Spotty liver disease in poultry

What do we know about spotty liver disease (Campylobacter hepaticus) in poultry?

In 2019 the first infection of Campylobacter hepaticus responsible for spotty liver disease (SLD) has been proven in a flock of Dutch laying hens (Molenaar 2019). However, the disease is not only emerging in the Netherlands, a fact proven by the publication of several articles on this subject in the recent years. This news article provides you with the practical information available so far.


The disease has already been described over 60 years ago and was mainly seen in the USA, UK and Germany since then. It gained increased interest when the number of outbreaks increased, starting in Australia. It was noticed that the incidence increased in line with an increase in birds in kept free range and in barns, instead of in cages (Van et al. 2017a).

Crawshaw et al. published about the identification of a novel Campylobacter strain in 2015. They described the isolation, biochemical, structural and molecular characteristics of the bacterium, but did not determine a name yet (Crawshaw et al. 2015).

Van et al. later also identified the same unknown Campylobacter species causing spotty liver disease in commercial chickens in Australia. Phylogenetic analyses based on the 16S rRNA gene and the heat shock protein 60 (hsp60) gene sequences indicated that the strains formed a uniform cluster that was clearly distinct from recognized Campylobacter species. When the average nucleotide identity was calculated, the new strains had a 99% concordance, but showed less than 84% similarity with the nearest sequenced species. A similarity of less than 95% indicates that the bacteria are from a different species, so Van et al. then proposed Campylobacter (C.) hepaticus as new name for this bacterium (Van et al. 2016).

The same group later proved that this bacterium is much more invasive to LMH cells (a chicken liver cell line) than other Campylobacter species. Besides, they showed that SLD could be induced by infecting mature layers orally with C. hepaticus and that the bacterium could be isolated from the liver and bile of these animals. They hereby fulfilled the postulates of Koch and proved C. hepaticus is the causative agent of SLD (Van et al. 2017a).

The bacterium

The most important characteristics of C. hepaticus are (Van et al. 2016):

  • bacterial morphology:
    • S-shaped;
    • contains long flagella at both poles;
    • motile;
    • 3-0.4 μm wide and 1.0–1.2 μm long after 3 days of incubation on HBA (horse blood agar) in a microaerophilic atmosphere at 37 °C;
    • Gram-negative;
  • colony morphology:
    • wet;
    • cream colored;
    • convex or flat and spreading;
  • biochemical characteristics:
    • non-hemolytic;
    • catalase positive;
    • oxidase positive;
    • urease negative.

In figure 1 you can see the morphology of C. hepaticus (Van et al. 2016).

Figure 1 Transmission electron micrographs of Campylobacter hepaticus showing their long bipolar flagella and S-shaped morphology (Vans et al. 2016).

A whole genome sequence has also been performed on C. hepaticus. This confirmed that this bacterium is most closely related to C. jejuni and C. coli, but still a distinct group (Petrovska et al. 2017). The phylogenetic tree is shown in figure 2.

Figure 2 Relationships between C. hepaticus and other Campylobacter species based on gene-by-gene analyses (Petrovska et al. 2017).


SLD occurs mainly in laying hens in free range systems, but has also been found in laying and breeding hens in barns and cages (Molenaar 2019; Van et al. 2016).

It is expected that birds get SLD after they get infected via the fecal-oral route with C. hepaticus. The bacterium is present in the gastro-intestinal tract of infected birds, and viable bacteria can be isolated from chicken faeces (Phung et al. 2020; Van et al. 2017a; 2017b).

C. hepaticus DNA has been identified in wild birds, rats, mites and flies. It has also been shown in water and soil from infected farms. It is however unknown if these are also vectors for viable C. hepaticus organisms. This means that more research is needed to determine their possible role in transmission and introduction on the farm (Phung et al. 2020).

Australian research has showed that the moment of infection does not have to correlate with the moment of mortality or lesions found at necropsy. Chickens can be infected with C. hepaticus up to eight weeks before SLD manifests itself clinically. A case has been described were birds were already infected during rearing (week 12). This implicates that an infection with C. hepaticus is not enough to cause SLD, but that other predisposing factors should also be present. Proposed predisposing factors are liver metabolism during peak production or changes in the gastro-intestinal microbiota (Phung et al. 2020). More research is needed to determine these factors.

Infections occur mainly during peak production, but are not limited to this period. Besides, after the initial infection at the peak of lay, further outbreaks can occur in the same flock at later ages (Phung et al. 2020).

