慢性肝病患者多半伴隨自律神經失調(67%),副交感下降,交感上升,姿勢性低血壓,血中血管舒張素(如一氧化氮)過多等,臨床醫師除治療肝病外也應治療自律神經失調

Autonomic Dysfunction in Chronic Liver Disease

Humoral and Genetic Disturbances

James Frith; Julia L. Newton

Authors and Disclosures

http://www.medscape.com/viewarticle/706971

Published: 09/10/2009



Abstract and Introduction
Search Strategy and Selection Criteria
The Autonomic Nervous System
Autonomic Dysfunction
Pathogenesis
Presentation of Autonomic Dysfunction in Chronic Liver Disease
Investigating the Autonomic Nervous System
Treating Autonomic Dysfunction in Chronic Liver Disease
Autonomic Function Following Liver Transplantation
What is the Prognosis?
Conclusions
References

Abstract and Introduction

Abstract

Autonomic dysfunction (AD) is common in chronic liver disease (CLD) of all aetiologies and even more so in those awaiting transplantation. As yet, the pathophysiology is not completely understood but the clinical effects are dramatic for the patient, who has a heavy symptomatic burden. There are several considerations, specific to liver disease, which complicate AD. Outlined here is a practical guide for clinicians detailing the common presentations and consequences of AD, investigation techniques and treatment options. As morbidity and mortality is increased in CLD patients with AD its recognition, investigation and management is important to all who encounter such patients.

Introduction

Autonomic dysfunction (AD) in the context of chronic liver disease (CLD) has been of increasing interest over the last 15 years. During this time it has become widely accepted as a complication of CLD, and a major contributor to the symptomatic burden. As the prevalence may be as high as 67%, and its association with increased mortality,[1] it is of great importance to clinicians who encounter CLD. The autonomic nervous system (ANS) is complex, with many investigations available. With its high prevalence and clinical significance it is important that hepatologists recognise dysautonomia and initiate appropriate investigation and management.



Search Strategy and Selection Criteria
Journal articles from 1950 to date were searched using ovidsp. Search terms used included 'autonomic nervous system diseases' and 'liver diseases'. Excluding non-English papers 17 papers were identified. The resulting reference list of this paper is composed of articles reviewed and selected by both authors with additional relevant papers identified through reference lists. Where there is a lack of evidence in the literature regarding a specific point general principles and expert opinion are applied – these comments are explicit when included.



The ANS comprises the sympathetic (SNS) and parasympathetic nervous systems (PNS) (Fig. 1). They are largely responsible for involuntary, subconscious control of viscera, smooth muscle and secretory glands. The autonomic efferent neurons originate in the spinal cord or brain stem (preganglionic), but differ from the somatic nerves in that the second neuron originates in an autonomic ganglion outside the central nervous system (post-ganglionic).

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Figure 1.

The autonomic nervous system and its functions.

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Figure 1.

The autonomic nervous system and its functions.

The sympathetic preganglionic neurons are limited to the thoracic and first three lumbar segments of the spine. The post-ganglionic neurons of the sympathetic system make up the sympathetic chain, found alongside the spine, and the celiac and mesenteric plexuses. Sympathetic preganglionic neurons release acetylcholine, whereas post-ganglionic neurons transmit noradrenaline (with the exception of sweat glands which are cholinergic, and the adrenal medulla which directly synapses with preganglionic neurons). The physiological responses of sympathetic nervous stimulation are increased heart rate (HR) and blood pressure (BP); dilatation of the bronchi; vasodilatation to skeletal muscle; vasoconstriction to the gastrointestinal tract; decreased gastrointestinal motility; increased sweating; smooth muscle sphincter contraction and pupillary mydriasis.

Parasympathetic preganglionic neurons are located in the third, seventh, ninth and 10th cranial nerve nuclei as well as second, third and fourth sacral cord segments. Again the post-ganglionic neurons are found outside the central nervous system contributing to plexuses such as Auerbach's (myenteric) and Meissner's (submucosal). The neurotransmitter of the PNS is acetylcholine, through which the following clinical responses occur: decreased HR and contractility; vasodilation; bronchial constriction; increased gastrointestinal motility; relaxation of smooth muscle sphincters and pupillary miosis.



Autonomic Dysfunction
Autonomic dysfunction is a change in normal functioning of the ANS which adversely affects health. It can be primary or secondary, acute or chronic and transient or progressive. This review will focus on chronic, secondary AD as a result of CLD.



Pathogenesis
The pathophysiology basis of AD secondary to liver disease is largely unknown. Immunological and metabolic abnormalities may play a role, but the resultant decreased parasympathetic and increased sympathetic activity may in part be explained by the following mechanisms.

