Surgery of pulmonary tuberculosis.
\r\n\tThis book aims to highlight the novel and innovative techniques for designing and fabricating 3D scaffolds, their physical, chemical, and mechanical properties, the role of scaffolds on cellular behavior such as proliferation, migration, differentiation, and alignment of cells in vitro and in vivo tissue development, targeted delivery and sustain release of drugs and bioactive compounds, and development of acellular tissue substitutes.
\r\n\tThe scope of this book will include, but will not be limited to, following topics:
\r\n\t- Fabrication and characterisation of 3D scaffolds
\r\n\t- Incorporation of bioactive compounds on materials for biofunctionalisation
\r\n\t- Cellular behaviours on functionalized biomaterials
\r\n\t- Development of tissue substitutes
\r\n\t- Drug delivery system for targeted delivery and sustain release
\r\n\t- Acellular tissue substitutes for tissue engineering and regenerative medicine
In the past, the assessment of surgical education started with the difficult acquisition of knowledge, reading through a total of six anatomy volumes published by Testut and Jacob and Testut and Latarjet. Besides, an unlimited number and type of general surgical procedures had to be carried out. Currently, surgical practice is mainly obtained through experimental models. These methods of teaching and learning surgical skills have shown that “if students outlive” the anatomical and functional steps, they will gain a greater understanding of anatomy and physiology. Nonetheless, surgeons must get a specific surgical specialty. In the future, surgeons will become subspecialists with genetic and robotic multitraining. However, it must be said that this issue may contain sensible medical ethical dilemmas, although this discipline derived from philosophy has grown in a very important way and surely will continue growing every day, mainly because of the positive impact of technological development on human well-being.
Regarding surgery, in the past, surgeons without any surgical specialty were capable of performing incisions in all cavities; they could correctly perform surgeries in the central nervous system, resolve cardiopathies, and dissect the abdomen. Currently, for instance in chest surgery, there are many subspecialties such as video-assisted surgery or interventional bronchoscopy performing surgeries such as pleural decortication, pulmonary resection, oncologic surgery, endocavitary aspiration, and transbronchial punctures for therapeutic, diagnostic or palliative purposes, and lately long-distance surgery and robotic surgery. The large number of subspecialties that have currently been added to pneumology, such as thoracic oncology, pulmonary pathophysiology, and intensive care of sleeping disorders, is worth noting. In addition to technological changes, in the future, thoracic surgeons will have to have knowledge/comprehend and support genomic medicine, molecular biology, epigenetics, computer networks, telecommunications, bioelectronics, artificial intelligence, communication and psychomedical techniques of treatment, geriatrics, preventive medicine, administration and health economics as well as ethics. Currently, thoracic surgery in the future will be practiced by groups of subspecialists that will need to be competent to select/have to choose from millions of data published daily in order to obtain and classify information.
“Writing about general chest surgery practiced since 50 years ago to date, and its future trends is to describe the medical-surgical fight against two important diseases: in the past, against pulmonary tuberculosis, and currently, against lung cancer. In the future, the challenge will be to unify video-assisted approach and robotics along with research and study of new drugs against these two diseases” [1].
Pulmonary tuberculosis or “the great white plague” was a serious public health problem worldwide since time immemorial, as confirmed by the forensic analysis of human remains showing signs of tuberculosis.
If we remember and think about Thomas Mann’s classic book “The Magic Mountain,” which began to be written in 1912 and was finished in 1924 and which describes the hospitals that existed in the mountains of Switzerland, we may recognize that in those times it was suggested that the air that could be breathed at those heights was a good treatment for the white plague. The hospital most talked about is the Walls Sanatorium in Davos, where lung collapse measures were used to treat tuberculosis patients. Nowadays, some of those homes once inhabited by patients with Koch bacillus, became fashion great luxury hotels.
The National Institute of Respiratory Diseases in Mexico (NIRDM) was inaugurated in 1936 as the Huipulco Tuberculosis Sanatorium (Figure 1), a place where most patients suffered from pulmonary tuberculosis. The sanatorium was architecturally designed in such a way that the rooms for patients had only three and a half walls to allow the free cycling of fresh air. NIRDM was built approximately 15 km away from the urban area, on green fields full of trees with temperatures ranging between 5 and 11°C [2].