Clinical disease

Flocks are often affected during peak production, but this can occur all year round (Molenaar 2019; Phung et al. 2020).
Flocks with SLD have higher mortality with acute deaths (Molenaar 2019). The mortality can be increased with more than 1% per day (Van et al 2017a) and can reach up to 10% in total (Phung et al. 2020).
In some flocks the egg production is decreased, with maximum decreases of 25% (Molenaar 2019; Phung et al. 2020). Sick animals are not always observed, due to the rapid death of affected animals (Molenaar 2019).


The disease is characterized by a large amount of small grey / white necrotic foci in the liver (spotty liver), as can be seen in figure 3 (Molenaar 2019; Van et al. 2016).
From the inoculation trials done by Van et al., it can be concluded that chickens with SLD can recover and that the liver lesions will then also disappear of the course of a couple of weeks (Van et al. 2017a).

Figure 3 Pathology of two birds with SLD: photo A of a bird that died, photo B of a bird that was euthanized and then necropsied (Van et al. 2017a).


All C. hepaticus isolates described in literature have been isolated from liver or bile samples, where it can often be found as monoculture (Phung et al. 2020; Van et al. 2017).
C. hepaticus is also present in the gastro-intestinal tract, with increasing concentrations along the gastro-intestinal tract (duodenum < jejunum < ileum < cecum). Despite the fact that gastro-intestinal concentrations are higher than liver concentrations, isolation from the gastro-intestinal tract has so far not been described (Phung et al. 2020; Van et al. 2017).

Cultivation of C. hepaticus is very difficult and it will not be successful by using standard cultivation methods (Molenaar 2019). C. hepaticus grows on nutrient agar with blood, but most don’t grow on MacConkey or Karmali agar (Van et al. 2016).

A PCR is available to determine if samples contain C. hepaticus DNA (Van et al 2017b). The analyses of cloacal swabs with PCR seems to be a reliable method to determine if C. hepaticus is present in live birds (Van et al. 2017).


Several antibiotics can be used to treat Campylobacter infections. Tetracyclines are generally first choice antibiotics. In the literature oxytetracycline is reported as main treatment option for SLD in Australia, but plasmid-borne resistance has already been reported (Phung et al. 2020).
Macrolides can also be used, but due to the risk of resistance in zoonotic Campylobacter species on public health, these are considered second choice antibiotics.
Lastly, also fluoroquinolones can be used.


Since C. hepaticus DNA has been shown in several materials incl. rats and wild birds, biosecurity seems to be a very important preventive tool to prevent infection of a farm, and also to prevent spread between stables.

There is no registered vaccine available. The use of herd specific (autogenous) vaccines is possible, but more experience will be needed to evaluate the efficacy.

Due to the fact that C. hepaticus was only recently identified as causative agent, little information is known about other preventive measures, such as the use of certain feed ingredients. Research did however already show some promising results for the use of biochar (Wilson et al. 2019). More research is however needed before this can be put into practice.


The whole genome sequencing showed that it is most closely related to Campylobacter jejuni and C. coli, which are both zoonotic bacteria. The bacterium however has not been detected in humans. More information is needed before a conclusion can be drawn on the zoonotic potential of Campylobacter hepaticus (Crawshaw 2019; Petrovska et al. 2017).


With RIPAC-LABOR we have a partner who is specialized in the isolation and cultivation of bacterial pathogens. RIPAC-LABOR invested in the culturing method of C. hepaticus and can now say that they can cultivate and identify C. hepaticus with MALDI-TOF. RIPAC-LABOR can also perform a PCR to detect C. hepaticus DNA in tissues.

The laboratory of RIPAC-LABOR is also possible and allowed to produce herd specific vaccines against C. hepaticus.

In case of a flock of which you suspect they are infected with C. hepaticus, you can always contact our Technical Support department to discuss the possibilities and further steps.


