Lymphangiectasia

Lymphangiectasia may be either primary or secondary. The primary form is of congenital or idiopathic nature while the secondary form is the consequence of conditions which alter the function of intestinal lymphatic vessels. Lymphangiectasia is characterised by lymphatic vessel dilation and/or leakage of lymph into the intestinal lumen or in deep mucosal portions. The term does not identify a specific disease but rather a condition associated with various disorders.

PATHOPHYSIOLOGY

The causes of primary lymphangiectasia are unknown; in human medicine congenital lymphatic vessel abnormalities and altered lymphangiogenesis have been hypothesised. Although there is no sure evidence on the genetic transmission of this disorder some breeds present a higher predisposition: Yorkshire Terrier, Soft-Coated Wheaten terrier, Lundehund, Maltese, Shar-pei and Rottweiler.   

Secondary lymphangiectasia is caused by a dysfunction and/or obstruction of lymphatic vessels, the main causes of which are inflammatory conditions, fibrosis, infectious disorders, neoplastic conditions and portal hypertension. The systemic causes of portal hypertension are thoracic duct obstruction, pericarditis, portal vein thrombosis and heart failure. With increased lymphatic vessel pressure these tend to dilate within the villi,  become fragile and easily rupture, causing the leakage of lymph into the intestinal tract.

The lymph being leaked is rich in lymphocytes, chylomicrons and proteins. Although proteins can be partially reabsorbed, if the lymphatic obstruction is significant and if the loss is greater than the reabsorption rate the subject can present with hypoproteinaemia, which can result in body cavity effusion or oedema. In addition, the condition which underlies or causes lymphangiectasia may further limit the reabsorption capacity of the intestinal mucosa, thus worsening the protein loss. The extravasation of chylomicrons, and hence of lipid material, is also a strong inflammatory stimulus.

The persistence of chronic lymphangiectasia may induce perivascular lymphatic fibrosis and the development of lipogranulomatous inflammation of the lymphatic vessels. Lipogranulomas are the consequence of lymph extravasation; lymph and calcium salts act as local irritants, causing a granulomatous inflammation similar to a foreign body reaction, with the prevalence of lypophages among the inflammatory cells. However, contrary to what was believed in the past, granulomatous lymphangitis is not frequently associated with lymphangiectasia; in two retrospective studies lipogranulomas were detected in respectively 2.6% and 11.8% of the 38 and 17 animals assessed. This low incidence is supportive of the idea that these lesions are the consequence and not the cause of lymphangiectasia.

Inflammatory bowel diseases affecting the lymphatic system are presumably the main cause of lymphangiectasia; some authors even consider this condition as a variant of idiopathic IBD. In reality, in the course of primary lymphangiectasia there is a predominance of lymphatic duct alterations, usually with a full thickness involvement of the intestinal wall, while in most cases of idiopathic IBD there is only a mild to moderate lymphatic vessel dilation.

CLINICAL SIGNS

The main clinical signs of lymphangiectasia are weight loss and diarrhoea. It is not rare to have only weight loss since, in spite of the lymph loss, the intestinal fluid resorption capacity may remain intact until late stages of the condition. At times the most relevant clinical manifestations are linked to the consequences of hypoproteinaemia, and hence to the presence of ascites, effusion, limb oedema and respiratory disorders. Diarrhoea, when present, is of semisolid or liquid consistency, and may be persistent or intermittent. Vomiting may also be present; one study reported its presence in 11 out of 17 patients. In secondary lymphangiectasia the clinical signs present are also dependent on the existing primary condition.

Subjects with lymphangiectasia are usually dysanorexic, however occasionally polyphagia may be present. The onset of clinical signs may be acute or chronic and the medical history may report the presence of intermittent signs, especially in the forms of lymphangiectasia secondary to IBD. In sporadic cases the presence of large lipogranulomas may be the cause of an obstructive-like syndrome, with the consequent presence of acute and worsening clinical signs.

DIAGNOSIS

The definitive diagnosis of lymphangiectasia is based on histopathology, however clinical suspicion may arise based on the finding of hypoproteinaemia in the presence of gastroenteric clinical signs. A common finding is pan-hypoproteinaemia, with total values ranging between 2.5 e 5 gr/dl and albumins between 0.8 e 1.6 gr/dl. In hypoalbuminaemic, but normoglobulinaemic, patients it has been hypothesised that the inflammatory infiltrate may stimulate an increased production of globulins which surpasses the gastroenteric loss. The diagnostic approach must still include the exclusion of other causes of hypoproteinaemia and primarily of hepatic and renal diseases; this is achieved by assessing respectively bile acids and the protein/creatinine ratio, however internal medicine textbooks should be consulted for additional and necessary information.

A complete blood count may detect lymphopenia secondary to lymph loss in the intestinal lumen. This alteration is found in around 70% of cases, however its value should not be overestimated as it is present also in the course of a stress leukogram, which is itself a rather frequent finding.

