1) delayed biliary excretion of endogenous pruritogens, (2) altered/diminished hepatic pruritogen metabolism, and (3) collateral disorders in opioid and serotonin pathways.9

Given the above understanding, putative pruritogens have been targeted through a number of medications, with the assumption that macroscopic obstructions have been alleviated, for example, stones removed, strictures dilated, sepsis treated, and offending drugs withdrawn. In line with standard guidelines, societies have recommended the following options (see Table 4).9, 10 These medications should be titrated based on refractoriness of symptoms.

Table 4.

Therapies for the Management of Pruritus

Subtype	Therapy	Dose	Comment
Cholestasis of pregnancy	Ursodeoxycholic acid (UDCA)	10‐15 mg/kg	Formally recommended for this group only; benefit even in mild serum bile acid elevations
Pruritus generally	Cholestyramine	4 g qid	Dosing separated from other medications given binding effects (including UDCA)
	Rifampin	150 mg bid	Discolored secretions Can induce metabolism of other medications
	Naltrexone	50 mg/day	Diminished global pain control if on narcotics
	Sertraline	100 mg/day	Concomitant benefit for depression

Adapted with permission from Hepatology.9 Copyright 2014, American Association for the Study of Liver Diseases; and Journal of Hepatology.10 Copyright 2009, European Association for the Study of the Liver.

Conclusion

This concise review calls attention to the symptoms of insomnia, muscle cramps, fatigue, and itching in cirrhotic patients. These symptoms are nuanced and their burden remains underappreciated. Current treatments reflect the paucity of our formal knowledge in this regard. Further mechanistic understanding and robust clinical trials are needed.