  1. Crawshaw, T. (2019) A review of the novel thermophilic Campylobacter, Campylobacter hepaticus, a pathogen of poultry. Transboundary and Emerging Diseases 66(4): 1481-1492.
  2. Crawshaw, T., Chanter, J., Young, S.C.L., Cawthraw, S., Whatmore, A.M., Koylass, M.S., Vidal, A.B., Salugero, F.J., Irvine, R.M. (2015) Isolation of a novel thermophilic Campylobacter from cases of spotty liver disease in laying hens and experimental reproduction of infection and microscopic pathology. Veterinary microbiology 179 (3-4): 315-321.
  3. Molenaar, Robert Jan (2019) Nieuws uit de monitoring – Spotty Liver Disease. Tijdschrift voor Diergeneeskunde.
  4. Petrovska, L., Tang, Y., Jansen van Rensbrug, M.J., Cawthraw, S., Nunez, J., Sheppard, S.K., Ellis, R.J., Whatmore, A.M., Crawshaw, T.R., Irvine, R.M. (2017) Genome reduction for niche associated in Campylobacter hepaticus, a cause of spotty liver disease in poultry. Frontiers in cellular and infection microbiology 7: 354.
  5. Phung, C., Vezina, B., Anwar, A., Wilson, t., Scott, P.C., Moore, R.J., Van, T.T.H. (2020) Campylobacter hepaticus, the cause of spotty liver disease in chickens: transmission and routes of infection. Infection. Frontiers in Veterinary Science 6:505.
  6. Van T.T.H., Elshagmani E., Gor M.C., Scott P.C., Moore R.J. (2016) Campylobacter hepaticus nov., isolated from chickens with spotty liver disease. International Journal of Systematic and Evolutionary Microbiology 66, 4518–4524.
  7. Van T.T.H., Elshagmani, E., Gor, M.C., Anwar, A., Scott, P.C., Moore, R.J. (2017a) Induction of spotty liver disease in layer hens by infection with Campylobacter hepaticus. Veterinary Microbiology 199: 85-90.
  8. Van, T.T.H., Gor, M.C., Anwar, A., Scott, P.C., Moore, R.J. (2017b) Campylobacter hepaticus, the cause of spotty liver disease in chickens, is present throughout the small intestine and caeca of infected birds. Veterinary microbiology 207: 226-230.
  9. Willson, N. L., Van, T., Bhattarai, S. P., Courtice, J. M., McIntyre, J. R., Prasai, T. P., Moore, R. J., Walsh, K., & Stanley, D. (2019) Feed supplementation with biochar may reduce poultry pathogens, including Campylobacter hepaticus, the causative agent of Spotty Liver Disease. PloS one, 14(4) e0214471.

Fatty liver haemorrhagic syndrome in poultry

Fatty liver haemorrhagic syndrome (FLHS) is a syndrome found mainly in laying hens. It is characterized by a sudden mortality, a decrease in egg production and large amounts of fat in the liver found during necropsy. In this article we want to share an overview of the main information including some recently published information about FLHS from the University of Queensland.


FLHS is a multifactorial syndrome for which several risk factors have been described:

  • a surplus of energy intake;
  • temperature extremes;
  • peak production (oestradiol);
  • low amount of liver phospholipids;
  • inflammatory challenges;
  • limited hen movement.

A surplus of energy intake

A surplus of energy intake seems to be the most important factor. Some authors conclude that the source of energy is irrelevant, but others conclude that diets high in carbohydrates are more likely to cause FLHS than high fat diets. It is hypothesized that feeding birds diets high in carbohydrates and low in fat results in a high de novo fatty acid synthesis in the liver. During the novo fat synthesis, fatty acids are formed from carbohydrates. These fatty acids can subsequently be converted into triglycerides or other lipids. The de novo fat synthesis puts much pressure on the liver fat metabolism. Diets with a higher fat concentration reduce the need for de novo fatty acid synthesis. FLHS is seen more in obese chicken than in chickens with a normal or low bodyweight. It is not known if this can be explained by the surplus of energy intake, or that it has a direct influence.

Temperature extremes

Hot temperatures are a well-known risk factor; FLHS is more prevalent during summer months. Exposure to extreme cold can also be a risk factor relevant for backyard chicken.
The explanation for the increased incidence after exposure to heat or cold stress is not completely clear. It has been shown in fowls that heat stress can influence the lipid metabolism. Other hypothesise are a reduce in energy requirement when environmental temperatures increase or a decrease in animal movement, which is also described as predisposing factor in caged hens.

Peak production (oestradiol)

High producing laying hens are mainly affected during peak production, which can be explained by the role of oestradiol (oestrogen); hens with FLHS have a higher plasma oestradiol concentration than non-affected hens. Oestradiol administration has also been used to induce FLHS in laying hens, which was most successful in hens that were also given ad libitum feed.
Oestradiol stimulates the fat storage in the liver, to provide for the fat needed for yolk production.

Liver phospholipids

The amount of phospholipids in the liver is also considered important for the development of FLHS; the phospholipid concentration is lower in chicken with FLHS than in healthy chickens. Phospholipids have a lipotropic action and are thus important for the mobilization of fat from the liver. Besides, they are present in the cell membrane where they regulate the integrity and porosity of the membranes, protecting cells.