There is a decreased response to vasoconstrictors which may be caused by increased concentration of vasodilators such as nitric oxide. An increase in portal BP, even mild, can lead to an upregulation of nitric oxide synthetase.[2] An increase in circulating vasodilators, a diseased liver and a portosystemic circulation bypassing hepatic metabolism will contribute to increased levels of vasodilators. Circulating vasodilators will activate the renin–angiotensin–aldosterone system and increase plasma levels of the vasoconstrictor – angiotensin II. Plasma concentrations of angiotensin II, are raised in patients with CLD, and correlate with disease severity.[3] Understanding angiotensin II in relation to control of the glomerular filtration rate is well understood, but it may also interact with the parasympathic control of heart rate variability (HRV). Infusion of angiotensin II causes a decrease in HRV and a reduction in vagal discharges to the heart; if the vagus nerve is severed there is no change in HRV when it is infused. Administration of an angiotensin-converting enzyme inhibitor improves the HRV confirming that angiotensin II plays a role in AD.[4] In addition, administration of antioxidants seems to reverse blunted BP responses suggesting that oxidative stress may also play a role in AD.[5]

Diabetes, which is a common cause of AD is common in CLD.[6,7] In diabetics who suffer iatrogenic hypoglycaemia there is a hypoglycaemia-associated autonomic failure (HAAF).[8] This is a result of decreased response of adrenaline and the SNS to hypoglycaemia. It may be possible that the hypoglycaemia induced by severe hepatic dysfunction may bring about HAAF. The resultant AD creates hypoglycaemic unawareness, and therefore a vicious circle of worsening AD.[9]

Autonomic dysfunction in advanced liver disease is associated with decreased baroreceptor sensitivity to hypotension, leading to impaired BP and HR responses.[10] Advanced liver disease and cirrhosis result in other complex cardiovascular abnormalities, such as arterio-venous communications, altered sodium handling and cirrhotic cardiomyopathy. These changes will exaggerate the abnormal effects of AD, but are outside the scope of this review.



Presentation of Autonomic Dysfunction in Chronic Liver Disease

Disease-specific features of AD are described in Table 1 .

The clinical picture of a patient with CLD presenting with AD is similar for chronic AD of any cause (Fig. 2). However, with the aforementioned cardiovascular changes the presentation can be more complex and difficult to distinguish from other sequelae of CLD, such as hypovolaemia (resulting from sepsis, blood loss or over-diuresis).

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Figure 2.

Symptoms of autonomic dysfunction frequently experienced by patients with chronic liver disease.

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Figure 2.

Symptoms of autonomic dysfunction frequently experienced by patients with chronic liver disease.

One of the commonest consequences of AD in CLD is orthostatic hypotension (OH),[16] with 33% of patients having dizziness on standing.[17] The patient typically complains of dizziness or lightheadedness on standing from a sitting or lying position. Other symptoms include blurring of vision, discomfort of head, neck or shoulder – the so-called 'coat hanger' headache, fatigue and in severe cases, syncope.

Fatigue is a common complaint of patients with CLD and ranges from slight impairment of daily living to severe debilitation. Liver function tests (LFTs) are often performed in the patient who presents with 'tiredness all the time' and fatigue may therefore be a presenting symptom of CLD. It can develop at any time in patients with existing liver disease, but it does not correlate with disease severity.[18, 19] The severity of fatigue experienced by patients correlates with increasingly severe AD, and must therefore be a major contributing factor in the aetiology of this symptom.[20] Other contributing factors may include metabolic disturbance, anaemia, altered sleep patterns and medication (benzodiazepines, antidepressants and β-blockers).

In addition to fatigue, AD can also reduce exercise tolerance. In patients with dysautonomia secondary to diabetes a blunted response of HR, BP, adrenaline and noradrenaline is seen.[21] The same response can be anticipated in those with AD in CLD.

Bladder dysfunction is a feature of AD; 10% of patients with CLD have symptoms of 'bladder disturbance' and 14% of pretransplant patients use incontinence pads.[17,22] Although there are very little data concerning bladder dysfunction in CLD we know from other AD-associated diseases that it may also manifest as urinary frequency, hesitation or retention; the consequences of which include urinary tract infections, renal failure and indignity.[23] Incontinence in CLD may be exacerbated by prescribing diuretics.

In patients with CLD there is both delayed gastric emptying of liquids and solids and a prolonged transit time from mouth to caecum,[24,25] symptoms include early satiety, nausea, vomiting, weight loss and epigastric pain. The decrease in small bowel motility resulting from AD is particularly important as it can cause bacterial overgrowth, with increased risk of encephalopathy and peritonitis. Delayed gastric emptying is associated with post-prandial hypoglycaemia, and may therefore worsen AD.[26] Changes in gastrointestinal motility alongside disturbances of sphincter control can cause diarrhoea, constipation and incontinence. Incontinence is exaggerated by prescribing laxatives.

