Tests recommended by the American Heart Association for surveillance of liver disease in post-Fontan patients.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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Doz. Dr. med. Dieter Schoepf works at Bonn University in leading position. He has been awarded continiously 2011 - 2018 as a top expert for affective disorders in German largest independent survey (i.e. Focus). His main research interest is dedicated to affective disorders and neural mechanisms of change during treatment as well as clinical epidemiology. He is a personal trainee of Prof. James P. McCullough and since 2007 the second US-certified CBASP-therapist and supervisor in Germany. He is also founder-member of CBASP-Network.org and its first vice president from 2008-2012. He established the CBASP Centre of Competence at Bonn University since 2006, where he is the principal site investigator of bi-centric and multicentre CBASP studies. In psychotherapy, his special subjects are classical, cognitive, and modern behavioral psychotherapies. 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Disorders of foods intake result in obesity, atherosclerosis, hormonal disturbances leading to type 2 diabetes mellitus and cardiovascular diseases. Brain cells need glucose for the activities. Increase in glucose intake results in obesity and metabolic syndromes. However, glucose intake is prerequisite for brain functions. Salt is also important for the electrolytes balances, but too much salt intakes result in hypertension and renal diseases. Hypertension causes atherosclerosis and thrombosis. In the brain, stroke takes place in narrowed arteries caused by constriction of vessels. Serotonin and kynurenine (tryptophan metabolites) are important factors in brain functions and periphery. IDO regulates functions of T-cells in tumors, especially in lung cancer.
\r\n\r\n\tIn this book, roles of tryptophan metabolites in activities of checkpoint inhibitors will be discussed. We welcome contribution of chapters from experts of nutrition and food related diseases to elucidate roles of eating in pathophysiology of body and brain functions.
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Himmerich studied medicine at the University of Mainz, Germany. He received his scientific and clinical training at the Max-Planck-Institute of Psychiatry in Munich and at the University of Marburg. He gained further clinical experience at the University Hospitals in Aachen and Leipzig. In 2009 he was appointed Professor for Neurobiology of Affective Disorders at the University of Leipzig and in 2013 Clinical Senior Lecturer in Eating Disorders at King’s College London.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada",profilePictureURL:"https://mts.intechopen.com/storage/users/248459/images/system/248459.png",biography:"Akikazu Takada was born in Japan, 1935. After graduation from Keio University School of Medicine and finishing his post-graduate studies, he worked at Roswell Park Memorial Institute NY, USA. He then took a professorship at Hamamatsu University School of Medicine. In thrombosis studies, he found the SK potentiator that enhances plasminogen activation by streptokinase. Using simultaneous analyses of plasma fatty acids, he indicated that plasma levels of trans-fatty acids of old men were far higher in the US than Japanese men. By using simultaneous LC/MS analyses of plasma levels of tryptophan metabolites, he recently found that plasma levels of serotonin, kynurenine, or 5-HIAA were higher in patients of mono- and bipolar depression, which is significantly different from observations reported before. In view of recent reports that plasma tryptophan metabolites are mainly produced by microbiota, he is now working on the relationships between microbiota and depression or autism.",institutionString:"Hamamatsu University School of Medicine",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Hamamatsu University School of Medicine",institutionURL:null,country:{name:"Japan"}}}],coeditorOne:{id:"231568",title:"Dr.",name:"Hubertus",middleName:null,surname:"Himmerich",slug:"hubertus-himmerich",fullName:"Hubertus Himmerich",profilePictureURL:"https://mts.intechopen.com/storage/users/231568/images/system/231568.jpg",biography:"Since 2015, Professor Dr. med. Hubertus Himmerich is a Clinical Senior Lecturer in Eating Disorders at King’s College London and a Consultant Psychiatrist on an inpatient ward for patients with eating disorders at the Bethlem Royal Hospital in London, UK. \nAfter studying medicine, he received his scientific and clinical training at the Max-Planck-Institute of Psychiatry in Munich and the Universities of Mainz and Marburg, Germany. In 2009 he was appointed Professor for Neurobiology of Affective Disorders at the University of Leipzig, Germany. \nHis scientific focuses include appetite regulation, psychoimmunology and military mental health. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"45678",title:"Dyspepsia and Opioid–Induced Bowel Dysfunction: The Role of Opioid Receptor Antagonists",doi:"10.5772/56624",slug:"dyspepsia-and-opioid-induced-bowel-dysfunction-the-role-of-opioid-receptor-antagonists",body:'Opioid analgesics are commonly and in most cases effectively used to manage chronic pain of moderate to severe intensity. Apart from analgesia, opioids exert numerous adverse effects, several of which impact the gastrointestinal (GI) tract. The chronic use of opioid analgesics in fact is commonly associated with adverse effects on the gastrointestinal tract. [1] Opioid–induced bowel dysfunction (OIBD) comprises gastrointestinal symptoms such as dry mouth, anorexia, gastroesophageal reflux (GERD), delayed digestion, abdominal pain, flatulence, bloating, nausea, vomiting, and constipation with hard stool and incomplete evacuation. Further, side effects from long–term opioid therapy may result in more serious intestinal complications such as faecal impaction with overflow diarrhea and incontinence, pseudo–obstruction (causing anorexia, nausea and vomiting), disturbance of drug absorption, and urinary retention and incontinence. OIBD may also lead to inappropriate opioid dosing and in consequence, insufficient analgesia. As a result, OIBD significantly deteriorate patients’ quality of life and compliance with their treatment. Approximately one-third of patients treated with opioid analgesics do not adhere to the prescribed opioid regimen or simply quit the treatment due to OIBD symptoms [2].
Several strategies have been advocated to prevent or treat OIBD. Use of traditional laxatives is limited by their effectiveness, yet conveys their own adverse effects. Other possibilities comprise an opioid switch or changing the opioid administration route. New therapies now target opioid receptors in the gut as they represent a main source of OIBD symptoms. A combination of an opioid and opioid antagonist (oxycodone/naloxone) in prolonged release tablets and purely peripherally acting opioid receptor antagonist (methylnaltrexone) available in subcutaneous injections are currently available treatment options. This chapter reviews the pathophysiological basis and possible treatment strategies for OIBD.
Opioids produce widespread effects throughout the gastrointestinal tract though several central and peripheral mechanisms. Such effects are a mixture of inhibitory and excitatory actions. Opioid peptides and their receptors are found throughout the gastrointestinal tract, especially in the gastric antrum and proximal duodenum. The basis for OIBD is therefore complex. The peripheral opioid effect on µ–opioid receptors in the gut wall likely plays a major role, but central effects may also be important [3]. µ–opioid receptors at a high density reside in neurons of myenteric and submucosal plexus and immune cells in the lamina propria [4]. Opioid receptors (predominantly µ, also κ and δ) are located in the gut wall in the myenteric plexus and in the submucosal plexus. The former are responsible for gut motility and the latter for secretion. These µ–opioid receptors are activated in the wall of the stomach, small and large intestine by both endogenous (e.g. enkephalins, endorphins and dynorphins) and exogenous (e.g. morphine, oxycodone, methadone) opioids and modify gastrointestinal function. Activation of µ–opioid receptors inhibits excitatory and inhibitory neural pathways within the enteric nervous system that coordinates motility. Inhibition of excitatory neural pathways depresses peristaltic contractions. On the other hand, the blockade of inhibitory neural pathways increases gut muscle activity, elevates resting muscle tone, and results in spasm and non–propulsive motility patterns. These mechanisms give rise to delayed gastric emptying and slowed intestinal transit [5].
Activation of opioid receptors in the submucosa inhibits water and electrolyte secretion into the gut lumen and increases fluid absorption from the intestine and accelerates blood flow in the gut wall [6]. Opioids increase activity in the sympathetic nervous system and thereby decrease secretion. Endocrine cells located in the epithelium also may play a role in regulating motor activity and secretion in the gut. Interms of motility, peripheral µ–opioid receptors inhibit intestinal transit independent of central µ–opioid receptors [7]. Moreover, opioids increase ileocaecal and anal sphincter tones and impair defecation reflex through reduced sensitivity to distension and increased internal anal sphincter tone [8]. Morphine administration leads to sphincter contraction and to a decreased emptying of pancreatic juice and bile [9], which may impair digestion. The anal sphincter dysfunction is an important factor in the sensation of anal blockage [10,11].
The central mechanism of opioid effects on the gastrointestinal tract is supported by the results of animal studies in which intracerebroventricular administration of morphine inhibited GI propulsion [12]. This effect was reversed by intracerebroventricular administration of naloxone [13] and vagotomy [14]. Intrathecal administration of morphine reduced gastroduodenal motility while intramuscular morphine gave additional effects. Thus, it seems that both central and peripheral opioid effects play a role in opioid GI effects [15]. The indirect evidence of both central and peripheral components of opioid effects on bowel function may be the observed 50–60% response rate to the treatment of OIBD with methylnaltrexone (MNTX), which displays only peripheral µ–opioid receptor antagonist effect in the treatment of patients with OIBD [16,17]. The stool remains in the gut lumen for a longer time, allowing greater absorption of fluid. Enhanced absorption combined with opioid inhibition of secretomotor neurons in the epithelium of the gut [18] leads to the stool becomes hard and dry. In summary, OIBD is the consequence of reduced gastrointestinal motility, increased absorption of fluids from the gut and decreased epithelial secretion.
