Splenic Rhythms and Postprandial Dynamics in Physiology, Portal Hypertension, and Functional Hyposplenism: A Review

Before the spleen was recognized as a lymphatic organ with immunological and haematological functions, for thousands of years, it was considered to have a principal role in the digestive system [1]. Today, medical systems such as traditional Chinese medicine [2] and more recent integrative approaches such as anthroposophical medicine [3] postulate concepts of a regulative function of the spleen in nutrition [4, 5]. Integration of these kinds of functional concepts and the therapeutic approaches arising from them only make sense when the anatomical and physiological basis is also researched as an integrative organology. We have recently reviewed the close phylogenetic, embryological, and anatomical connections between the spleen and the stomach with regard to a “splenogastric system,” where direct communicating arteries and veins between the gastric fundus and the upper splenic pole have been rediscovered through modern surgery, thus reopening old questions from medical history about a direct secretory or resorptive function between the spleen and the stomach [6].

The herewith presented article aimed to focus on the dynamic interplay between the spleen and the gut and review the regulative functions of the spleen in relation to the splanchnic circulation in particular. We discuss postprandial haemodynamics and their clinical relevance, illustrated by splenomegaly in portal hypertension, as well as functional hyposplenism using inflammatory bowel diseases and coeliac disease as major examples.

We searched MEDLINE by combining the search terms “spleen,” “splen*,” “hyposplen*,” and “hypersplen*” (in title) with the medical subject headings “Diet, Food, and Nutrition,” “Digestive System and Oral Physiological Phenomena,” and/or “Digestive System Diseases,” as well as by using a combination of the search terms “rhythm,” “dynamic*,” “postprandial,” and “food*.” We selected relevant topics from the results by screening the abstracts and reference lists. We worked through 5 major book publications on the spleen and consulted 15 experts on anatomy, evolutionary biology, physiology, surgery, gastroenterology, and anthroposophical medicine. We organized 2 scientific conferences at Witten/Herdecke University, where we presented and discussed our intermediate results.

The rhythmical basis and the haemodynamics of the spleen in the splanchnic region were studied in the 19th and 20th centuries, particularly in German-speaking countries, and published mostly in the form of monographs. Citations of these articles and their bibliographies were followed up to the present day using Google Scholar and Elsevier Scopus. As far as we are aware, the physiological observations described in these publications are now made available to the English-speaking world for the first time.

Depending on body size and sex, the mean splenic volume is 166 cm³ (5th/95th interpercentile range: 80–324 cm³), with spleen length 10.9 cm (range: 8.7–13.3 cm) showing the strongest correlation to spleen volume [7]. Even the earliest writings of the Corpus Hippocraticum state that the size of the spleen is not static but variable [8]. Spleen volume decreases by up to 40% during sports activities [9]; hypoxia, for example, in apnoeic diving [10]; and other physiological stressors and leads to a corresponding increase in the haematocrit and the oxygen-carrying capacity of the blood [11]. Similarly, the spleen provides a reservoir function for platelets (30% of the body reserve) and lymphocytes (40% of the body reserve). An example of this is the remarkable splenic responses after a stroke. Splenic lymphocytes migrate to the infarct area to be involved in the poststroke inflammatory cascade, causing a drastic reduction in spleen volume [12]. These active, single contractions of the spleen provide a blood reservoir for the systemic circulation. Contractions are anatomically based on contractile proteins in the capsule and trabeculae of the spleen, as well as in the walls of arteries, veins, reticular cells of the white pulp, and sinus-lining cells of the red pulp. They are mediated by alpha-adrenergic fibres in the splenic nerve, which consists 98% of sympathetic nerve fibres and, therefore, can be therapeutically modulated using catecholamines [11, 12].

Active contractions must be distinguished from continuous, autonomous contractions and dilations of the spleen, which form a basic rhythm that was first discovered in animal experiments at the start of the 20th century. These experiments, first made by Roy [13], used surgically attached plethysmographs [14, 15] and graphically documented volume changes of the spleen by means of what are known as “splenograms” (Fig. 1). The regular “systoles and diastoles” of the spleen [13], later also called splenomotoric waves [16], appeared to be independent of other rhythms (pulse, breathing, blood pressure, and Traube-Hering-Mayer waves) and had period lengths of just under a minute [15, 17, 18]. The innervation and possible modulation by substances such as vasoconstrictors and vasodilators [16, 19‒21], and the effects of physical activity, breathing, and physiological and psychological stress on this basic rhythm were studied in detail [19, 22‒24].