Huipulco tuberculosis sanatorium, Mexico City, 1936.
Over the years, overpopulation and the consequent urban growth have caused environmental changes along with different ways of thinking about the treatment of some diseases, including tuberculosis. Because tuberculosis has been earmarked with lower income, less financial resources are allotted to its treatment while much more money is allocated to chronic-degenerative diseases.
In the past, young students´ restlessness and an unreal desire to dress in the surgeon’s uniform made the work even harder. The process was relatively slow since during the period as a medical student and specifically during the first 2 years, two tremendous subjects had to be studied exhaustively: the first one was descriptive anatomy. This task implied using “The Treatise on Descriptive Human Anatomy” by Testud and Jacob as a bedside book. The second subject was topographic anatomy based on “The Compendium of Topographic Anatomy” by Testut and Latarjet, a textbook that described human anatomy by regions.
Currently, much functional knowledge of the human body is mainly obtained in a practical way, either through experimental models or with dummies that had shown that “if students outlive” the anatomical and functional study steps, they will indisputably gain a greater understanding of anatomy and physiology knowledge.
When a medical student studies, learns clinical subjects such as pneumology, gastroenterology, or cardiology among other subjects, he or she does it closely to his or her tutor. The semiological study of the patient is performed on the analysis of the patient’s symptoms, that is, if the patient presents clinical signs such as dyspnea or cough, lung anatomy will be remembered, as well as the physiology of the lower airways regarding ventilation, perfusion, and diffusion; the surgical coil will especially be thought about when procuring the patient’s benefit. I think that in the future, all surgical/medical decisions will have to be taken by a group of experts, and a biologist-immunologist must be considered as one of them.
As for surgery, in the past, it was said that “the great surgeons made large incisions.” Furthermore, these great surgeons surgically intervened all the organs of the different cavities of the human body, and, as I experienced while I was a medical student, I saw the same surgeon from The General Hospital of Mexico practicing surgeries very dexterously in the central nervous system, or to alleviate heart diseases as well as the most frequent procedures practiced in the abdomen, such as colicystectomies and intestinal resections.
When I was in the fourth year of my Bachelor’s studies in medicine, I started studying the respiratory apparatus. It was the time when several types of thoracoplasty and some pulmonary resections were performed. After entering the surgery and seeing the surgical technique of thoracoplasty and the type of anesthesia used, I was impressed by the incision at the skin level, by the muscular separation, the entrance to the pleural cavity, and the desperiostization of the first, second and third ribs. So I decided to learn the surgical method and the postoperative management of this irreversible pulmonary collapse. Likewise, observing pulmonary resection was surprising too, due to the dissection of the pulmonary hilum and by the different techniques used to close the lobular bronchus or the lung.
In Mexico, Koch’s bacillus caused severe damage to the population, and around 1890s, health authorities and the distinguished physician Eduardo Liceaga started an organization to fight against the infection by Mycobacterium tuberculosis. Among their actions, they initiated a medical service called Observation and Treatment of Tuberculosis.
In 1905, The General Hospital of Mexico was inaugurated. There, two pavilions were assigned for tuberculosis patients only, and after the Mexican Revolution (1910), this pathology incidence increased because of the poverty increment after the armed conflict [1].
In those years, no specific treatment against M. tuberculosis was available and its therapeutic management was based on herbal medicine without any etiological basis, even though the causal agent of this millennial suffering had been discovered since 1882 by the German doctor Roberto Koch.
In those previous years, “pulmonary resections” were performed by placing the pulmonary hilum, either lobar or the whole lung, in a tourniquet, and a dissection was performed. True cunning was required in order to apply a tourniquet to the entire pulmonary hilum to perform the pneumonectomy. This surgery caused significant bleeding and bronchopleural fistulas with 25–30% of mortality rate. Indisputably, in order to practice a pneumonectomy, the surgeon must dissect the veins, artery, and bronchus either from the segment, the lobe, or the lung. Doctor Overholt, who intervened his patients in a face-down position on an operation table specially designed by him, insisted in the dissection of the pulmonary hilum. Leo Eloesser also supported this surgical procedure.