Inflammatory challenges

Shini and his study group found that the inflammatory response is a contributor to the pathogenesis of FLHS in chickens already experiencing fat infiltration in the liver (steatosis). His study group found a higher concentration of fibrinogen and leucocytes (heterophils and lymphocytes) in chickens which suffered from FLHS than in control groups. Also the mRNA expression of IL-1β and IL-6 was higher. These cytokines are known to be involved in the activation and promotion of leucocyte infiltrations at sites of injury. Inflammation was found to be local (hepatic) and systemic.
In these animals, FLHS was induced by oestrogen and LPS (lipopolysaccharide). LPS is a component of the outer membrane of gram negative bacteria, which were used induce an immune response.
In the study it appeared that LPS were the reason for transition of a simple steatosis to FLHS. In commercial conditions the inflammatory reaction causing this transition can be caused by other factors, including nutritional and environmental factors. To our knowledge, there are not yet any researchers which studied the effect of anti-inflammatory veterinary medicinal products on FLHS.

Limited hen movement

FLHS has a higher incidence in hens in (enriched) cages, due to the limited movement of hens.


Mycotoxins have also been thought to be related to FLHS, but this is considered questionable. At least for aflatoxin it is known that they cause other hepatic lesions.

Figure 1 Figure from Shini (2014) showing the effect of estrogen treatment in combination with restricted feed intake (ERF) or ad libitum feed intake (EAL) on the estradiol levels.

Figure 1 Figure from Shini (2014) showing the effect of estrogen treatment in combination with restricted feed intake (ERF) or ad libitum feed intake (EAL) on the estradiol levels.

Onset of disease

Even though problems are often encountered during the production peak, the onset of FLHS started already at an earlier stage. The first changes in the liver can already be observed at the onset of the reproductive period, and are related to the increase in synthesis of lipids and proteins destined for the egg yolk. However, no clinical signs are detected at this stage. The most profound changes occur at or after the peak of lay most probably induced by oestrogen persistence throughout the laying period.

Susceptibility of birds

Why are birds so susceptible to this condition? This can be explained by marked differences between birds and mammals.

  1. Birds have a poorly developed intestinal lymphatic system. Therefore, fatty acids are secreted directly into the portal blood system as very low density lipoproteins (VLDL, portomicrons). All these portomicrons will pass the liver, predisposing birds to fat deposition in the liver.
  2. White adipocytes in birds have limited capacity for lipogenesis, resulting in a higher pressure on the liver for this task.
  3. The lipid requirement for the egg yolk must be met by de novo synthesis of fat in the liver, because portomicrons will not be used by the ovaria. The intensive synthesis of yolk lipoproteins by the liver occurs faster than their mobilisation, resulting in an increase in liver size and lipid content. Additionally, the rate of clearance of VLDL by the ovarian follicles is not as fast as hepatic release, resulting in an increase in circulating triglycerides.

Backyard chicken

FLHS is not only important for commercial hens. It is also an important cause of non-infectious mortality in backyard chicken. Especially nutritionally over-conditioned hens are at risk for developing FLHS, particularly in the spring and summer months. The increase in production of eggs in the spring in combination with the high temperatures seem to the cause.


Flocks with FLHS problems are often characterized by a sudden increase in mortality despite good laying percentages. The mortality is seen mainly in hens which are in full production. The mortality is usually 3-5%, but higher mortality rates have been reported. Birds that are found dead can be pale, but usually did not show any other clinical symptoms.
In some cases, the mortality can be accompanied by a (sudden) decrease in egg production.
In live animals it is very difficult to distinguish affected from healthy hens, although some hens do develop pale combs.


Necropsy on the birds found dead often reveals abdomens filled with large blood cloths, arising from the liver. Several abnormalities can be found in the liver, including:

  • hepatomegaly;
  • engorgement of fat. Usually 50-60%, but up to 70% of the dry matter can exist of fat;
  • a different colour which has been described as yellow, pale or putty coloured;
  • friability of the liver tissue;
  • small hematomas in the liver parenchyma of both dead and alive and seemingly healthy birds. Previous haemorrhages are often found in the margins of the liver lobes.

Large amounts of fat are not only found in the liver, but also in the abdominal cavity around the viscera. The ovaries are often active, at least in the early stages of FLHS. When the syndrome persists, inactive ovaries can also be found.