In humans, the basic splenic rhythm was confirmed using the diagnostic procedure of splenoportography [25‒27] in which the spleen was laparoscopically punctured and connected to a manometer. In healthy patients, Wannagat [28] observed continuous intrasplenic pressure fluctuations with period lengths of around 45 s. He also noticed that under increasing portal pressure, the elasticity and rhythm of the spleen steadily diminished. In patients with chronic elevated portal hypertension, the rhythmical amplitude of the spleen dwindled to a fixed single-value curve and was accompanied clinically by a large and spongy congested spleen.

In conclusion, 3 causes for volume changes in the spleen need to be distinguished: (a) autonomous contractions and dilations of the spleen corresponding to a basic rhythm, (b) sympathetically mediated single contractions that provide the circulation with pooled blood, and (c) passive, that is, congestive, dilations from the portal vein system. These congestive dilations are related to the pressure and circulatory conditions of the splanchnic blood flow, which leads to the relationship between the spleen and nutritional metabolism.

Beginning in the first half of the 19th century, systematic studies on changes in spleen size after eating a meal were undertaken, prompted by the assumption of mechanical and chemical interactions between the stomach, liver, and spleen [29‒31]. In postmortem examinations of dogs, guinea pigs, rabbits, and cats, enlarged spleens were observed up to several hours after food intake and studied in detail [29, 30, 32‒36]. The anatomist Henry Gray [37], who was able to confirm postprandial spleen enlargement in 30 rabbits in his own dissertation, summarized the available literature in 1858 as follows: “The size of the spleen is increased during and after digestion” [38]. Similar remarks also appeared in physiological textbooks of the time [39].

Following the plethysmographic measurements, Hargis and Mann [40] evaluated the effect of food on variable spleen volume in dogs by means of splenograms. They confirmed a splenic rhythm with a mean contraction and dilation cycle of 47 s and were able to demonstrate for the first time a clear postprandial increase in spleen volume depending on the composition of the meal and lasting for several hours. The splenogram showed a higher amplitude after consuming animal fat (hog lard: peak after 40 min), protein-rich meat (lean beef: peak after 20 min), and, to a lesser degree, carbohydrate (corn syrup: peak after 30 min). Ingesting milk led to a temporary reduction in spleen volume.

In order to explain these postprandial volume dynamics, studies were conducted on the relation of the spleen to the haemodynamics of the splanchnic circulation. The splanchnic circulation comprises the arterial and venous blood flow in the digestive system and displays interdependencies among peristalsis, the portal venous system, the liver, and the spleen [41, 42]. If blood flow and pressure in the elastic mesenteric and portal vessels increase, the splenic artery reacts with vasoconstriction, leading to a reduced arterial blood supply [43, 44]. Conversely, a decrease in the portal pressure leads to an opening of the arterial branch of the spleen. This “venovasomotor reflex” (Fig. 2) allows for a subtle balance between the portal pressure and the arterial blood flow in the spleen. A constant portal blood flow, particularly in the liver, can thus be guaranteed. Conversely, with increased portal pressure, the portal circulation can be relieved by reducing the splenic arterial flow. The spleen was, therefore, justifiably viewed as an important “regulatory factor in the portal system” [45].

After eating a meal, the splanchnic blood flow increases markedly by up to 200%, depending on the quantity and composition of the food [46]. This postprandial hyperaemia leads to a sequential increase in blood flow in the mesenteric vessels and in the portal system, with a peak around 30 min after food intake [46, 47]. Following the venovasomotor reflex, the spleen initially responds with a reduction in its arterial supply and an amplified and slower rhythm [41, 42].