Similar to fatigue LFTs may be performed when investigating a patient who presents with sexual dysfunction, and may identify liver disease (13% of men presenting with erectile dysfunction have abnormal LFTs).[27] Sexual problems may arise either from fatigue, altered body image, AD, haemodynamic changes or from alterations in circulating sex hormones. Females show higher levels of dysfunction in end-stage liver disease,[28] although in cirrhotic patients males place greater importance on it.[29] Diuretics, β-blockers and antidepressants can all exacerbate sexual dysfunction.

Despite 5% of patients with CLD have sweating abnormalities[17] it is uncommon to encounter either a patient who complains of excess or impaired sweating as it has little impact on daily life. Unless questioned specifically patients may not appreciate the significance of symptoms of temperature regulation and sweating. Clinically the usefulness of this in relation to diagnosing AD is questionable.

Investigating the Autonomic Nervous System
The simplest clinical method to test for AD is to test for OH. Firstly, measure baseline BP following a supine rest period, then make the patient stand, measuring BP immediately, and repeat at 3-min standing. Ask the patient about symptoms. A diagnosis of OH is made if there is a systolic drop in BP of ≥20 mmHg or a diastolic drop of ≥10 mmHg within 3 min.[30] In patients with CLD, before a diagnosis of OH is made, hypovolaemia should be excluded (typically hypovolaemia will cause an isolated systolic drop with no diastolic drop in pressure, however this is unreliable) and causal medications should be reviewed.

Another simple clinical test is a resting electrocardiogram. A normal resting HR would lie between 60 and 80 bpm; levels above this could indicate parasympathetic dysfunction. However, anaemia, hyperthyroidism, sepsis, hypovolaemia, arrhythmias and phaeochromocytomas can also cause resting tachycardias. The presence of rate-limiting medication can also mask parasympathetic dysautonomia.

Other tests of autonomic function are available (see Table 2 ), but these are specialised and not practicable in every clinic. However, an understanding of them is of value in order to understand specialist investigation and research. Measuring autonomic function is unreliable in those patients who are on β-blockers, as normal sympathetic responses will be blunted.



Treating Autonomic Dysfunction in Chronic Liver Disease
There are numerous factors which complicate the treatment of dysautonomia in the patient with CLD. Patients may be on diuretics, β-blockers, antidepressants or sedatives all of which affect the ANS. Lactulose and diuretics as discussed previously can contribute to incontinence or sexual dysfunction, and a risk/benefit analysis may need to be undertaken with the patient.

Pronounced splanchnic vasodilation following paracentesis of ascitic fluid results in a prominent activation of the SNS[32] leading to, at worst, circulatory collapse.[33] This is avoided by infusion of intravenous albumin to maintain a normovolaemic circulation.[32]

Specific treatment options for patients with CLD and OH are lacking, therefore therapeutic options for OH of other causes may be applied with expert opinion. The most troublesome of dysautonomic symptoms is usually treated successfully with conservative measures. A typical recommendation for patients with OH of any cause is to maintain their intravascular volume by drinking at least 2–2.5 L of fluid per day. This may however, complicate CLD, especially those who are fluid overloaded but who are unable to maintain their fluid in the intravascular compartment. Compression stockings help to redistribute extravascular fluid, and also prevent peripheral venous pooling on assuming an upright posture. Large meals should be avoided to minimise post-prandial hypotension, and all patients should adopt a slow, gradual staged movement on rising into standing position. Pharmacological options are available for those few who do not respond to conservative measures. Fludrocortisone can improve OH of any cause by causing sodium and water retention, but may be contraindicated or used with great caution in CLD where secondary hyperaldosteronism may already be present. Midodrine, which is used off-license in UK, improves OH by agonising α1-adrenoreceptors. Extreme caution should be taken when using in patients with CLD, as it can worsen liver function. Other agents which have been used for OH (but not specifically used in CLD) are β-blockers, clonidine, pyridostigmine, erythropoietin and selective serotonin re-uptake inhibitors.