In 1882, the same year in which Robert Koch (Figure 2) discovered the causal agent of pulmonary tuberculosis, Carlo Forlanini devised intrapleural pneumothorax [3]. Since Koch’s postulates have been valid for 135 years, it is worth remembering them:
The bacterial pathogen is isolated from sick animals and never from healthy animals.
Bacteria can be isolated, cultivated, and purified from sick animals.
If bacteria are inoculated into a healthy susceptible host, illness would occur.
Robert Koch.
In 1954, Dr. Miguel Jiménez Sánchez registered a book describing the doctrine of respiratory trauma very well. His intention was to prevent it and give rise to the collapse therapy. It is worth describing this concept in the words of Dr. Jiménez:
“By the action of the inspiratory muscles, the lung tissue is subjected to a centrifugal distension that increases during inspiration, but does not disappear in the expiratory phase, since, during this phase, it occupies a space much bigger than the corresponding to its true complete rest position, which is the total collapse of the viscera, in which its retraction force is annulled, a circumstance that does not occur “in vivo” due to the existence of the pleural attraction that keeps the lung in a state of constant distension in the vicinity of the costal wall. In other words, the lung during expiration (physiological rest) is in a state of centrifugal hyperdistention that increases during each inspiration by the mechanisms already indicated.”
Also in the words of Dr. Jimenez: “The lung has a very delicate anatomical constitution and is formed of a tissue that is essentially elastic, uniform and eccentrically dilatable in the course of inspiration. It can be considered as a small elastic balloon that cannot dilate or retract as long as the inspiration does not allow the entrance of the air and the exhalation its exit. The alveolus is subjected to two opposing forces; on the one hand, the inspiratory muscles tend to dilate it, and on the other, the narrowing of the airways, by delaying the arrival of the air, oppose this dilatation. It is notable that a tissue as weak as that of the alveolus, due exclusively to its elastic expansion potential, can dampen the action of two opposing forces; and if its very delicate wall is not injured, it is that its dilatability is superior to the inspiratory dilation of the thorax” [4] (Figure 3).
Right pneumothorax X-ray image.
These concepts described by Dr. Forlanini and established by Dr. Jimenez led to the idea that normal function became abnormal because of lung disease.
It must be mentioned that inflammatory factors generated by pulmonary infection develop pleuritis, since the pleural leaves are adhered, and because their function to impede lung collapse gets compromised, Dr. Forlanini implemented a surgical technique called “section of adhesions,” to section them and avoid the lung’s collapse. When this procedure was executed, the urethroscope was used because there was no other equipment (as, for instance, a pleuroscope) available to section the parieto-visceral adhesions.
With Dr. Forlanini’s idea of causing pulmonary immobility, several physicians who treated pulmonary tuberculosis performed irreversible pulmonary collapse using different surgical techniques that comprised resection of the ribs in order to “letting the lung fall”, that is, inducing pulmonary collapse and, consequently, improving mainly cavitary lesions.
Breathing is carried out through inspiration and expiration in a number of 12–18 breaths per minute in diseased lungs, and this gave Dr. Carlo Forlanini the notion of the respiratory trauma concept. He explained that in lungs infected with M. tuberculosis, the inspiration and expiration “beat” the lung parenchyma, therefore increasing the pulmonary injury, and his idea was to avoid the respiratory trauma through the intrapleural pneumothorax as far as possible.
The discovery of M. tuberculosis coincides with the concept that respiratory trauma caused the persistence of the pathology. Dr. Carlo Forlanini claimed that inspiration and exhalation hit the lung fundamentally on the thoracic area that he called “dominant lines” which he described in the diaphragm and in the pulmonary hilum areas, and he concluded that an injured lung suffered from respiratory trauma while the movement of inspiration and expiration did not affect the parenchyma of healthy lungs. Based on this idea, it was concluded that a measure for the treatment of pulmonary tuberculosis was to keep the patient at rest since it was a patient with respiratory trauma. To achieve this goal, different methods were conceived.
Subsequently, in Naples, Italy, Dr. Monaldi pursued the endocavitary aspiration to eliminate caseum from the tuberculous cavern, because the greatest amount of bacilli concentrates in that area [5].
Another surgical procedure practiced to avoid respiratory trauma was the phrenicectomy, although it caused respiratory insufficiency, paralysis of the hemidiaphragm, and therefore serious pulmonary ventilation problems.