Dysfunction of the upper gastrointestinal tract (esophagus, stomach and duodenum) often manifests as dyspepsia. Dyspepsia represents a constellation of symptoms rather than a single disease entity. Its diverse symptoms may be expressed as epigastric pain, anorexia, belching, heartburn, bloating, nausea and vomiting, post–prandial fullness, early satiety, and/or regurgitation [19].
Two types of dyspepsia may be diagnosed:
In cancer patients, it may be iatrogenic (e.g.; opioid–induced delayed gastric emptying) and associated with disease-related complications like hepatomegaly or massive ascites. Furthermore, paraneoplastic visceral autonomic neuropathy seems to play an important role. Opioids and other drugs such as anticholinergics, tricyclic antidepressants, benzodiazepines, nitrates and calcium channel blockers may decrease lower esophageal sphincter tone and lead to reflux (GERD) that would be aggravated secondarily by delayed gastric emptying. Gastric secretory and motor activity may be also affected by chronic alcoholism, diabetes, uremia, anxiety and depression. Gastroparesis is a symptomatic chronic disorder characterized by impaired gastric emptying in the absence of a structural cause. This occurs as a component of paraneoplastic syndromes, most commonly in the course of small cell lung, breast, ovarian cancer, Hodgkin disease or multiple myeloma. In addition to opioid adversely affecting gastric emptying, other drugs such as anticholinergics, neuroleptics or tricyclic antidepressants can aggravate gastroparesis. Meanwhile, concurrent conditions such as diabetes, prior gastric surgery, and neuromuscular disorders may further impair gastric emptying. Lastly, gastric or pancreatic tumors can inflict a mechanical outlet obstruction.
Another component that might co-exist is gastroesophageal reflux disease (GERD) due to reflux of gastric contents into the esophagus, causing mucosal damage and heartburn.
The prevalence of functional dyspepsia is high in the normal population (24–34%) and even higher in cancer patients (70%) [20]. Opioids adversely affect the esophagus. This class of drugs impairs esophageal inhibitory innervation and so induces spastic esophageal dysfunction while impairing lower esophageal relaxation, leading to swallowing difficulties (dysphagia). Opioids also reduce the lower esophageal sphincter (LES) pressure, thereby decreasing the barrier pressure between the stomach and the esophagus, producing acid-reflux symptoms. This effect is reversed by naloxone. Opioids inhibit gastric emptying, a product of enhanced gastric relaxation and heightened pyloric tone. This decrease in gastric emptying results from both central and peripheral effects, although a peripheral μ–opioid receptor mechanism is dominant. Opioid administration increases duodenal motility by generating patterns of contractions resembling migrating motor complex (MMC) phase III patterns. Endorphins in humans decrease antral phasic pressure activity and increase pyloric phasic pressure activity and induce MMC III–like bursts of contractile activity in the proximal gut followed by motor quiescence. Exogenous and endogenous opioids impair gastric emptying [21,22].
The evaluation of patients with functional dyspepsia and gastroparesis is based on a careful history taking and physical examination that allow differentiating between functional and structural dyspepsia and GERD. The symptoms of gastroparesis, as quantified by the Gastroparesis Cardinal Symptom Index (GCSI), consists of 9 symptoms, each graded from 0 (none) to 5 (very severe), divided into 3 subscales: postprandial fullness/early satiety, nausea/vomiting, and bloating [23]. Upper endoscopy is usually needed to exclude mechanical obstruction and to assess for mucosal lesions. It is recommended in patients with alarming symptoms e.g.; those suspected for gastrointestinal bleeding. Endoscopy may be also conducted when symptoms develop with NSAIDs administration and when treatment with antisecretory drugs or antacids is unsuccessful. Blood tests assessing complete blood count and biochemistry might be useful. An ultrasound or CT abdominal scan is helpful to assess for cancer spread. In some patients, solid phase gastric scintigraphic emptying studies or breath tests may be needed to confirm gastroparesis. Other investigations such as electrogastrography, antroduodenal manometry are infrequently used in cancer patients.
Non–pharmacological measures
Treatment should be directed at cause of symptoms. Functional dyspepsia may be treated with non–pharmacological measures and drugs. The former comprise explanation and education of patients and families. Advice on the diet may play an important role. Fatty foods should be avoided as lipids impair gastric emptying, while lipids entering the duodenum may aggravate impaired gastric accommodation and gastric hypersensitivity. Medications that may cause dyspepsia (e.g. NSAIDs) should be discontinued when possible [24].
Pharmacological approach
Pharmacological treatment is usually needed. First-line therapy for dyspepsia is usually acid suppression. Proton pomp inhibitors (PPIs) such as omeprazole, esomeprazole or pantoprazole are used once daily in doses 20–40 mg, best given 30 minutes before breakfast. In cancer patients, prokinetic agents are commonly administered, aiming to counteract opioid–induced motility disorders.
Typically, metoclopramide is prescribed (commonly as 10 mg t.i.d.) for patients with functional dyspepsia, especially when symptoms arise from gastroparesis. Metoclopramide works mostly in the upper GI tract through blocking dopaminergic receptors. As metoclopramide also acts centrally, its use is associated with the added risk of extra–pyramidal effects, particularly in younger patients and children. Metoclopramide also inhibits the cytochrome, CYP2D6 enzyme [25]. The most common adverse effects of metoclopramide are restlessness, drowsiness and fatigue. Concomitant use of antidepressants, such as tricyclics, selective serotonin reuptake inhibitors (SSRIs) and newer serotonin–noradrenalin reuptake inhibitors (venlafaxine, duloxetine), may aggravate the adverse effects of metoclopramide [26]. Extrapyramidal effects are unlikely to occur when using domperidone, which does not cross blood–brain barrier [27]. Cisapride is a 5HT4 receptor agonist, affecting the entire GI tract; however, its cardiotoxicity has limited use [28].
Itopride works through peripheral blocking dopaminergic receptors. It inhibits acetylcholinesterase and so increases acetylcholine levels. Itopride works through the whole GI tract. It is devoid of activity at 5–HT4 and 5–HT3 receptors. Itopride is metabolized through monooxidase system. Thus, it has no significant risk of pharmacokinetic interactions with other drugs. Itopride does not cross blood–brain barrier and in consequence does not induce extrapyramidal effects. The dose usually equals 50 mg t. i. d. [29]
Prucalopride, a new prokinetic agent, is a highly selective 5HT4 receptor agonist that stimulates gut motility
Linaclotide is a minimally absorbed peptide guanylate cyclase-C agonist that appears quite effective for chronic constipation and the irritable bowel syndrome [33,34]. It looks promising in the treatment of gastroparesis and so may have a role in OBID.
Lubiprostone, a bicyclic fatty acid derived from prostaglandin E1, acts by specifically activating chloride channels on the apical aspect of gastrointestinal epithelial cells, producing a chloride-rich fluid secretion. These secretions soften the stool, increase intestinal motility, and so promote spontaneous bowel movements. Lubiprostone thus has value in treating functional constipation.
General measures to be taken in patients with OIBD and OIC include the assessment and applying prophylactic measures matched to the patient’s general condition [35]. Change of diet (increased food and fluid intake), more physical activity, assuming a sitting position during bowel movement and obtaining privacy during defecation process are recommended [36]. Patients treated with opioids should be considered for prokinetic administration [37]. Any reversible causes such as hypercalcaemia should also be treated. Discontinuing or decreasing doses of drugs that may aggravate constipation (e.g. tricyclics, neuroleptics, anticholinergics) should also be considered. Patients and families should be educated about the means to prevent and treat OIBD [9].
In most patients with OIBD, laxatives are necessary. The general recommendation is to combine orally administered osmotic agents – usually lactulose or macrogol (PEG – polyethylene glycol) which have an osmotic effect in the colon [10] with stimulants activating on neurons in the myenteric and submucosal plexus in colon and reducing absorption of water and electrolytes from the intraluminal contents: anthracenes (senna), polyphenolics (bisacodyl) or sodium picosulphate. Unfortunately, these drugs exhibit limited efficacy in patients suffering from OIBD. Moreover, they may cause several adverse effects and must be administered on a regular basis [38]. Other classes of laxatives are faecal lubricants (liquid paraffin), stool softeners (surfactants: sodium docusate); however, they are usually ineffective when administered alone [39]. The use of bulk–forming agents such as fibre, bran, methylcellulose and psyllium seeds has limited role in patients with advanced constipation and warrant ingesting adequate fluids (at least 2 liters per day) [40–42]. Castor oil is not recommended due to its sudden stimulating effect on bowel motility and the risk of developing severe abdominal cramps [43]. If oral laxatives are found to be ineffective, rectal treatment should be considered.
Rectal laxatives comprise suppositories increasing intestinal motility through direct stimulation of the nerve endings in the myenteric ganglia of the colon, thus inducing peristalsis (bisacodyl) or using osmotic drugs (glycerol), which act by irritating the rectal mucosa and also enhance the colonic motility that subsequently triggers the defecation reflex. The next step if these agents prove ineffective is rectal enemas, either as normal saline (100–200 ml) or phosphates (120–150 ml).