If the increasing postprandial hyperaemia and dilatation of the portal vessels reach a critical point where the spleen cannot withstand the increased portal pressure, it swells from the venous side and suspends its rhythmicity [41, 45]. In this second response, the spleen functions like an upstream “pressure reservoir” [41] which protects the liver and portal system from excessive overflow. This temporary venous congestion of the spleen continues until the hyperaemia has subsided. A wide range of 20th-century authors have described this function of a “hepatolienal pendulum” [14] and, therefore, termed the spleen an “auxiliary motor” [48], a “pump” [42, 45], a “Windkessel function” [14], or, in analogy to the systemic circulation, an “elastic heart in the portal vein system” [49].

We suggest that the postprandial enlargement of the spleen should be interpreted primarily as a portal pressure compensation and not a temporary reversal of the portal flow to the spleen, as some authors have postulated [42, 48]. This difference seems important, as the portal blood does not flow towards the spleen but congests back due to the increased portal pressure.

Steiner and Kolisko postulated that the rhythmical function of the spleen with a compensative enlargement of the organ is primarily called upon for irregular food intake, that is, after meals at irregular times [50, 51]. Regular and timed meals lead to an anticipation of gastrointestinal motility, secretion, and increased activity of digestive enzymes [52, 53]. It is quite conceivable that with untimed meals, the liver and portal system have greater demands placed on them and the spleen has to increase its balancing activity. This idea is put to use in the integrative concept of anthroposophical medicine [3], where regular low-fat and low-meat food with smaller snacks are recommended in order to decrease the demands on the spleen [4]. Further studies are required to evaluate the effect of regular and irregular food intake on the functioning of the spleen.

In the era of modern imaging techniques, there are 3 studies which have investigated volume changes in the spleen after food intake. Using single-photon emission computed tomography, Roshdy et al. [54] were able to detect a minimal but statistically significant decrease in spleen volume, averaging 3.2% in 20 healthy volunteers, 30–45 min postprandially (1,600 kJ). Betal et al. [55] came to a similar result in their measurements on 10 healthy test subjects using magnetic resonance tomography; 30–45 min after eating (2,460 kJ), they observed an average decrease in spleen volume of 6.6% [55]. The authors interpreted their results in terms of the venovasomotoric reaction with a reduction in arterial blood flow.

In our crossover study, 10 healthy test subjects were either randomly given a substantial meal (3,600 kJ) or kept fasting. Spleen volume was systematically followed using sonographic video measurements at 5 measurement points over 7 h. Splenic volume increased significantly by 38.2 ± 51.2 cm³ (17.3%; p = 0.04), with a peak 30 min after food intake. In males, splenic volume 30 min after a meal was 70.2 ± 21.6 cm³ higher (p = 0.002) than that after the fasting condition, and 60 min later, it was still significantly increased. We interpreted these findings as postprandial congestion, where the spleen balances the increased portal hyperaemia through a temporary enlargement [56].

The recently available non-invasive technique of elastography allows the elastic properties and stiffness of the liver and spleen to be determined using ultrasound or magnetic resonance combined with a vibration module [57]. A postprandial increase in liver and spleen stiffness is well documented in patients with chronic liver disease and portal hypertension [58‒60]. The increase in stiffness after food intake correlates with the stage of liver fibrosis and the increased portal flow (peak 30 min after food intake) [61]. Interestingly, a postprandial increase in liver stiffness [57, 62, 63] and spleen stiffness [63] was also shown in healthy controls and in patients with only minor or no signs of liver fibrosis.

In summary, we suggest differentiating between 2 postprandial spleen reactions: in the case of a slight hyperaemia in the portal system, the spleen reacts with reduced arterial blood flow, enhanced rhythm, and a slight decrease in volume and stiffness. With a greater hyperaemia, such as after ingestion of a heavy meal, the increasing portal pressure leads to an increased stiffness of the spleen with a temporary loss of its rhythm and enlargement of the organ – this condition becomes chronic in the case of portal hypertension.

Clinically, portal hypertension occurs when the pressure in the portal vein system exceeds the standard values (1–5 mm Hg) based on increased intrahepatic vascular resistance [64]. The most common causes worldwide are liver cirrhosis and schistosomiasis. Increasing complications arise with a portal pressure >10 mm Hg. Associated risks are the formation of portosystemic collaterals that can lead to oesophageal and gastric varices with a high risk of bleeding and mortality [65].