In 1952, Waksman was awarded the Nobel Prize for his research in streptomycin discovery, a drug that fortunately led to a significant reduction in surgical measures for the treatment of pulmonary tuberculosis.
There are different procedure types of thoracoplasty as follows:
Total thoracoplasty.
Subtotal thoracoplasty.
Upper partial thoracoplasty.
Partial inferior thoracoplasty.
The widened thoracoplasty.
Iterative thoracoplasties.
Thoraco-apicolysis.
Frequently, pulmonary tuberculosis caused infection in the pleural cavity or empyema tuberculosis. In most cases, this pathological situation required draining of pleural pus through a water seal connected to suction. Furthermore, the pleura responded to the M. tuberculosis invasion with inflammation and thickening of both visceral and parietal leaves of the pleura; the lung remained “imprisoned” by the pleural response. Simultaneously, “pulmonary incarceration” caused ventilation disorders, and it was necessary to practice surgery and resect the “pleural shell,” removing the tuberculosis pleura and improving ventilatory mechanics.
In 1935, Dr. Leo Eloesser devised a surgical technique called Eloesser’s Window to drain the tuberculous empyema by opening the pleural cavity. This “window” was a 2 × 3 cm2 cut into the costal wall and thus allowing the cleaning of the cavity to perform the pulmonary decortication (Figure 4).
Eloesser’s window technique for pleural drainage.
Extrapleural pneumolysis. To collapse the pulmonary apex, extrapleural pneumolysis was devised. It consists of lowering the “tip of the lung” via the extrapleural route to allow collapsing of the cavernous lesions of the upper pulmonary segments. One of the problems with this technique was to support the collapse of the vertex because the application of air was difficult due to the presence of fibrous tissue. This led to the inclusion of different materials as, for instance, lucite balls (similar to ping pong balls) into the extrapleural space to maintain the pulmonary collapse and facilitate the application of air into the extrapleural space.
Around 1933, Dr. Banyai, while trying to perform an intrapleural pneumothorax in a tuberculous patient, introduced air into the peritoneal cavity, causing a pneumoperitoneum (Figure 5) that enhanced the evolution of tuberculosis lesions in the inferior lung lobes. This gave rise to the fact that in certain topographic situations of the tuberculous lesions, the pneumoperitoneum will be used.
Pneumoperitoneum X-ray image.
All surgical interventions, intrapleural pneumothorax, extrapleural pneumothorax (difficult to maintain), plumbing (Figure 6), lucite balls (Figure 7), phrenicectomy, pneumoperitoneum, and all types of thoracoplasty mentioned earlier are practiced to keep the lung at rest to avoid respiratory trauma.
Plumbing X-ray image.
Lucite balls X-ray image.
Although nowadays, efficient primary and secondary drugs for tuberculosis treatment exist, the lack of education and low-economic income have contributed to bacillary resistance, and occasionally thoracic surgery must be practiced to maintain the lung at rest.
Undoubtedly, as it has been stated by well-known tisiology specialists “tuberculosis has been an excellent teacher and an important teaching and learning factor in the management and treatment of different diseases of the chest.”
On the other hand, thoracoplasties consist of removing the posterior and lateral edges of the ribs, which are the parietal pleural support. This excision induced the lung collapse, and the surgical techniques are shown in Table 1 [6].
1. Intrapleural pneumothorax | |
1882 | Forlanini |
1898 | Murphy |
1908 | Saugman |
1909 | Brauer |
1912 | Jacobeus |
2. Phrenic nerve palsy | |
1911 | Stüertz |
1913 | Sauerbruch |
1920 | Felix/Goetze |
3. Thoracoplasty | |
1907 | Friedrich |
1911 | Wilms |
1913 | Sauerbruch |
1922 | Brauer |
1925 | Alexander |
1935 | Semb |
1954 | Björk |
4. Extrapleural pneumolysis | |
1891 | Tuffer |
1913 | Baer |
1936 | Graff |
5. Pneumoperitoneum | |
1933 | Banyai |
Klopstoc | |
Vajda | |
1938 | Bennet |
Surgery of pulmonary tuberculosis.