The management of faecal impaction depends on the severity of symptoms (rectal pain, abdominal colicky pain, protruding hard faeces and faecal leakage). If the symptoms are not severe in case of soft faeces, administer bisacodyl 10–20 mg once daily either rectally or orally until bowel movements are achieved. If hard faeces are present, use glycerol and bisacodyl suppositories or osmotic enemas. Enemas of arachis oil (130 ml) or of decussate sodium (100 ml) followed by a phosphate enema next day may be appropriate. Macrogol (PEG) reduces the need for digital disimpaction. Digital stool evacuation may be necessary in cases of severe symptoms, when neither oral nor rectal treatment gives a desired effect and faecal impaction is not relieved, causing significant distress to the patient. As the procedure is quite painful and distressing, it should be performed with great caution and only when necessary and sometimes necessitating intravenous sedation with midazolam combined with opioids plus topical analgesics [44].
Polyethylene glycol (PEG) and sodium picosulphate are more effective than lactulose in OIC in cancer pain patients [45]. PEG specifically appears to be more effective than lactulose in terms of weekly bowel movement frequency, patient satisfaction, ease of defecation and reduced constipation symptoms with similar treatment tolerance and slightly higher lactulose costs [46]. For palliative care patients, different laxative regimens have no real differences. Overall, there is limited efficacy of traditional laxatives; well-done randomised controlled trials are lacking [47].
The possibility of opioid switch for OIBD should be considered as one of the available treatment options. Opioids, which seem to be more often associated with constipation, are codeine and dihydrocodeine (opioids for mild to moderate pain), morphine, oxycodone and hydromorphone (opioids for moderate to severe pain). These opioids may be switched to other opioids belonging to the same group but having less constipating effect: codeine or dihydrocodeine may be switched to tramadol; morphine, oxycodone or hydromorphone to transdermal opioids (fentanyl, buprenorphine) or to methadone [48,49]. The most convincing evidence supporting the benefits of the opioid switch as regards constipation relief comes from the morphine to transdermal fentanyl switch [50–53]. In contrast to clinical studies, observational surveys do not provide evidence for advantages of transdermal fentanyl over other opioid analgesics with respect to bowel function. [54-55] Other studies report similar or less intense constipating effects with transdermal buprenorphine compared to CR morphine [56] and after a switch from morphine to methadone [57–59]. There may be a benefit to administering tramadol rather than small morphine doses [60–62] or dihydrocodeine [63] with respect to the constipation intensity. However, no differences were found in constipation in cancer patients with pain between transdermal opioids (buprenorphine and fentanyl) and oral controlled release hydromorphone [64].
Few clinical studies compared the efficacy of different laxatives [65] and controlled studies are lacking [66]. Certainly traditional laxatives do not target the cause of OIBD, which is predominantly associated with opioid analgesics binding and activating µ–opioid receptors in the GI tract [67]. Treatment directed at the cause of OIBD involves either using a combination of opioid analgesics with opioid receptor antagonists, which act both centrally and peripherally, or administering opioid receptor antagonists, which act exclusively peripherally. An important advantage of this approach is the fact that it is targeted treatment of OIBD and that it may be combined with oral laxatives, if necessary. Finally, this approach may eliminate the need for rectal measures, which patients tolerate poorly.
Apart from opioid antagonists with exclusively peripheral effects, opioid receptor antagonists with a central mode of action are naloxone, naltrexone and nalmefene. The majority of studies performed so far have used immediate release formulation of oral naloxone (IR naloxone). In spite of high IR naloxone efficacy in the treatment of OIBD, some patients experience opioid withdrawal symptoms and attenuation of analgesia, rendering IR naloxone less useful when administered alone [68–70]. Nalmefene [71] and nalmefene glucuronide [72] behave similarly.
One of methods to decrease the frequency of constipation in patients requiring strong opioids is using formulation composed of an opioid and opioid receptor antagonist. The formulation combining oxycodone and naloxone is available in the form of prolonged release (PR) tablets containing both drugs in the ratio of 2:1 (PR oxycodone/PR naloxone 5 mg/2.5 mg, 10 mg/5 mg, 20 mg/10 mg, 40 mg/20 mg) [73]. The optimal 2:1 ratio of PR oxycodone/PR naloxone tablets was demonstrated in a phase II study rendering effective analgesia and improvement in bowel function with good treatment toleration in patients with severe chronic pain [74]. PR oxycodone/PR naloxone is registered for the indication of severe pain, which may only be successfully treated with opioid analgesics. In this formulation, naloxone counteracts the development of OIBD through inhibition of oxycodone effect on opioid receptors in the gut wall [75]. The starting PR oxycodone/PR naloxone doses in opioid–naive patients is 5 mg/2.5 mg b.i.d. Patients unsuccessfully treated with opioids for mild to moderate pain (tramadol, codeine, dihydrocodeine) may start with the dose 10 mg/5 mg b.i.d. When rotating from other opioids for moderate to severe pain to PR oxycodone/PR naloxone, the starting dose is established individually depending on the amount of previously administered opioid, analgesia and adverse effects. The maximal daily dose of PR oxycodone/PR naloxone recommended equals 40 mg/20 mg twice daily. However, in a study conducted in cancer patients with pain higher daily doses up to 120 mg/60 mg were effective and well–tolerated while symptoms of OIBD were decreased, compared to PR oxycodone administered alone [76].
Following oral administration, oxycodone displays high bioavailability (60 – 87%) and provides effective analgesia [77,78]. Naloxone exhibits low bioavailability after oral administration (< 2%) and undergoes extensive first–pass metabolism in the liver with the formation of naloxone–3–glucuronide [79]. Analgesic effect is not reversed by naloxone and no symptoms of opioid withdrawal occur. This effect of orally administered naloxone depends on normal liver function. Thus, any hepatic impairment should be carefully considered. In patients suffering from decompensated liver disease, PR oxycodone/PR naloxone administration is not recommended. There is a clinically observed difference between the administration of IR and PR formulations of naloxone. IR naloxone in some patients may attenuate analgesia or induce opioid withdrawal symptoms. The PR naloxone formulation prevents saturation of hepatic enzyme system responsible for naloxone metabolism and reduces the risk of opioid antagonism in the CNS [3].
PR oxycodone/PR naloxone provides similar analgesic efficacy to oxycodone with improvement in bowel function, a lower consumption of laxatives and more frequent spontaneous bowel movements [82]. during treatment with PR oxycodone/PR naloxone in comparison to PR oxycodone therapy [80–82]. Long–term therapy (up to 52 weeks) with PR oxycodone/PR naloxone in daily doses up to 80 mg/40 mg appears effective and safe [83]. Analgesia is effective while bowel function and quality of life improved with PR oxycodone/PR naloxone (20 mg/10 mg to 40 mg/20 mg) treatment in patients with severe neuropathic non–malignant pain [84]. Even at quite high doses, PR oxycodone/PR naloxone doses exhibited a benefit compared to PR oxycodone administered alone [85]. PR oxycodone/PR naloxone in doses up to 120 mg/60 mg per day provides effective analgesia while improving bowel function [76]. Adverse effects of PR oxycodone/PR naloxone and PR oxycodone are similar; the frequency of diarrhea is slightly higher in PR oxycodone/PR naloxone compared to PR oxycodone administered alone (5.2% vs. 2.6%) [81]. However, PR oxycodone/PR naloxone less frequency induces nausea (6.3% vs. 10.5%), vomiting (1.3% vs. 4.3%), abdominal pain (1.3% vs. 4.3%) and dyspepsia (0.6% vs. 2.5%) in comparison to PR oxycodone administered alone [82]. These differences might be explained by naloxone antagonist effect on gastric and gut opioid receptors and in consequence, naloxone prokinetic properties [86]. PR oxycodone/PR naloxone studies were performed mainly in patients with chronic, non–malignant pain [80–83, 85, 89]. Opioid switch to PR oxycodone/PR naloxone for cancer patients generally provides adequate analgesia and improved bowel function [87], but in some requiring heightened analgesia, very high doses of PR up to 240 mg per day oxycodone administered alone may be necessary [88].
The contraindications for PR oxycodone/PR naloxone comprise bowel obstruction, acute abdominal conditions, diarrhea and an allergy to the drug. PR oxycodone/PR naloxone is available in several European countries. One pack contains 60 PR oxycodone/PR naloxone tablets of 5 mg/2.5 mg, 10 mg/5 mg, 20 mg/10 mg, 40 mg/20 mg strength. Direct treatment costs for PR oxycodone/PR naloxone in patients with moderate–to–severe non–malignant pain and opioid–induced constipation is slightly higher compared to oxycodone PR. When analysing constipation treatment costs and benefits of PR oxycodone/PR naloxone in terms of improved quality–adjusted life–years, PR oxycodone/PR naloxone appears to be cost–effective option in the UK [90]. Government and other insurance schemes however may not reimburse PR oxycodone/PR naloxone tablets.