The spleen plays an important part in the diagnosis and risk appraisal of portal hypertension. Elastographic studies of spleen stiffness and combined scores of spleen diameter, liver stiffness, and platelet count are considered to be a simple, non-invasive, and cost-effective alternative to oesophagogastroduodenoscopy and can assess the presence of oesophageal varices with high sensitivity and specificity [66‒68]. Spleen stiffness also seems to be a significant and helpful parameter in the follow-up of patients with chronic hepatitis C or hepatocellular carcinoma [69, 70]. Evaluation of basal rhythmical splenic contractions and dilatation could add to a sensitive instrument to record early changes in the splanchnic circulation and evaluate possible effects of medication. New and innovative approaches for a non-invasive modern splenogram are required and could be used in screening, diagnosis, and follow-up procedures.

The consequences of portal hypertension for the spleen appear in several stages. First, the spleen reacts according to the pressure compensation with splenomegaly, that is, a large, spongy congested spleen with loss of its rhythmical function in nutrition, increased volume, and increased tissue stiffness. Due to the prolonged congestion, further structural alterations occur with hypertrophy of the elastic contractile elements, thickening of the spleen capsule and trabecula, and an increase in the white pulp resulting from an immunological reaction with reticuloendothelial hyperplasia [71, 72]. Enlargement of the venous sinusoids leads to increased blood pooling and greater sequestration of platelets, erythrocytes, and leucocytes, producing a drop in all 3 cell populations in the peripheral blood count [72]. The formation of portosystemic collaterals appears to be helpful in relieving the portal vein system. However, the subsequent reduced splanchnic circulation leads to reactive splanchnic and systemic vasodilation [73, 74]. Portal pressure and splenomegaly are then no longer based solely on congestion and increased intrahepatic resistance (backward theory) but maintained by a generally increased arterial supply (forward theory). In the final stage of this condition known as “hyperdynamic circulation,” progressive vasodilation affects the whole circulatory system with low vascular resistance and increased cardiac output, all the way to multiple organ failure [75, 76].

In summary, splenomegaly in portal hypertension appears initially as a gradual loss of rhythm, venous congestion, and structural hyperplasia with pooling of the blood and finally as an overflow related to the hyperdynamic circulation. Further studies on these stages are required in order to define the transitions with regard to the rhythmical function of the spleen more clearly.

Functional hyposplenism is defined as an impaired spleen function that is commonly associated with a small to atrophic spleen [77, 78]. As in the case of asplenia, where the spleen is congenitally missing or absent due to surgical removal, hyposplenism leads to the risk of fulminant sepsis with high mortality (overwhelming postsplenectomy infection) due to reduced immune function. Suitable prophylactic management is recommended for hyposplenic patients [77, 79, 80].

Clinical diagnosis of hyposplenism is based on an assessment of the spleen’s filtering function by radioisotopic methods [81] or quantitation of cell abnormalities in the peripheral blood smear [82]. Counting Howell-Jolly, Heinz, and Pappenheimer bodies is a reliable and established screening method for hyposplenic states. As their specificity and sensitivity have been disputed especially in mild forms of hyposplenism, some authors suggest pitted erythrocytes as the new gold standard [77]. Counting pitted erythrocytes (membrane abnormalities visible with phase-interference microscopy) is a simple, repeatable, and cost-efficient method of assessing hyposplenism [79, 83].

Coeliac disease is one of the most commonly associated underlying conditions of hyposplenism. Impaired spleen function occurs in 33–76% of patients and correlates with the severity and complication rate [84]. As long as the spleen tissue is not totally destroyed, spleen function can be restored using a gluten-free diet [85]. Functional hyposplenism is also common in chronic inflammatory bowel diseases. It occurs in around up to a third of all patients with ulcerative colitis and, although less frequently, in Crohn’s disease [84]. In these cases, impaired spleen function and size are again dependent on the severity of the disease, and complications such as perforations, fistulas, abscesses, bleeding, and toxic megacolon have been more frequently observed in conjunction with a small spleen [78]. Interestingly, functional hyposplenism also occurs in patients under long-term parenteral nutrition, where the length of the intravenous nutrition is correlated with the percentage of pitted red cells [86].