Fatigue is often multifactorial and difficult to manage. In CLD associated fatigue patients should be encouraged to adopt a steady state of activity, and avoid intense bouts of activity when energy is present. In resistant cases of primary biliary cirrhosis (PBC), where fatigue is associated with excessive daytime sleepiness, modafinil has been used successfully.[34] It is relatively contraindicated in hypertensive patients, and BP should be monitored while on treatment. Starting dose is 50–100 mg and titrated accordingly. Side effects include headaches, sleep disturbance and hypertension. In those who suffer from insomnia a sedative may improve sleep thereby improving daytime wakefulness. In those who suffer broken sleep or display risk factors for sleep apnoea a referral for sleep studies should be considered. In patients on β-blockers a risk/benefit analysis should be undertaken on an individual basis, as β-blockers can cause profound fatigue.[35]

Current treatments for delayed gastric emptying are, on the whole, disappointing. There are no trials addressing this issue in CLD specifically and evidence must therefore be taken from trials assessing delayed gastric emptying of other causes. Medical management includes erythromycin which improves motility but does not improve symptoms, and domperidone which seems to be more effective at symptom control, in diabetic patients with gastroparesis.[36] Surgical options as yet are limited as trials have been retrospective and uncontrolled, but gastrostomy, botulinum neurotoxin and implantable electrodes to stimulate motility have shown promise.[36–38]

Gastrointestinal mobility disorders may be initially managed with diet, followed by medications such as laxatives or bulking agents, and constipating agents with planned enemas, although specific evidence in relation to CLD is lacking, expert opinion would suggest using the above simple measures as a first line treatment. For severe, resistant cases with significant impact on daily living surgical options exist (evidence not specific to CLD). For incontinence the anal sphincter can be repaired or substituted, but with disappointing long-term success.[39] For incontinence and constipation colectomy with or without stoma formation may improve symptoms.[40]

Treatment options for neurogenic bladder dysfunction are generic and expert opinion allows us to apply the evidence to any causal disease. Evidence suggests that urodynamic studies will help direct appropriate management.[41] First line treatment for urinary frequency includes bladder retraining (increasing time between voiding) or regular toileting (micturating every 2–4 h).[23] Pharmacological treatments include antimuscarinics which can worsen AD and α-blockers which can cause profound OH.[42] For severely hypotonic bladders intermittent catheterization may reduce incontinence, infections and renal failure.[43]

It is difficult to distinguish between AD, medication adverse effects and psychological disturbance as the cause of sexual dysfunction. Contributing medications should be reviewed. Despite lower levels of testosterone and increased levels of oestrogen, supplementing testosterone is not effective at improving erectile dysfunction.[44] Unsurprisingly sexual dysfunction does improve in alcoholic men who abstain.[45] The incidence of erectile dysfunction more than doubles in men who undergo transjugular intrahepatic portosystemic stenting.[46] There is evidence that the pharmacokinetics of phosphodiesterase type-5 inhibitors in those with hepatic impairment is not altered,[47] however there are also case reports of hepatotoxicity associated with sildenafil.[48]

Although not specific to CLD, disorders of sweating, especially axillary, palmar and gustatory hyperhidrosis, may respond to treatment with botulinum neurotoxin.[49]



What is the Prognosis?
The association between liver disease severity and the incidence of AD is equivocal with conflicting results.[1,52–54] Mortality is increased in patients with CLD and AD; 4-year mortality is 30% in CLD with AD compared with 6% in CLD without AD.[55] AD is an independent risk factor for mortality in both compensated and decompensated cirrhotic patients.[1] In one study which followed patients awaiting LT for 10 months, six patients died, each had AD leading the authors to conclude that consideration should be given for early LT in those with AD.[1] In addition to increased mortality in those with cardiovascular abnormalities, patients with PBC who suffer from fatigue have an increased mortality.[56]

The aforementioned sequelae of AD add significantly to poorer quality of life in patients already burdened with chronic disease. Recent studies are also beginning to define additional potential consequences of AD in those with liver disease such as cognitive impairment.[57] As dysautonomia is increasingly common in older age we should expect to see more consequences of AD as the liver disease population ages. Falls, OH, incontinence and cognitive impairment are all more common with age and will pose significant problems in this population.

Although the increase in mortality associated with AD is significant, hepatologists should not solely focus on survival or laboratory markers, but address symptomatic burden and quality of life. Challenging, vague symptoms can often be improved through active listening and empathy, improving patients' expectations and satisfaction. If patient care is to be improved, outcome measures which enable patients to represent the treatment effects which make a real difference to their lives must be incorporated into routine clinical practice.[58]



Conclusions
Although greater understanding of the pathogenesis of AD in CLD is required its effects on patients are becoming increasingly recognised. The symptomatic burden of patients with CLD and dysautonomia is high, but may be overlooked in favour of laboratory markers of disease severity. Many of the symptoms, such as fatigue and sexual dysfunction, pose difficulties for clinicians, as they may be considered low priority, ubiquitous and un-modifiable. Simple measures such as reviewing medications (β-blockers, diuretics and antidepressants) may lead to improvements in the patients' symptoms and quality of life. Recognising AD will help to identify those patients who are at increased risk of death, and may contribute to the consideration for LT.