Biochemical assays may detect the presence of hypocholesterolaemia, hypocalcaemia and hypomagnesaemia. Hypocalcaemia is correlated with serum hypoalbuminaemia, but it may persist also after correction of the protein value. This calcium reduction is secondary to fat malabsorption and the consequent formation of complexes between calcium and fatty acids within the intestinal lumen, as well as a consequence of vitamin D malabsorption.

A recent retrospective study reported the moderate increase of transaminases and of alkaline phosphatase as a frequent alteration in the course of lymphangiectasia. The same study showed that most patients with a normal lymphocyte count and normal cholesterol and globulin values are usually affected by mild or moderate degree lymphangiectasia, while the severity of the hypoalbuninaemia is correlated with the most severe forms.

When lymphangiectasia is suspected a complete coagulative profile is also necessary. This assay is of prognostic and therapeutic value, rather than diagnostic, since hypercoagulability and thrombosis are, in general, among the major risks of lymphangiectasia and of protein-losing enteropathy. The mechanisms underlying these conditions are the enteric loss of antithrombin III, platelet hyperaggregation, increased fibrinogen and vascular damage.

Radiography in the course of lymphangiectasia does not show evidence of typical alterations and in addition the possible presence of ascites further reduces its usefulness and applicability. Ultrasonography may detect abnormalities of the intestinal wall and may be suggestive of the presence of lymphangiectasia, especially in the presence of a thickened intestinal wall (> 3 mm), hyperechogenicity of the mucosal layer, corrugated intestinal loops, focal thickenings of the small bowel, ill-defined intestinal layering as well as focal and diffuse hypermotility; the presence of hyperechogenic mucosal striae has been specifically associated with lymphatic vessel dilation (Fig. 1). In spite of this, no ultrasonographic finding is pathognomonic of lymphangiectasia, and the diagnosis cannot be established based on this examination alone. In addition, ultrasound abnormalities do not seem to correlate with the severity of lymphangiectasia.

The diagnosis of lymphangiectasia is confirmed by histology. Since hypoproteinaemic animals tend to be hypovolaemic, as a consequence of reduced oncotic pressure, oncotic support with plasma or with synthetic colloids is recommended before anaesthesia, which is necessary when taking a biopsy. With regard to biopsy techniques, views vary. In patients with lymphangiectasia, which are usually malnourished and hypoproteinaemic, the risk of wound dehiscence is present, with a consequent risk of peritonitis when using a laparotomic technique. With an endoscopic biopsy medical treatment with steroids can be started just after the procedure, an approach which entails some risks in the case of a surgical biopsy.

The endoscopic presentation of lymphangiectasia is variable. The intestinal mucosa may appear macroscopically normal or only mildly oedematous (Fig. 2). Whitish, pin-point lesions are usually present, or so-called “rice grain” alterations which correspond to the villi being dilated by prominent lymphatic vessels (Fig. 3). In some cases focal or nodular-like alterations of the mucosa are present, which appear whitish in colour with undefined margins. Endoscopic biopsies enable to detect the spread of a whitish material on the mucosa, which is compatible with lymph. According to some authors the administration of a liquid meal rich in fats, such as corn oil, from 2 to 4 hours before the endoscopic examination, may facilitate the macro- and microscopic detection of lymphangiectasia. In a recent study on Rottweiler dogs with PLE (protein-loosing enteropathy) it has been suggested that the focal, “rice grain” presentation correlates with moderate severity lymphangiectasia, while the diffuse and pin-point presentation is typical of more severe forms.

To increase the likelihood of collecting a diagnostic bioptic sample, especially in the presence of focal and non-diffuse lymphangiectasia, the ileum should also be explored. If not carried out properly, endoscopic biopsies may be too superficial and therefore not sufficient to establish a diagnosis. Laparotomy allows to assess macroscopically the serosal surface of the entire intestinal system and to identify thickened intestinal loops, dilated lymphatic vessels at the level of the serosa and mesenterium and occasionally lipogranulomas (Figs. 4 and 5). Mesenteric lymph nodes may also be increased in volume and within them white-yellowish, 1-3 mm nodules may be detected around the lymphatic vessels. When a full-thickness biopsy is taken from hypoproteinaemic animals the recommendation is to suture with non absorbable surgical thread and perform an omentalisation in order to reduce the risk of wound dehiscence. In a retrospective study on 17 subjects undergoing surgical biopsy two deaths were reported due to post-laparotomy complications.