As far as known, there are no studies to date on the relationship between splanchnic haemodynamics, spleen rhythm, and functional hyposplenism. However, some preliminary indirect data are available. Patients with active untreated coeliac disease, ulcerative colitis, and Crohn’s disease demonstrate a significantly increased blood flow in the mesenteric and portal vessels and correspondingly lower resistance indexes [87‒90]. Magalotti et al. [91] studied this hyperdynamic splanchnic circulation, for example, in coeliac patients before and after eating a meal and were able to demonstrate a reduced and delayed postprandial hyperaemia. They found that 60 min after food intake (800 kcal), the blood flow in the portal vein increased by 97% in the control group but in the coeliac group by only 49% and remained increased for 3 h after eating, unlike the control group.

Considering the rhythmical function of the spleen, it is quite remarkable that if postprandial hyperaemia is reduced (e.g., in coeliac disease) or completely absent (in parenteral nutrition), an impaired spleen function results in the long term. It seems most likely that the rhythmical function of the spleen – in a similar way to portal congestion – is also suspended in functional hyposplenism, thus initiating the loss of the organ’s function. A continuous evaluation of the rhythmical function by means of splenograms could be of great significance for the early ­pathogenesis and therapeutic modulation of the disease. We would like to recommend that, besides the immunological interactions, further studies should pay more attention to these haemodynamic relationships between the spleen and the intestine.

This review considers the spleen to be a rhythmical regulatory and balancing organ in 2 ways. As part of a functional unit with the splanchnic circulation, the spleen reacts to the pressure and circulatory conditions in the portal vein system and guarantees a constant portal flow (venovasomotor reflex). As part of a functional unit with the digestive tract, the spleen balances the postprandial hyperaemia via temporary enlargement of the organ (postprandial congestion). The spleen can, therefore, be described as a regulative organ for the nutritional system.

Innovative ways of assessing the rhythmical spleen function are now required in which postprandial congestion must be distinguished from sympathetically modulated stress contractions. What is particularly interesting about the postprandial congestion is when and how the change to enlargement of the organ occurs.

In nutritional studies, the type, quantity, and composition of the food appear to be crucial for the magnitude of the splanchnic blood flow. Stronger spleen reactions are to be expected from solid, calorie-rich food than with smaller meals with liquid, low-calorie, and low-fat food. The hypothesis that irregular food intake results in greater postprandial blood flow and spleen reactions than with timed meals also needs further study. It should be noted for all these investigations that the spleen is exceptionally sensitive to respiration. Breathing manoeuvres (e.g., in imaging methods) must be avoided because even short apnoeas lead to sympathetically mediated single contractions to provide the circulation with pooled blood [92].

In terms of clinical research, more studies are required on the early signs and gradual loss of the rhythmical spleen function, all the way to splenomegaly in portal hypertension or to functional hyposplenism such as in coeliac disease and chronic inflammatory bowel diseases. Investigations on therapeutic modulations of the splenic rhythm should focus on both pharmacological approaches and the patient’s psychosocial dimension as the original splenograms showed clear splenic responses to psychological factors such as anxiety and stress [14, 40].

Referring to haemodynamic studies of the late 20th century, we postulate a model of the spleen’s rhythmical regulatory function in the splanchnic circulation. The spleen’s rhythmical regulatory function in nutrition is based on an autonomous rhythm comprising cycles of contractions and dilations of the spleen of around 1 min. These cycles can be influenced by sympathetically mediated single contractions with a release of pooled blood or by portal vein congestion. After food ingestion, the spleen responds either with contraction according to a vasomotor reaction or postprandial congestion with significant increases in volume. The spleen’s rhythmical function is lost in the clinical picture of portal hypertension or in coeliac disease and chronic inflammatory bowel diseases. In the aforementioned gastrointestinal diseases, we recommend taking more account of the haemodynamics between the spleen, liver, and intestine. New innovative techniques for recording splenograms are required which, besides elastographic measurements of spleen stiffness, could offer an important tool for early detection, diagnosis, and therapeutic evaluation.

The authors declare that they have no conflict of interest. The study was not influenced by the foundations that provided financial support.

We gratefully acknowledge the financial support of the Christophorus Stiftung and the Software AG Stiftung.

All authors made substantial contributions to the conception of this review. J.W. wrote the final manuscript, which was reviewed, edited, and revised by L.G., T.S., L.A., and P.H.