Methylnaltrexone (MNTX), a derivative of naltrexone, is a peripheral µ–opioid receptor antagonist, which does not cross blood–brain barrier [91]. Because of its low oral bioavailability, MNTX is administered subcutaneously or intravenously [92]. However, MNTX taken orally prevents the delay in oro–ceacal transit time that follows intravenous morphine administration [93]. MNTX plasma half–life equals 105 to 140 minutes. 50% is excreted unchanged in the urine. MNTX is a weak CYP2D6 inhibitor with no significant drug interactions [94]. MNTX is used to treat OIC in adult patients with advanced diseases when constipation does not respond to conventional oral laxatives. The drug is available in ampoules containing 12 mg MNTX bromide in the volume of 0.6 ml and is applied via subcutaneous injections. The recommended single MNTX dose is 8 mg in patients with body weight 38–61 kg or 12 mg if the body mass is 62–114 kg [95]. Those falling outside of this range should receive a dose of 0.15 mg/kg. No dose adjustment is necessary for patients with mild to moderate hepatic or renal impairment. However, in patients with severe renal failure (creatinine clearance < 30 mL/min) the MNTX dose should be reduced by one–half [96].
A bowel movement within 4 h after MNTX injection is observed in 50–60% patients (the median time to bowel movement after the drug administration is 30 minutes). If no therapeutic effect is observed, the injection may be repeated every other day. MNTX adverse effects comprise abdominal pain (28% of the treated patients), flatulence (13%), nausea (11%), dizziness (7%) and diarrhoea (5%) [16]. However, the administration of MNTX may be associated with an increased risk of gastrointestinal perforation in patients with diseases that decrease gut wall integrity (cancer, peptic ulceration and Ogilvie’s syndrome) or on concomitant medications (NSAIDs, bevacizumab). GI perforation occur at different possible locations (duodenum, small and large bowel). A possible contributing factor might be the prokinetic effect of MNTX. It is not known if dose and duration of the treatment with MNTX relate to this complication [95]. As MNTX does not cross the blood–brain barrier, there is no attenuation of analgesia nor is there an opioid withdrawal syndrome [17]. The use of MNTX is contraindicated in patients with mechanical bowel obstruction, in acute abdominal conditions and in case of allergy to the drug. MNTX may be used in palliative care patients with OIBD not amenable to the treatment with oral laxatives. Several clinical studies have demonstrated the effectiveness of MNTX in patients with advanced diseases and with OIBD [16,17,95,96,98–100]. Peripherally active opioid receptor antagonists in the treatment of OIBD are effective and safe in [101-4]. Long–term efficacy and safety of opioid antagonists is not yet clearly established, in part due to a limited number of randomized studies [105-6].].
The Expert Working Group of the Polish Association for Palliative Medicine developed a three step ladder for the management of OIC (Fig. 1) [43]. This updated version of the ladder takes into account new therapies directed at the underlying mechanism of OIBD [107].
The three-step ladder of the management of opioid–induced constipation [
At the first step traditional oral laxatives and/or PR oxycodone/PR naloxone may be considered. PR oxycodone/PR naloxone targets the source of OIBD (prevention and treatment) as PR naloxone blocks opioid receptors in the gut and PR oxycodone provides effective analgesia. PR oxycodone/PR naloxone may be considered in cancer pain patients who are at high risk of OIBD development such as those with GI tumors, patients who require combined treatment with opioids and other drugs disturbing normal bowel function, e.g. advanced cancer patients. At the second step subcutaneous administration of MNTX may be considered when traditional oral laxatives are ineffective, which may allow avoiding invasive and often painful invasive procedures at step 3 of the ladder.
OIBD in patients diagnosed with chronic diseases is a challenging problem that health care providers often underestimate. This is particularly important in patients regularly receiving opioids for pain or other indications. Thanks to newly introduced drugs that target the cause of OIBD, a more effective therapy is available. The experience with MNTX and PR oxycodone/PR naloxone in patients suffering from OIBD is promising. Further clinical studies are needed to develop more effective guidelines for the management of OIBD and to establish more precisely the role of opioid receptor antagonists. The role of opioid receptor antagonists as potential antiemetic and prokinetic agents should be further explored as suggested by experimental studies in animals. The cost-benefit from new therapies must be carefully considered; overall resources may actually be saved from reduced use of traditional laxatives. The most important advantage of targeted therapies is to decrease patient suffering from OIBD, substantial reduce the need to perform invasive rectal procedures and most importantly, improve quality of life.
Heart failure (HF) is a systemic clinical syndrome with typical symptoms and signs (e.g., dyspnea, paroxysmal nocturnal dyspnea, orthopnea, elevated jugular venous pressure, and peripheral edema) caused by a structural and/or functional cardiac abnormality, resulting in reduced cardiac output and/or elevated intracardiac pressures. It is a major public health problem with an estimated prevalence of 1–2% of the adult population in the developed countries, rising to ≥10% among people >70 years of age [1]. Although much of the research on its systemic interactions has focused on the so-called cardio-renal syndrome, cardio-hepatic interactions are arousing great interest in recent years [2]. These cardio-hepatic interactions have been classified into three groups according to the role of each organ as culprit or victim of the other [3, 4]: (1) liver disease resulting from heart disease; (2) heart disease resulting from liver disease (e.g., cirrhotic cardiomyopathy); and (3) systemic diseases that affect both the heart and the liver (e.g., systemic amyloidosis).
This chapter seeks to make a comprehensive review of the first group: liver disease resulting from heart disease. This type of liver disease has generally been referred as “cardiac hepatopathy,” although there is still no consensus on terminology [5, 6]. The two main forms of cardiac hepatopathy are acute cardiogenic liver injury (ACLI) and congestive hepatopathy (CH). ACLI most commonly occurs in the setting of acute cardiocirculatory failure, whereas CH results from passive venous congestion in the setting of chronic right-sided HF. Both conditions often coexist and potentiate the deleterious effects of each other on the liver [5, 6, 7]. In the following pages, we aim to describe their pathophysiology, clinical features, diagnosis, and treatment.
The liver receives a dual blood supply from the hepatic artery and portal vein. The former delivers well-oxygenated blood and comprises approximately 25% of total hepatic blood flow, whereas the remaining 75% is deoxygenated blood supplied by the portal vein. The total hepatic blood flow ranges from 800 to 1200 ml/min, representing up to 25% of the total cardiac output [7]. As a highly vascular organ, it is sensitive to hemodynamic changes but resilient to ischemic damage through its robust vascular mechanisms of defense [3]. The hepatic artery buffer response is one of such mechanisms whereby decreased portal flow instigates compensatory up-regulation of hepatic arterial flow. It is estimated that it may be capable of compensating for up to a 60% decrease in portal flow [3, 7, 8]. The signaling pathway for this response is local, with the reduction of portal flow resulting in an increase in concentration of the vasodilator adenosine [9]. Unlike the hepatic artery, the portal vein does not have the ability to autoregulate its flow and is dependent on cardiac output and the gradient between portal and hepatic venous pressures [7, 8]. The high permeability of sinusoids represents a second mechanism of defense against hypoxia. It favors oxygen diffusion to the hepatocytes, increasing oxygen extraction to levels near 90%. It prevents any change in liver oxygen consumption despite decreases in liver blood flow up to half of its normal. It must be highlighted that this remarkable ability is exclusive to the liver [7, 10, 11].
By contrast, the protective mechanisms against congestion are less developed and mainly rely on the highly connected sinusoidal network to relieve the increase in pressure. This elevated pressure hits the sinusoidal bed without attenuation since the hepatic veins lack valves [6]. As will be explained in greater detail below, the pre-existing hepatic congestion predisposes the liver to hypoxic injury under any acute event resulting in reduced hepatic blood flow [7, 12].
ACLI has also been referred to as ischemic hepatitis, shock liver, or hypoxic hepatitis in medical literature. These terms reflect the long-standing debate regarding its pathogenesis [7]. In 1901, F.B. Mallory (of Mallory-Denk body fame) first described the typical pattern of centrilobular liver necrosis (CLN) characteristic of this entity based on a series of autopsies in Boston. He proposed a toxic theory whereby liver damage was secondary to toxins released by bacteria into the circulation [13]. This theory was soon challenged by Lambert and Allison who found no proof of bacterial infection in a series of 112 patients deceased from congestive HF, 30% of whom had CLN [14]. They then proposed passive congestion as its prime etiological factor, and this “congestion theory” prevailed for more than 50 years. The emergence of transaminases measurement in the early 1950s revealed the massive increase of these enzymes that come in parallel with CLN. The association between shock, CLN, and significant rise in transaminases found by different studies led some investigators to propose liver ischemia as the sole factor responsible for liver cell necrosis [15, 16, 17, 18]. It was then that the terms “shock liver” and “ischemic hepatitis” were introduced by Birgens et al. [19] and Bynum et al. [20], respectively. Hence, by the late 1970s, the “ischemic” theory had replaced the “congestion” theory and remained unquestioned until 1990. In this year, Henrion et al. reported the first prospective series with hemodynamic data of 45 episodes of ischemic hepatitis. They observed that a shock state was only present in 47% of the episodes and proposed renaming this liver injury “hypoxic hepatitis” as hypoxia from a variety of etiologies (e.g., sepsis and respiratory failure) was present in all cases [21]. These findings were later confirmed by the final report from the same authors including 142 episodes [22] and by the series of 322 cases of ischemic hepatitis published later by Birrer et al. [23]. Thus, the term hypoxic hepatitis together with ACLI is currently used to name this entity. Some authors believe that ACLI provides more details about the underlying pathophysiological process as an acute cardiac event in a patient with an underlying congestive liver represents the most common clinical scenario [2, 5, 24, 25].