Plumbing, a technique that consisted of the application of oil to provoke lung collapse and diminish the respiratory trauma, lowers the apex of the lung, and the introduction of lucite balls into the pleural cavity was also used to avoid respiratory trauma. These methods occasionally caused erosions of the bronchi; even though oil could be expulsed through air expulsion, the lucite balls had to be surgically removed.
Thoracoplasty was another surgical method used to reduce respiratory trauma. It consists of the resection of the first five ribs in two surgical times, from the vertebral joint to the sternum costal joint. All patients submitted to thoracoplasty had paradoxical breathing due to the lack of support offered by the ribs, to the development of pleural adhesion, and to consequent negative pressure. These disturbances on the pulmonary ventilation “mediastinal swing and loss of costal support” invited the surgeon to practice a different type of thoracoplasty, that is, performing a partial resection of the ribs. This type of surgery, called chondroflexion, decreased the hemithorax space and no paradoxical breathing was produced (Figure 8).
Right thoracoplasty X-ray image.
In some patients, a post-thoracoplasty resection was prescribed in order to remove excavated lesions through lobar or segmental resection.
In addition to thoracoplasties, to keep the lung at rest, the phrenic nerve was sectioned with the purpose of paralyzing the corresponding hemidiaphragm and avoid trauma in the inferior dominant line. This surgery was performed for many years but unfortunately caused respiratory insufficiency because of diaphragmatic immobility and infections that were consequence of poor secretion management. In the long term, hemodynamic disorders such as pulmonary artery hypertension developed (Figure 9).
Left thoracoplasty X-ray image.
In Mexico City, the first lung resection was performed by Leo Eloesser at the Huipulco Tuberculosis Sanatorium (NIRD), and he was assisted by William B. Neff, who took care of the general anesthesia (Figure 10).
From right to left: Ismael Cosio Villegas, Leo Eloesser, William B. Neff, and Donato Alarcón at the National Institute of respiratory diseases (NIRD), Mexico City.
In the 1950s, staplers were developed in the Soviet Union to perform resections of pulmonary pathology in “wedge,” that is, without dissecting the corresponding hilum. This surgical method was used in the Soviet Union mainly due to the serious problem of pulmonary tuberculosis that they faced in addition to the lack of pleuropulmonary surgeons. Over time, these staplers were used less frequently to perform wedge resection but more often mainly to perform pulmonary resections stapling the bronchus only, to try to solve bronchial fistulas (Figure 11).
Russian stapler.
Pulmonary tuberculosis repeatedly causes pleural effusion due to infected pulmonary peripheral nodules. This situation causes tuberculous empyema and bronchopleural fistula. These patients with tuberculous empyema were handled by Dr. Leo Eloesser through a drainage of the pleural cavity to the outside, communicating the pleural cavity by means of a 2- or 3-cm opening to the outside. This technique facilitated the daily cleaning and healing of the pleural cavity, and due to the symphysis of the pleural leafs, there was no total pulmonary collapse. This surgical technique, called Eloesser, was generally followed by decortication of the pleural cavity and closure, if any, of the air leakage of the lung parenchyma. In the past, Eloesser’s surgery in addition to antituberculosis drugs provided good results, and currently Eloesser’s method continues to be performed from time to time (Figures 12 and 13).
Pleural effusion X-ray image.
Drainage of the pleural cavity by communicating the pleural cavity to the outside through an incision.
The discovery of streptomycin by Waskman in 1943 was worth the Nobel Prize for Medicine and caused the surgical measures for the treatment of pulmonary tuberculosis to decrease significantly. Streptomycin sulfate is an aminoglycoside that has activity against aerobic gram-negative bacteria such as the tuberculosis bacillus. Streptomycin penetrates the cell membrane of bacteria, fixes to the ribosome, and therefore does not stop the initiation of protein synthesis in bacteria. Unfortunately, in some cases, it causes renal failure and deafness, and patients receiving this antibiotic must be closely monitored.
Tuberculosis patient’s expectoration also affected the trachea producing ulcers and sometimes retraction by proliferation of connective tissue and stenosis. This, at least a 50-year-old problem, was a very serious complication without antituberculosis drugs, since morbidity and mortality rates and low-economic income contributed to the failure of its surgical treatment. Dr. Hermes Grillo started tracheal surgery and devised different surgical techniques with good results. A very important contribution for the study of the trachea was made by Dr. Chevalier Jackson (1865–1958) who is considered the father of bronchoscopy and laryngoscopy; he designed rigid bronchoscopes and used them for diagnosis and bronchodilation (Figure 14).