The final diagnosis of lymphangiectasia is based on the histopathological examination (Fig. 6). Submucosal lymphatic vessel dilation is traditionally considered as the typical hystopathological sign of lymphangiectasia and its identification requires a surgical biopsy sample. In reality most studies report the constant involvement of the mucosal portion, which presents distension of the lymphatic vessels within the villi as well as within the underlying layers. In cases of chronic lymphangiectasia, perivascular lymphatic fibrosis and occasionally lipogranulomas may be detected. Lymphangiectasia must also be distinguished from normal postprandial dilation of lymphatic vessels. In the presence of secondary lymphangiectasia the histological examination allows to detect the alterations caused by the primary disease, such as IBD, however it is not always easy to define if the inflammatory infiltration is the cause or rather the consequence of lymphangiectasia.

TREATMENT

The treatment of secondary lymphangiectasia is based on the identification and treatment of the primary disease. Primary lymphangiectasia requires a mixed therapeutic approach based on correct dietary management and adequate pharmacological therapy. In the presence of marked hypoproteinaemia and oedemas or effusions an intensive type medical therapy is necessary with the goal of preserving the oncotic pressure and of preventing the risk of a marked hypoalbuminaemia.

In the management of lymphangiectasia the diet is the most important variable. Ideally, the diet should contain a minimum amount of fats and an adequate amount of high quality proteins. Triglycerides containing long-chain fatty acids should be avoided since their transport requires the lymphatic system and hence they may overload the system itself. Short-chain fatty acids are to be preferred as they are directly absorbed by the portal system. In the initial stages a homemade diet may be used, containing a protein source poor in fats or without fats, such as milk flakes or ricotta cheese, as well as carbohydrates poor in lipids such as boiled rice or potatoes. Indicatively, the homemade diet may be dosed with one part of protein and three parts of carbohydrates. Alternatives to cheese as a protein source are chicken or turkey, oily fish, cooked egg albumen or yogurt. If the homemade diet is used for long periods of time supplementation with liposoluble vitamins is necessary (Vit. A, D, E, K). Until a few years ago supplementation of the diet with short-chain fatty acids was recommended, with the goal of increasing the caloric density of the diet without overloading the lymphatic system as these should be directly absorbed by the portal circulation. The suggested dose varied from 0.5 to 1.5 ml for every Kg of body weight together with the food; products containing short-chain triglycerides usually have a caloric value of 8 Kcal per millilitre. Recently this supplementation has been questioned as such products are expensive, not palatable and their absorption is complex and not totally innocuous.

Some authors prefer the use of commercial diets. These include low-fat diets (<15% dry matter), diets with protein hydrolisates or mono-protein hypoallergenic diets. Patients with lymphangiectasia often present dysorexia or anorexia and being the nourishment of these subjects very important the palatability of the diet is not a secondary added value. Different diets are therefore often tried and in some cases palatising agents such as cyproheptadine are used. In patients with ascites the resolution of the effusion with direct aspiration or with the use of diuretics may decrease the sense of unease and may favour the return of appetite. Some authors suggest supplementing the diet with glutamine.

Many patients with primary lymphangiectasia benefit from the use of corticosteroids. When the lymphangiectasia is secondary to a primary inflammatory process corticosteroids are administered at the same dose and with the same timing used in the course of IBD. In the presence of a non-severe primary lymphangiectasia the use of corticosteroids at an anti-inflammatory dosage (0,5 mg/kg sid per os) may reduce the mucosal oedema while increasing appetite at the same time. In these cases it is not necessary to extend the therapy for 4-8 weeks; the administration may be suspended after a shorter period of time and depending on the evolution of the clinical signs. In cases of steroid-refractive lymphangiectasia secondary to IBD or of a steroid sparing approach the use of other immunomodulators, such as azathioprine o cyclosporine, is possible.

Antibiotic therapy is useful and is used in most cases of primary and secondary lymphangiectasia since intestinal dysbiosis is favoured by lymph leakage into the intestinal lumen. Metronidazole and tylosin are the most commonly used agents, with the same modality used for IBD and ARE (antibiotic-responsive enteropathy). Amoxicilline-clavulanic acid, oxytetracycline and enrofloxacine may also be used at a standard dosage and for variable time periods, although never for less than 3 weeks.

The use of probiotics and prebiotics is recommended in the presence of diarrhoea, while cobalamin supplementation is necessary in case of deficiency. In addition, in the course of lymphangiectasia, just as for IBD, “symptomatic” drugs may be used, such as antacids, proton-pump inhibitors, antihemetics, antiparasitic and antidiarrhoic drugs depending on the prevalent clinical signs.

The prognosis of lymphangiectasia is difficult to establish as no studies have identified statistically significant prognostic factors. In one publication the presence of lipogranulomas was associated with a worse prognosis. Primary lymphangiectasia is a condition which can never be entirely resolved, it can only be compensated. Affected subjects are and remain underweight; owners must be made aware of the fact that the presence of this disease makes the overall clinical condition delicate and with a constant risk of worsening (as a consequence of even simple stressful events or of concomitant disorders).

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