The prevalence of ACLI among patients admitted to hospital varies greatly depending on the severity of illness. Indeed, in a recent meta-analysis of 1782 cases, ACLI was present in two every 1000 patients for all levels of hospital care but increased to 2.5 out of every 100 patients in intensive care units (ICUs) [26]. Studies including very critically ill patients have described maximum figures ranging from 11.9 to 21.9% [27, 28, 29]. Although previously debated [7], recent series indicate that the presence of a primary liver disease also increases the risk of ACLI. In a nationwide study including patients with hemodynamic instability, Waseem et al. observed a prevalence of acute liver injury of 22% in patients with underlying liver disease compared to only 3% in those without baseline hepatopathy [30].
These variations in frequency of ACLI not only respond to the severity of illness or the presence of a primary liver disease, as sometimes the diagnosis is overlooked clinically and variable cutoffs of transaminases are an important determinant of prevalence. Thus, in the previous meta-analysis, different liver enzyme cutoffs were used among studies as inclusion criteria, and the highest frequency of ACLI was among patients with increased serum aminotransferases above 1000 IU/L, where the prevalence reached 57% [26]. Therefore, current prevalence rates of ACLI might be underestimated [7, 12].
Liver damage in ACLI is the result of several mechanisms: passive congestion reduced hepatic blood flow, total body hypoxemia, inability to utilize oxygen, and ischemia/reperfusion injury. Necrosis, rather than apoptosis, is the main mode of death due to these mechanisms [31]. Although frequently multifactorial, the predominating mechanism of damage can be different depending on the underlying condition [7, 12]. In this regard, the most frequent diseases leading to ACLI are HF, respiratory failure, and septic shock, accounting for more than 90% of cases [7]. These diseases often coexist and lead to ACLI. Hence, Fuhrmann et al. identified more than one disease contributing to ACLI in 74% of their study population [27].
As mentioned previously, HF represents the main underlying condition in ACLI. The proportion of ACLI cases due to HF published in the literature ranges from 39 to 78% [7, 12, 22, 23, 26, 27, 28]. In this condition, the main mechanisms involved in the development of ACLI are passive congestion and ischemia of the liver. Indeed, in this scenario, ACLI is believed to reflect the extreme of a spectrum of liver injury that begins with passive hepatic congestion since the vast majority of patients have markedly elevated cardiac filling pressures [17, 22, 26, 32, 33]. Thus, several studies have shown how, despite similar hemodynamic derangements, only those with a pre-existing congestive liver developed ACLI [23, 29, 33]. This crucial role of passive congestion of the liver justifies the rare occurrence of ACLI in hemorrhagic or hypovolemic shock [7]. Most importantly, Seeto et al. showed that 15–20 minutes of hypotension is sufficient to provoke ACLI [33]. This explains why hemodynamic instability is not systematically observed, since such a brief period can easily be unrecognized.
Respiratory failure accounts for approximately 15% of ACLI cases [7]. Severe hypoxemia resulting from an exacerbation of chronic respiratory disease is the main mechanism leading to ACLI. Very low levels of arterial pressure in oxygen (i.e., under 40 mmHg) are commonly observed, as well as the coexistence of hepatic venous congestion. In this setting, cardiac output and hepatic blood flow are normal or even increased [22, 23].
Septic shock is the cause of ACLI in 15–30% of cases. The prime factor leading to hypoxia is both the increased demands of oxygen and the decreased ability of hepatocytes to utilize oxygen [7]. It has been postulated that inflammatory mediators and endotoxins may be behind this abnormal oxygen utilization [7, 34, 35]. Although at the initial phases of septic shock hepatic blood flow is increased, the progression from high to low cardiac output may occur rapidly and aggravate the hypoxic damage [12].
While the previously described mechanisms induced ACLI by causing liver hypoxia, it has been postulated that re-oxygenation is also required [7, 12]. Several observations support this role of ischemia/reperfusion injury in ACLI: (1) it has been described that liver cell necrosis occurs at the time of reperfusion not ischemia [7]; (2) the incidence and severity of CLN correlate with the duration of shock. In fulminant and refractory cardiogenic shock (median duration of shock was 3 hours), CLN was only observed in a minority of patients and was mild [21, 29], whereas earlier studies showed how the longer the period of shock the greater the severity and frequency of CLN [36, 37]. One explanation of these findings is that long-lasting shocks probably harbor transient periods of hemodynamic stability and re-oxygenation that can cause ischemia/reperfusion injury and subsequently induce ACLI. (3) In a minority of ACLI cases, liver necrosis is limited to the mediolobular zone and spares the centrilobular zone [38, 39, 40]. Henrion et al. postulated that this atypical histological pattern could be due to an incomplete liver reperfusion prior to death that only reached periportal and mediolobular liver cells. Hence, periportal and centrilobular cells would have survived, the former because of oxygen delivery remained sufficient, and the latter because of the absence of reperfusion injury. Mediolobular hepatocytes, on the other hand, would have been destroyed due to ischemia/reperfusion injury [7].
The majority of ACLI cases occur in elderly men (i.e., 65–70 years) with congestive HF that has deteriorated over the past few days. It must be highlighted that a shock state is far from being a constant feature as is observed in around half of the cases. Moreover, the cardiac component may not be apparent at first evaluation as usual signs of HF, such as painful hepatomegaly, ankle edema, or hepatojugular reflux, are frequently lacking. Therefore, the diagnosis of ACLI cannot be rejected because of the absence of shock and of signs of HF, and in case of uncertainty, a cardiac evaluation is warranted [6, 7]. Symptoms due to ACLI are often absent or resemble those from acute viral hepatitis [24], and more commonly, the clinical picture is dominated by symptoms of the underlying conditions. Overt jaundice is absent at admission, and encephalopathy can develop but is usually the result of hemodynamic instability and hypoxia, rather than liver failure [7, 12].
Laboratory tests show a substantial and rapid increase in aminotransferases and lactate dehydrogenase (LDH) levels to 10–20 times the upper limit of normal, usually 1–3 days after hemodynamic deterioration. These elevations generally return to normal within 7–10 days if hemodynamic stability is restored [3, 41]. A progressive increase in bilirubin is usually seen but is seldom severe [3, 7, 12]. The higher values reported by recent series may be explained by the inclusion of more patients with septic shock. Nonetheless, the mean bilirubin value in these studies was lower than 6 mg/dL [27, 28]. Higher values may suggest progression to acute liver failure [6]. Unlike in children where hypoglycemia has been regarded as a distinct feature of ACLI, in adults both hypoglycemia and hyperglycemia have been reported [7, 12]. Although no analytical alteration is pathognomonic of ACLI, there are some findings that suggest its diagnosis [7]: (1) an alanine aminotransferase (ALT)-to-LDH ratio <1.5 is of great help in the differential diagnosis as it is rarely seen in other etiologies of hepatitis [42]; (2) the aspartate aminotransferase (AST) generally peaks earlier and higher than ALT [41]. The rational behind this finding lays on the concentration of aminotransferases throughout the hepatic acinus. ALT reaches the highest concentration at the level of periportal hepatocytes (Rappaport liver zone 1) and the lowest concentration at the level of pericentral hepatocytes (Rappaport liver zone 3), while AST maintains a stable concentration throughout the entire acinus. Hence, after the hypoxic insult, the initial concentrations of AST are higher than those of ALT, since the lower oxygen concentration of pericentral hepatocytes makes them more susceptible to hypoxic damage [43]. Once the cause of liver damage is resolved, the concentration of ALT exceeds that of AST in subsequent days, due to its longer half-life (47 ± 10 hours versus 17 ± 5 hours, respectively) [44]. Aboelsoud et al. [41] universally observed this pattern, but it was only described in 75% of the cases in Henrion’s study [22]. The rapid decline and reversal of the AST-ALT ratio may explain these differences, and therefore, an ALT higher than AST should not discard ACLI; (3) an early and sharp deterioration in prothrombin activity and renal function also supports ACLI. Such abnormalities are unusual at presentation in patients with viral or drug-induced hepatitis, unless ALF is already established [7]. Figure 1 shows a typical biochemical profile of ACLI in a patient treated in our hospital.
Laboratory parameters during the course of ACLI in a patient with respiratory failure due to drug overdose. Abbreviations: AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; LDH: Lactate dehydrogenase; Bb; bilirubin; INR: International normalized ratio.
In accordance with the above, diagnosis of ACLI is usually made when the following criteria are met [12, 22, 26]: (1) an appropriate clinical setting of cardiac, respiratory, or circulatory failure; (2) a severe increase in aminotransferase levels; and (3) exclusion of other causes of acute liver damage. The differential diagnosis for severe elevations of transaminases is relatively limited and includes ACLI, acute viral hepatitis, toxin- or drug-induced liver injury, autoimmune hepatitis, Wilson’s disease, acute bile duct obstruction, and acute Budd-Chiari syndrome [44]. Imaging techniques are essential to rule out some of these etiologies and can also support the diagnosis by finding a dilation of inferior vena cava and suprahepatic veins due to passive congestion [7]. Liver biopsy is rarely necessary and only when the underlying cause remains unclear. It will show features of coagulative necrosis of centrilobular hepatocytes without significant inflammation (Figure 2A–C). In biopsies delayed several days, however, there may be neutrophils infiltrating the affected regions [25]. As already stated, necrosis rarely occurs predominantly in the middle zone [38, 39, 40].