Tracheal surgery.
Isoniazid was discovered in 1945; this drug inhibits the synthesis of mycolic acid on the wall of the bacteria. On the other hand, parasinosalicylic acid (PAS) is a bacteriostatic of the tuberculous bacillus, which is very useful in inhibiting or retarding bacterial resistance to streptomycin and isoniazid. With isoniazid, streptomycin, PAS, and ethambutol (1961), thoracic surgery decreased due to diminished indications in pulmonary tuberculosis therapies and new drug treatments.
It is impossible to explain and describe the surgical techniques of the past without mentioning some words about pulmonary tuberculosis. Pulmonary tuberculosis was the pathological condition that originated the art of its surgical management.
Currently, the prevalence of tuberculosis patients has decreased significantly, whereas diseases such as cancer, pulmonary fibrosis, and asthma have increased in a high percentage. In the future, chronic-degenerative diseases will dominate respiratory pathology, and so in this section, we must indicate and contraindicate methods such as video-assisted and robotic surgeries.
In addition, although drug administration is not a surgical procedure, the synergy of drugs based on studies of molecular biology for the treatment of chronic-degenerative diseases will be very important.
Currently, there are many surgical subspecialties and technological advances, that is, chest surgery procedures such as pleural decortication, pulmonary resection, endocavitary aspiration, and transbronchial punctures are performed in order to obtain lymph node tissue through video-assisted surgery (Tables 2 and 3) [7].
Advantages | Disadvantages |
---|---|
Lesser traumatic interventions | Difficult access in deep lesions |
Better postoperative recovery | Increased possibility of leaving hidden disease |
Faster functional recovery | More postoperative follow-up due to increased chance of hidden disease |
Better immune response | Greater difficulty in the evaluation of surgical margins. |
Quicker reincorporation to full activity | |
Lower economic cost |
Advantages and disadvantages of video-thoracoscopic surgery [7].
Absolute | Relative |
---|---|
Dense pleural symphysis | Significant hilar lymphadenopathy |
Absence of pleural space | Mayor emphysema |
Inability of achieving ipsilateral pulmonary collapse | Nodular lesions less than 1 cm deep |
Inability of tolerating monopulmonary ventilation | Tumor size greater than 5 cm |
Decompensated cardiovascular disease | Chest wall involvement |
Thrombocytopenia of less than 60,000 or INR greater than 20 | Serious deformity of the thoracic cage |
Inadequate visualization and instrumentation | Radiotherapy or neoadjuvant chemotherapy |
Contraindications of video-thoracoscopic surgery [7].
As of today, the long-distance surgery along with robotic surgery will be preponderant in the future. The large number of subspecialties currently underway should be noted, that is, surgical oncology, interventional bronchoscopy, or cochlear implants and surgeons must become subspecialists with genetic and robotic multitraining.
The medicine of the future plus multiple technological changes will force a student who chooses a medical degree to rely on genomics, molecular biology, epigenetics, computer networks and telecommunications, bioelectronics, artificial intelligence, communication and psycho-medical sciences, treatment techniques, geriatrics, preventive medicine, administration, and health economics and ethics. Likewise, the health professional will need to be competent in selecting worthy information from millions of data published daily. It is also important to point out that the knowledge obtained will be added to information in the basic subjects, and both will enable the medical student to prevent some diseases like diabetes. All this accumulation of knowledge will mean that the medicine of the future will be practiced by groups of specialists and subspecialists, as it is already being done in some countries; conceivably, individual practice is going to decrease significantly.
The book of the General Health Council entitled “Futures of the formation of human resources for health in Mexico” by Dr. Enrique Ruelas Barajas, Dr. Antonio Alonso Concheiro, and Guadalupe Alarcón Fuentes has been fundamental to integrate this topic. It includes references from complementary medicine (herbal and acupuncture), which, in some European countries, is already part of the medical profession. Some groups of professionals even include specialists in administration and health economics [8].
Finally, some sensible words about medical ethics must be mentioned: this discipline derived from philosophy has grown in a very important way and is surely going to increase every day, mainly because of the positive complexity of technological development.