(A) Postmortem example of a liver with ischemic zones around centrilobular veins. (B) Centrilobular regions show congestion and coagulative necrosis (hematoxylin-eosin). (C) Same findings than 2.B with greater magnification.
The prognosis of ACLI is poor with an overall hospital mortality of 51% [26] and 1-year survival rate of approximately 25% [7]. The cause of death is usually the underlying condition, as it is an uncommon cause of ALF. In a study from the Acute Liver Failure Study Group, only 4.4% of the ALF cases had ACLI as their final diagnosis [45]. Nevertheless, there is some indirect evidence that suggests that ACLI influences outcome in this setting. Hence, prolonged international normalized ratio (INR) and jaundice have been identified as independent risk factors for ACLI mortality [27, 28, 41, 46]. Other factors that have been associated with increased risk of in-hospital mortality include a baseline liver disease [30], higher elevations of transaminases [27, 45], LDH [27, 41], serum phosphate [45], concomitant renal failure [28, 41], septic shock [27, 28], and more advanced encephalopathy [45].
The management of the underlying diseases remains the only established treatment for ACLI. Although data are limited, some experts recommend using N-acetylcysteine, avoiding excessive vascular filling to minimize passive congestion of the liver, and favoring the use of dobutamine in patients with low cardiac index given its inotropic and vasodilating effects [2, 3, 7, 12].
Liver disease as a consequence of HF has been known for a long time. The histological description of the “nutmeg,” congestive liver is attributed to Kiernan in 1833 [25, 47]. Earlier studies from the beginning of the twentieth century started providing data on the structural and functional changes that develop in the liver in the setting of HF [47, 48]. The classic work from Sheila Sherlock, published in 1951, stood for decades as the standard reference on this entity. In this article, the renowned author correlated liver tests, systemic hemodynamic parameters, and histology [47]. Progress has been made since then, but there are still important gaps concerning its pathophysiology, assessment of liver fibrosis, and clinical impact on overall HF prognosis [2, 6].
CH occurs in the setting of any cause of right ventricular failure such as constrictive pericarditis, mitral stenosis, severe tricuspid regurgitation, cor pulmonale, or end-stage cardiomyopathies [8, 49]. The current spectrum of CH differs from earlier reports due to several reasons [3, 4, 6, 50]: (1) the etiology of HF has changed over the years with ischemic cardiomyopathy surpassing rheumatic valvular disease; (2) after major advances in medical treatment and the widespread use of heart transplantation, the prognosis of HF has greatly improved, and as a result, cardiac cirrhosis is declining; (3) these same medical advances are responsible for the improved survival of patients with a variety of congenital heart diseases that lead to right HF. The most illustrative example is the Fontan procedure to palliate single-ventricle physiology. Unlike patients with acquired heart disease, these patients may develop “cardiac cirrhosis” in early adulthood.
This heterogeneous cause of CH together with the limited validated techniques available to diagnose and, specially, stage the disease may explain that the burden of CH has not yet been adequately described [51]. Non-congenital HF studies using liver blood tests to determine the prevalence of CH have described figures ranging from 15 to 80%, depending on the severity of heart disease [24, 52, 53, 54, 55, 56, 57]. However, liver blood tests neither accurately diagnose CH nor reflect the stage of liver disease [51]. Future studies should use a more comprehensive approach to overcome these biases and to provide solid data on this issue.
Congestion produces liver damage through several pathogenic mechanisms: (1) increased sinusoidal pressure leads to hepatic stellate cell activation and decreases nitric oxide production by endothelial cells through shear stress, all of which induce sinusoidal ischemia and promote fibrogenesis [51, 58]; (2) decreased hepatic blood flow further aggravates liver ischemia. Portal venous inflow is reduced as a result of the transmission of the elevated central venous pressure to the sinusoidal network, while arterial flow can also be compromised in patients who also harbor a left-sided HF [8, 51]; (3) Accumulation of exudate into the space of Disse due to the existing congestion impairs diffusion of oxygen and nutrients to hepatocytes and accelerates fibrosis pathways [8]; (4) Sinusoidal stasis and congestion promote sinusoidal thrombosis, which in turn contributes to liver fibrosis by causing parenchymal extinction and by activating hepatic stellate cells via protease-activated receptors [59, 60]. The former refers to a hypothesis based on retrospective observations of ex-vivo human liver specimens of patients with CH. In this autopsy study, Wanless et al. demonstrated sinusoidal thrombi confined to areas of fibrosis, thereby suggesting that intrahepatic thrombosis is involved in liver fibrosis progression [61]. A recent experimental study provided evidence of the mechanistic link between CH and liver fibrosis through this mechanism [58]. These findings settle the rational basis for testing anticoagulant drugs in patients with CH, but so far, no clinical trial has addressed this issue. In comparison, research in this area in primary liver cirrhosis is more advanced. Hence, several experimental studies have shown that anticoagulant therapy improves liver fibrosis and reduces portal hypertension [62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73], and a clinical trial demonstrated that anticoagulation led to a reduction in portal thrombosis and other complications of liver disease and to increase in survival [74]. New clinical trials are needed in order to confirm these preliminary results and to establish whether the stage of liver disease may influence its efficacy [75].
It must be highlighted that contrary to primary liver diseases, in CH inflammation seems to play no role in the progression of liver fibrosis. Indeed, several studies of patients with Fontan circulation demonstrated minimal inflammatory changes in liver biopsy specimens, despite accentuated hepatic fibrosis [76, 77, 78].
CH may be asymptomatic for a long time, and frequently, its presence is suspected through abnormalities in liver tests [8]. Symptoms attributed to CH may include dull right upper quadrant pain, nausea, vomiting, anorexia, early satiety, malaise, and mild jaundice [3]. The abdominal symptoms respond to the stretching of the liver capsule due to hepatic congestion and may occur in the absence of overt ascites or lower extremity edema. These symptoms, however, are usually masked by those related to right-sided HF [2].
Physical examination may often show hepatomegaly and signs of HF, including hepatojugular reflux and peripheral edema. A pulsatile liver may also be seen, and its loss suggests progression to cardiac cirrhosis [49]. Overt ascites is also a frequent finding, although it is rarely refractory. In a series of 83 patients with CH of whom only one had established cardiac cirrhosis, up to 57% had ascites. Moreover, ascites and edema had no relation to the extent of liver fibrosis, and therefore, they are due to elevated right-sided cardiac pressure hitting the sinusoidal network [50]. The differentiation of cardiac ascites from cirrhotic ascites can be cumbersome. In these conditions, the serum-ascites albumin gradient is ≥1.1 g/dL since they both respond to hepatic sinusoidal hypertension [79]. There are, however, some ascites findings that are useful to make a differential diagnosis. Cardiac ascites has higher protein levels (>2.5 g/dL). This is due to preserved liver synthetic function and absence of capillarization of the liver sinusoidal endothelial cells [3, 8, 80]. The latter refers to the lost of fenestrae and development of a basement membrane by these cells as a consequence of liver fibrosis. In cirrhosis, these features make hepatic sinusoids less leaky and prevent the passage of proteins to the space of Disse and from here to the peritoneal fluid [81]. Other less reliable findings in cardiac ascites are higher LDH levels and higher red blood cell counts due to leaking of red blood cells into the ascites via lymph tissue, with resulting lysis [80]. Despite these differences, a significant number of cases are still misclassified. Measurement of serum B-type natriuretic peptide (BNP) or of its inactive pro-hormone (N-terminal-proBNP) in serum and ascites has been recently suggested as an aid tool in uncertain cases. Thus, Sheer et al. reported that both serum and ascites NT-proBNP levels had high sensitivity and specificity in predicting HF as the cause of ascites [82]. More recently, Farias et al. found serum BNP to be superior to the total ascitic fluid protein concentration with regard to discriminating cardiac ascites from cirrhotic ascites. A serum BNP cutoff of >364 pg/mL had 98% sensitivity, 99% specificity, 99% diagnostic accuracy, and a positive likelihood ratio of 168.1 for the diagnosis of cardiac ascites. Conversely, a serum BNP cutoff of ≤182 pg/mL was excellent for ruling out ascites due to heart failure [79].