In accordance with Louie et al., which report an early experience with robotic lung resection, it resulted in similar outcomes when compared with mature video-assisted thoracoscopic surgery (VATS) cases. However, a potential benefit of robotics may relate to postoperative pain reduction (p = 0.039), and early return to usual activities (p = 0.001) was shorter in the robotic group [9].
The Spanish Royal Academy defines a robot as a programmable electronic machine with the capacity to manipulate objects and carry out operations that only the human being is capable of doing. In this regard, it is also known that the word robot derives from the word robota, which in Czechoslovakia designates “compulsive work.” These words appeared in the play Rossum’s Universal Robots written in 1921 by Karem Kapeq, a story about the sudden inability for humans to reproduce and a war between robots and humans [10]. On the other hand, the American Institute of Robotics expresses the following idea of a robot: a machine of human form that performs the tasks of a human being, but without sensitivity. Meanwhile, the University of Nebraska in the United States was one of the earliest institutions to employ distance-assistance methods in the 1950s. It was until 1986 that the first satellite program was launched by the Mayo Clinic in Rochester, Minnesota, and the Scottsdale Clinic in Arizona. These facts gave rise to the era of telemedicine that would later establish the foundation of remote surgery.
The concept of robotic surgery with telepresence was born by the effort and collaboration of the Research Institute of Stanford University, NASA, and the United States Department of Defense to treat wounded soldiers. This technology was initially assigned to the neurosurgeons, and in 1985 the first surgical procedure with a robot was performed with the Mitsubishi system to obtain a brain biopsy through stereotaxy.
In 1988, the PROBOT system was created in England to aid in a transurethral prostatic resection. It consisted of the elaboration of a three-dimensional model of the prostate where the surgeon delineated the limits of the resection and the robot calculated the trajectories of the incisions. In 1992, IBM produced a robot called ROBODOC for orthopedic interventions; the number of surgeries performed by this method increased with hip replacement surgery.
In Mexico City in 1996, two cholecystectomies were operated from a distance of 10 m by a robotic arm with 6° of pronosupination.
In November 2001, a robotic arm was used to assist in a hysterectomy [11].
In 1997, Dr. Garcia Ruiz of Mexico and Dr. Falcone of the Cleveland Clinic performed the first remote robotic surgery that consisted of a tubal reanastomosis. This performance demonstrated the feasibility of making endoscopic sutures, which surgeons said were faster and more accurate. In 1996, at the Mexican Institute of Social Security of Tijuana, doctors Carvajal and Fogel performed a laparoscopic cholecystectomy in porcine models.
In 2001, the Zeus project (a system of robotic instruments) performed hiatus and gall-bladder operations [12].
Unfortunately, the cost of a robot, which is around one million dollars, increases the costs of surgeries. For example, the costs of the Da Vinci system are higher than of a laparoscopy, and some doctors refer to the robot as “expensive toy.”
Hopefully, robot systems will be smaller in the future and, therefore, cheaper.
Swanson et al. [13] compared hospital cost and clinical outcomes for lobectomies by video-assisted thoracic surgery (VATS) and wedge resections versus robot-assisted (RATS) lobectomies. Data from 15,502 surgeries were analyzed. The average cost of inpatient procedures with RATS was $25,040.70 US Dls versus $20476.60 for VATS (p = 0.0001) for lobectomies and $19,592.40 versus $16,600.10 (p = 0.0001) for wedge resections. Inpatient operating times were longer for RATS lobectomy than for VATS lobectomy (4.49 vs. 4.23 h; p = 0.959) and wedge resection (3.26 vs. 2.86 h; p = 0.003). The length of stay was similar with no differences in adverse events. They concluded that RATS lobectomy and wedge resection seem to have higher hospital cost and longer operating times, without any differences in adverse events.
Resection with robot seems to be an appropriate alternative for VATS and with better results than with an open surgery [14].
“Robotic lobectomy for cancer offers excellent results, with excellent lymph node removal with minimal morbidity, mortality and pain. Despite its costs, it is cost-effective for the hospital system. Disadvantages include capital costs, equipment learning curve, and lack of lung palpation. Robotic surgery is an important tool in the arsenal for the thoracic surgeon, but its precise function continues to evolve” [15].