The differentiation of cardiac cirrhotic ascites from cardiac ascites without cirrhosis is especially challenging and of great clinical importance. On the one hand, the diagnosis of cardiac cirrhosis warrants further evaluations such as bi-annual surveillance ultrasonography or endoscopic screening for esophageal varices. On the other hand, its presence may preclude a heart transplant or require a combined heart-liver transplant. Apart from some diagnostic tools such as liver biopsy and hepatic venous pressure gradient (HVPG) that will be later discussed, there are some clinical clues that help in the differential diagnosis. In patients with cardiac ascites without cirrhosis, splenomegaly and spider angiomata are absent, and varices are rarely identified on upper endoscopy [3, 49]. This can be explained by the fact that varices represent collateral vessels from the high-pressure portal system to the low-pressure systemic circulation, and in CH without cirrhosis, no pressure gradient exists because pressure remains high along the entire path of venous return to the right atrium [50]. Complications of cirrhosis may occur in the late stages of cardiac cirrhosis. Although in the past the traditional patient with cardiac cirrhosis died from his cardiac disease before progressing to decompensated cirrhosis, advances in medical and surgical treatments are responsible for the increased number of liver complications in this setting [3]. The risk of hepatocarcinoma after the Fontan procedure is probably the best example. The success of this surgery to palliate right-sided congenital heart lesions permits long-term survival in the setting of elevated right-sided heart pressures. Eventually, the liver disease could become as clinically important as the cardiac disease and further complicate its management [51].
Besides the presence of right-sided HF (or other cause of high central pressures) and the aforementioned clinical findings, the diagnosis of CH should be further supported on compatible results of diagnostic tools and exclusion of other possible causes of liver disease [49, 50].
Elevation of serum cholestasis markers (alkaline phosphatase, GGT, and bilirubin) is characteristic of CH. Total bilirubin levels rarely exceed 3 mg/dL, and indirect bilirubin usually predominates over direct bilirubin [3]. The degree of cholestasis is related to the severity of both the elevation of right atrial pressure and tricuspid regurgitation [55, 83]. These data suggest that elevated right-sided filling pressures may contribute more to LFT elevation than reduced cardiac output [2]. The mechanism of cholestasis in this setting is thought to be due to the compression of the bile canaliculi and small ductules by centrally congested sinusoids [25]. Other laboratory findings include mild elevations of serum aminotransferases to two to three times the upper limit of normal and mild hypoalbuminemia. The latter may also be secondary to malnutrition or protein-losing enteropathy [8]. As liver disease progresses, liver function tests (i.e., bilirubin, INR, and albumin) may continue to worsen. Importantly, liver enzymes are often normal, and in the presence of other findings suggestive of CH, this diagnosis cannot be ruled out based on these normal values [3]. As already discussed, CH predisposes the liver to ACLI in the face of hemodynamic instability, instigating the aforementioned marked elevation of liver enzymes [8].
Imaging tests help both to support the diagnosis of CH and to identify complications. Characteristic conventional imaging findings include dilation of inferior vena cava and hepatic veins, loss of normal triphasic hepatic venous wave-form, and abnormal kinetics of intravenous contrast enhancement (e.g., delayed bolus arrival to the liver suggesting slow systemic circulation, diffusion of extracellular contrast media into the periportal lymphatic space in the delayed phase, retrograde hepatic venous opacification during the early phase of intravenous contrast material injection into the upper extremities, and a predominantly peripheral heterogeneous pattern of hepatic enhancement due to stagnant blood flow) [84] (Figure 3A, B). Importantly, the appearance of a nodular or heterogeneous liver on standard imaging is not sufficient to diagnosis cirrhosis in CH [51].
(A) Idiopathic membranous inferior vena cava obstruction in a 44-year-old man. MRI shows a mildly nodular liver with altered parenchymal perfusion and dilatation of hepatic veins. (B) Severe tricuspid regurgitation in a 49-year-old man. CT scan shows dilatation of hepatic veins and reflux of contrast into the inferior vena cava and hepatic veins.
CH may lead to the generation of benign regenerative nodules or focal nodular hyperplasia (FNH)-like lesions and hepatocarcinoma. The former is referred to as “FNH-like” despite having characteristic pathological findings of FNH due to the presence of abnormal background liver parenchyma. Although they most commonly demonstrate typical imaging findings (i.e., well-circumscribed, homogeneous nodule with late arterial hyperenhancement that fades to isointensity/isoattenuation on delayed phase imaging), they sometimes have a washout appearance that could be mistaken for hepatocarcinoma due to abnormally increased background parenchymal enhancement in the delayed phase [84] (Figure 4). Indeed, distinguishing hepatocarcinoma from these atypical imaging represents an unmet need, and biopsy is frequently required for accurate diagnosis. Radiological findings that support the diagnosis of hepatocarcinoma include the following: significant change in appearance of a nodule, venous invasion, a heterogeneous-appearing mass, and elevated alpha-fetoprotein [51, 84]. There are currently no screening guidelines for hepatocarcinoma in CH. In post-Fontan patients, some experts recommend to begin screening at 15–20 years after the operation [51], while the newly released guidelines from the American Heart Association recommend a much more comprehensive surveillance (Table 1) [85]. In patients with CH due to other conditions, it seems reasonable to perform bi-annual screening once cardiac cirrhosis is established.
Idiopathic membranous inferior vena cava obstruction in a 44-year-old man. The image shows the dynamic phase of MRI. Besides the significant hypertrophy of segment I, MRI shows a mass (3.8 cm × 4.2 cm) that after administration of intravenous contrast presents a heterogeneous enhancement in the arterial phase with washout in the portal phase. Liver biopsy showed histological changes compatible with focal nodular hyperplasia.
Basic* | In-Depth* | Investigational* | |
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Tests recommended by the American Heart Association for surveillance of liver disease in post-Fontan patients.
Tests are stratified as basic (fundamental and rudimentary level of assessment), in-depth (more detailed level of characterization), and investigational (possible or likely of value; however, greater experience and study may be necessary before widespread use can be suggested).
Abbreviations: CMP: comprehensive metabolic panel; CT: computed tomography; GGT: γ-glutamyl transferase; INR: international normalized ratio; MRI: magnetic resonance imaging; PT: prothrombin time.
The congestive liver explant has been characterized as a “nutmeg liver” due to the presence of dark centrilobular zones that reflect sinusoidal congestion alternating with pale periportal zones with normal or fatty liver tissue [84] (Figure 5A). Characteristic histological findings include sinusoidal dilatation and congestion, hepatocyte atrophy most prominent in zone 3, extravasation of red blood cells into the space of Disse, regenerative hyperplasia emerging from periportal regions, and centrilobular fibrosis (Figure 5B, C) [25]. The degree of sinusoidal dilatation is positively correlated with the degree of elevation of right atrial pressure. As liver disease progresses, bridging fibrosis typically extends between central veins to produce a pattern that has been name “reversed lobulation” since it contrasts to the typical fibrosis pattern found in most primary liver diseases where bridging fibrosis occurs between portal triads (i.e., zone 1) [3]. As far as the correlation between fibrosis extension and systemic hemodynamic parameters is concerned, there are discordant results with most studies finding no correlation [50, 54, 86, 87, 88, 89].
(A) Postmortem example of the classical “nutmeg” liver with centrilobular congestion in CH. (B) Centrilobular regions show congestion and extravasation of red blood cells. (C) Same findings than 5.B with greater magnification.
It must be highlighted that the distribution of fibrosis throughout the liver is extremely heterogeneous in patients with CH [86, 90], and it may be explained by the fibrogenic effects of intrahepatic thrombosis caused by static blood flow [61]. This variability raises concern about sampling error and about the role of liver biopsy as the gold standard tool for fibrosis assessment. Moreover, liver biopsies may not predict post-heart transplant outcomes. In a retrospective study, Louie et al. found that the presence of bridging fibrosis was not significantly associated with post-operative survival or post-operative liver failure, based on which they concluded that patients with bridging fibrosis may still be considered viable candidates for isolated heart transplantation [90]. Similar results were described by Dhall et al. [86]. Regardless of these limitations, liver biopsy still plays an important role in the assessment of the stage of liver disease, in ruling out hepatocarcinoma and alternative etiologies of liver disease and in determining candidacy for isolated heart transplantation or combined heart-liver transplantation. Its findings, however, should be correlated with the clinical presentation and results of other diagnostic tools [51, 86].
Non-invasive diagnostic tests of liver fibrosis have been extensively studied and have excellent predictive value for advanced fibrosis in patients with viral hepatitis and non-alcoholic fatty liver disease [91]. Nevertheless, the performance of these tests in assessing the severity of fibrosis in CH is poor. A detail description of each of these tests in this setting is beyond the scope of this chapter and can be found elsewhere [51, 92, 93].
Briefly, among serological markers, the Model for End-Stage Liver Disease (MELD)-XI score has been suggested to be potentially useful as some studies have shown a moderate correlation with the stage of fibrosis in post-Fontan patients [94, 95]. This score excludes INR given the high prevalence of anticoagulation use in CH. Despite these results, further studies are needed as other studies have described opposite results [78, 90]. The remaining tests (i.e., standard serum markers, FibroSure testing, hyaluronic acid levels, and most clinical risk calculators) are inaccurate at staging liver fibrosis [51]. The use of liver stiffness tools is hampered by the fact that congestion increases liver stiffness values [91]. Hence, in CH, it provides unreliable information regarding the grade of fibrosis, although some evidence suggests that liver and spleen stiffness calculated by magnetic resonance elastography may be more accurate. Finally, new advances in imaging techniques, such as magnetic resonance imaging with diffusion-weighted imaging, may potentially differentiate fibrosis from congestion but require validation [51].
Hepatic vein catheterization with measurement of the HVPG is currently the gold standard technique for determining portal pressure. It represents the difference between the wedged hepatic venous pressure (WHVP) and the free hepatic venous pressure (FHVP). The WHVP is usually measured by occluding the right hepatic vein through the inflation of a balloon, whereas the FHVP is measured without occluding it. The occlusion of the vein forms a continuous static column of blood between the catheter and the hepatic sinusoids. Thus, WHVP measures sinusoidal pressure. Due to the scarce connections between sinusoids existing in cirrhosis, pressure cannot be decompressed through the sinusoidal network, and therefore, WHVP reflects portal pressure in this setting. FHVP, on the other hand, is a surrogate for inferior vena cava pressure. Normal values of HVPG are <5 mmHg. The HVPG is a strong and independent predictor of outcomes in compensated and decompensated cirrhosis due to primary liver diseases [96, 97, 98].
The diagnostic and prognostic value of HVPG measurement in CH has not been adequately assessed. In this context, both FHVP and WHPV are elevated, and the HVPG is within the normal range (Figure 6). Once cardiac cirrhosis is established, the HVPG is expected to increase beyond 6 mmHg (Figure 7) [51]. Hence, HVPG could theoretically provide relevant information about the stage of CH. The few clinical studies that have provided hemodynamic data in this regard have described inconsistent results. For instance, in the study of Myers et al., esophageal varices were seen in some patients despite having a HVPG below 6 mmHg. As previously explained, the high pressures along the entire path of venous return to the right atrium prevent the formation of varices unless the establishment of cirrhosis creates a pressure gradient between the portal and systemic circulation. In order to explain these discordant results, the same authors argued that it was possible that the varices observed in a few patients represented either false-positive endoscopies or undetected concomitant disease such as portal vein thrombosis [50]. Moreover, it has not yet been demonstrated that the HVPG correlates with the stage of fibrosis in CH [50, 86]. These findings probably respond to several confounders: the inclusion of few patients with advanced fibrosis, the variable distribution of fibrosis throughout the liver, and the absence of a full and reliable characterization of the liver disease. As far as its prognostic utility is concerned, no study has evaluated the HVPG for predicting hepatic decompensation events and survival after isolated heart transplantation [51]. Despite this, many academic centers, including our own, measure the HVPG to assist in the transplant decision-making process. Finally, it must be reminded that the hepatic vein catheterization also allows performing a transjugular liver biopsy. This technique is safer than the percutaneous biopsy and can be performed even under anticoagulation or ascites [99].
(A) A typical hemodynamic tracing of a patient with congestive hepatopathy due to cor pulmonale. The HVPG is calculated as the difference between WHVP and FHVP. Both of them are elevated, but the HVPG is within the normal range. (B) Transjugular liver biopsy was performed and showed sinusoidal dilatation without significant fibrosis (hematoxylin-eosin stain; the image of Masson stain is not shown). (C) Occlusion of the hepatic vein with the balloon catheter. Abbreviations: MAP: Mean pulmonary arterial pressure; PCP: Pulmonary capillary pressure; RAP: Right atrial pressure; IVCP: Inferior vena cava pressure; FHVP: Free hepatic venous pressure; WHVP: Wedged hepatic venous pressure; HVPG: Hepatic venous pressure gradient.
(A) A typical hemodynamic tracing of a patient with severe tricuspid regurgitation and concomitant hepatitis C. The HVPG is calculated as the difference between WHVP and FHVP. Both of them are elevated, and the HVPG is slightly elevated. (B) Transjugular liver biopsy was performed and showed significant fibrosis forming nodules (Masson stain). (C) Occlusion of the hepatic vein with the balloon catheter. Abbreviations: MAP: Mean pulmonary arterial pressure; PCP: Pulmonary capillary pressure; RAP: Right atrial pressure; IVCP: Inferior vena cava pressure; FHVP: Free hepatic venous pressure; WHVP: Wedged hepatic venous pressure; HVPG: Hepatic venous pressure gradient.
The underlying cardiac disease generally determines prognosis in CH. Liver enzymes (i.e., bilirubin, alkaline phosphatase, GGT, and albumin) and scores such as the MELD and MELD-XI have been associated with prognosis in HF patients [53, 56, 100, 101, 102, 103]. Based on these findings, both the American College of Cardiology and the European Society of Cardiology Heart Failure Guidelines recommend the inclusion of liver function tests in the diagnostic workup of all patients presenting with HF [1, 104]. However, it must be pointed out that they predict cardiac or overall mortality, not liver-related mortality. Therefore, they seem to act as indirect markers of the severity of cardiac disease rather than reflecting the effect of liver disease on outcomes. Indeed, the effect of cardiac cirrhosis on overall prognosis has not been clearly established [6].
Management of the underlying cardiac disease is the mainstay of treatment. There is no specific therapy of CH [8]. Concerns about modification of drug dosage have been raised, although there are no solid rules in this regard. This is partially explained by the lack of correlation of available diagnostic tools with the hepatic function [5]. Theoretically more relevant are the detrimental effects that some of the medical therapies used to treat HF may have on the physiopathology of cirrhosis. For instance, vasodilators such as angiotensin-converting-enzyme inhibitors are contraindicated in decompensated cirrhosis, and doses of diuretics in HF are often higher than in cirrhosis and may precipitate hepatorenal syndrome [3]. Again, no solid recommendations are available, and treatment modifications should be patient-specific. Eventually, some patients will require a heart transplant, and this poses the question of whether the liver is “in shape” to tolerate a heart transplant.
Given the aforementioned limitations of available invasive and non-invasive tests to assess hepatic fibrosis and function, determining whether a patient with CH is a candidate for isolated heart transplantation or may require a combined heart-liver transplantation is especially challenging. Not surprisingly, there are no official guidelines, evaluation is institution dependent, and the decision is often taken on a case-by-case basis. It must be highlighted that cardiac cirrhosis may be reversed after heart transplantation. Based on this premise, some centers use an HVPG value of <12 mmHg as a cutoff for offering isolated heart transplantation instead of combined heart-liver transplantation. Nevertheless, this protocol requires validation before its widespread use in clinical practice. Figure 8 shows our protocol for determining our recommendation regarding liver disease in a potential candidate for a heart transplant when CH is suspected.
Protocol to determine the recommendation regarding liver disease in a potential candidate for a heart transplant when CH is suspected. We proceed to HVPG measurement and transjugular biopsy in those patients in whom advanced liver disease cannot be ruled out after the initial evaluation (e.g., nodular appearance of the liver). Our recommendation is hemodynamic-dependent, regardless of the fibrosis stage. In cases with a HVPG below 5 mmHg, there is no contraindication to perform an isolated heart transplant, whereas a HVPG >10 mmHg discards it (no combined heart-liver transplantation has been performed so far in our hospital). In patients with a concomitant primary liver disease and a HVPG between 6 and 10 mmHg, the decision is patient-specific and relies mainly on the type of disease. If it is treatable (e.g., hepatitis C or B), we recommend proceeding with the heart transplant. Same recommendation is given in the absence of a primary liver disease and a HVPG between 6 and 10 mmHg. Abbreviations: CT: Computed tomography; MRI: Magnetic resonance imaging; HVPG: Hepatic venous pressure gradient.
The diagnosis of ACLI cannot be rejected because of the absence of shock and of signs of HF, and in case of uncertainty, a cardiac evaluation is warranted.
CH is frequently observed in patients suffering ACLI since it predisposes the liver to hypoxic damage.
Diagnosis of ACLI can be suspected based on the following analytical alterations: ALT-to-LDH ratio <1.5, AST higher than ALT at initial phase, and an early and sharp deterioration in prothrombin activity and renal function.
The current spectrum of CH differs from earlier reports with HF due to ischemic cardiomyopathy and congenital heart disease having surpassed rheumatic valvular disease.
Contrary to primary liver diseases, inflammation seems to play no role in the progression of liver fibrosis in CH.
The clinical picture of CH is usually masked by symptoms and signs related to right-sided HF.
There are some ascites findings that help differentiate cardiac ascites from cirrhotic ascites: higher protein (>2.5 g/dL) and LDH levels, and higher red blood cell counts. Serum BNP also seems to be a useful tool in this regard.
The diagnosis of cardiac cirrhosis warrants further evaluations such as bi-annual surveillance ultrasonography or endoscopic screening for esophageal varices.
CH may lead to the generation of benign regenerative nodules and hepatocarcinoma. Distinguishing one from the other frequently requires a liver biopsy due to the abnormal background liver parenchyma.
In contrast to most primary liver diseases where bridging fibrosis occurs between portal triads, in CH it typically extends between central veins to produce a “reversed lobulation” pattern.
The distribution of fibrosis throughout the liver is extremely heterogeneous in CH leading to sampling error. Moreover, fibrosis stage determined by liver biopsies does not seem to predict post-heart transplant outcomes.
The performance of non-invasive diagnostic tests of liver fibrosis in CH is poor.
HVPG measurement might be a useful tool for assessing the stage of CH and helps in the decision-making process of transplant candidacy. However, no evidence in this regard has been published so far.
In both ACLI and CH, the prognosis is dependent on the underlying condition, and treatment is focused on the latter.
The authors declare no conflict of interest.
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