General thorax surgery was a series of maneuvers especially indicated in pulmonary tuberculosis, so it is not possible to describe a technique without describing the pathology indicated. This treatment was carried out, as has been mentioned before, in the past, because today the drug treatment is very useful in tuberculosis.
Currently, lung cancer, which is the main cause of hospitalization and the invasive methods that apply to this disease, has advanced very importantly as video-assisted surgery and surgery performed with a robot.
Histopathological diagnoses vary in lung cancer. These techniques are being applied for diagnosis, and therefore the treatment is modified. Immunohistochemical techniques help improve and personalize the patient’s treatment. For these histological studies, a sample can be taken by video-assisted surgery, and in some pulmonary resections surgery with a robot is practiced. Biopsies taken by VATS are possible in the topographic areas of the thorax, and with robotic surgery it is possible to perform pulmonary excision and, if necessary, pneumonectomy. There is no doubt that with VATS and RATS (robotic surgery), the advance has been of great importance because the incisions are small, and the days of hospital stay also and the costs in the VATS have decreased, but unfortunately this has not been so in the RATS. Undoubtedly, this type of treatment in general chest surgery will change radically because of the important advance that the technology has had. It is currently possible to detect pathology that in previous years was not feasible to diagnose. The latest publications on these topics of surgery describe them favorably and the results on VATS and RATS also; new generations of human resources must be very attentive to technological changes and should be mentally prepared to learn and perform this type of surgery. However, a very important doctors´ complaint is the impossibility of palpating some of the pathologies. There is no doubt that this situation will be solved “with a new technology” that tells us the organs´ consistency or about hidden ganglia.
According to different opinions from 2020 to 2030, there will be several disciplines that currently do not exist in the curriculum of students due to scientific and technological advances [8].
As I mentioned in the previous lines, surgery and armed interventions have been practiced more in pulmonary tuberculosis in the past and currently in lung cancer and chronic-degenerative conditions.
There is no doubt that knowledge, technology, and the spirit of research have achieved this progress in addition to the progress in basic matters such as molecular biology, epigenetics, immunology, and so on. In brief, there will be further great progress. Many physical examinations can be achieved in lung cancer patients using the mediastinoscope and fibrobronchoscopes. Fortunately, different types of antibodies that are tested for diagnostic purpose have been found and will, surely, have very positive effects.
An example I find very illustrating can be found on page 241 of the book “The Shock of the Future” by Alvin Toffler. The biochemist Marvin Johnson from the University of Wisconsin wrote: “Recently, microorganisms have been domesticated because human did not know its existence” [16]. Currently, human not just knows them but gets many benefits from them, that is, large-scale production of vitamins, enzymes, antibiotics, citric acid, and other useful compounds. In a few years, biologists will create microorganisms to feed animals and ultimately humans.
The authors are grateful to Miss María de Lourdes Espinosa Cruz for her invaluable dedication and secretarial assistance as well as to Mr. Manuel Silva Alvarado for the elaboration of the drawings.
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).
\nThis 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.
\nThe 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].
\nBy 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].
\nACLI 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].
\nThe 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].
\nThese 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].
\nLiver 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].
\nAs 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.
\nRespiratory 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].
\nSeptic 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].
\nWhile 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].
\nThe 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].
\nLaboratory 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.
\nLaboratory 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].
\n(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].
\nThe 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].
\nLiver 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].
\nCH 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.
\nThis 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.
\nCongestion 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].
\nIt 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].
\nCH 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].
\nPhysical 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].
\nThe 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].
\nBesides 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].
\nElevation 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].
\nImaging 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].
\n(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.
\nIdiopathic 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.
\n | Basic* | \nIn-Depth* | \nInvestigational* | \n
---|---|---|---|
Childhood (every 3–4 years) | \n\n
| \n\n
| \n\n
| \n
Adolescence (every 1–3 years) | \n\n
| \n\n
| \n\n
| \n
Adulthood (every 1–2 years) | \n\n
| \n\n
| \n\n
| \n
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].
\n(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].
\nNon-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].
\nBriefly, 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].
\nHepatic 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].
\nThe 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].
\n(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].
\nManagement 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.
\nGiven 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.
\nProtocol 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.
\n
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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