Recovery of the liver parenchyma will result in fibrosis. This can also be observed in hens that have recovered from FLHS. Due to the fibrosis after recovery of the disease, clinical symptoms can also occur during repeated mild episodes of FLHS and build-up of fibrotic tissue in the liver.

Figure 2 Necropsy of a bird with FLHS ( Trott et al 2014)

How do the excessive amounts of fat in the liver result in sudden haemorrhage? It has been proposed that excessive fat may disrupt the architecture of the liver and result in weakening of the reticular framework and blood vessels. Another proposed mechanism is focal necrosis of hepatocytes leading to vascular injury. Excessive lipid peroxidation of unsaturated fatty acids in the liver may overwhelm the cell repair mechanisms and result in tissue damage.


Besides the clinical symptoms and pathology, there is little one can do to diagnose this disease. There are unfortunately no diagnostic tests available.
Because of the difficulty of recognizing FLSH and the absence of diagnostic tests, the syndrome is often overlooked.


As explained in the first paragraph, FLHS is a multifactorial syndrome. The key part of prevention depends on prevention of the above mentioned risk factors.

Phospholipids and choline

Phospholipids are structural lipids, they are structural elements of cells. Lecithin is the major phospholipid and is an integral part of the structure of lipoproteins and the microsomal membranes to join them and therefore plays an essential role in the formation of very low density lipoproteins (VLDLs) and thus for the transport of fat from the liver to other tissues. Lecithin deficiency is associated with an accumulation of fat in the liver and a decrease in the quantity of fat deposited in the egg yolk.

One of the main components of lecithin is choline (phosphatidylcholine). Choline is therefore important for the incorporation and mobilization of triglycerides present in the liver and called a lipotropic factor. Besides, it is important for the utilization of fat.

Choline supplementation in laying hens is associated with elevated serum VLDL levels and a reduction of cardiac, hepatic and abdominal fat. The combination of these functions result in the prevention of abnormal accumulation of fat in the hepatocytes, the so called “fatty liver”.

The requirement of choline increases with high-fat diets. The supplementation of choline can also be particularly interesting during periods of heat stress, since the deposition of fat in the liver increases significantly at higher temperatures.

Due to the severity of this syndrome, it is vital to act quickly. Complementary feeds which provide for example choline, are therefore preferentially given via the drinking water.

Dopharma has a complementary feeds with choline in combination with betaine, methionine, lysine, sorbitol and plant extracts. This liquid product Heparenol is very suitable for use in drinking water in poultry.

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  3. Crespo, R. (2020) Fatty liver hemorrhagic syndrome in poultry. Consulted February 5th
  4. Crespo, R., Shivaprasad, H.L. (2008) Developmental, metabolic, and other noninfectious disorders. Chapter 30 in Diseases of Poultry, 12th edition, Edited by Saif, Y.M.
  5. Dong, X.F., Zhai, Q.H., Tong, J.M. (2019) Dietary choline supplementation regulated lipid profiles of egg yolk, blood, and liver and improved hepatic redox status in laying hens. Poultry science 98: 3304-3312.
  6. Gilman, G.G. e.a. (1990) Choline. In: The pharmaceutical basis of therapeutics, p 1542-1544.
  7. Griffith, M., Olinde, A.J., Schexnailder, R., Davenport, R.F., McKnight, W.F. (1969) Effect of choline, methionine and vitamin B12 on liver fat, egg production and egg weight in hens. Poultry science 48(6): 2160–2172.
  8. Hossain, M.E., Das, G.B. (2014) Effects of supplemental choline on deposition of cardiac, hepatic and abdominal fat in broiler. Bangladesh journal of animal science 43(2): 118-122.
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  11. Kahn, C.M. (2005) The Merck Veterinary Manual 9th Chapter Poultry – Fatty liver syndrome page 2226-2227.
  12. Khosravinia, H., Chethen, P.S., Umakantha, B., Nourmohammadi, R. (2015) Effects of lipotropic products on productive performance, liver lipid and enzymes activity in broiler chickens. Poultry science journal 3(2): 113-120.
  13. Kpodo, K.R. (2015) Dietary supplementation of choline and betaine in heat-stressed broilers. Thesis for the master of science degree at the University of Tennessee, Knoxville.
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  17. Ramo Rao, S.V., Sunder, G.S., Reddy, M.R., Praharaj, N.K., Raju, M.V., Panda, A.K. (2001) Performance of broiler chicken in early life on methionine deficient feed with added choline and betaine. British poultry science 42(3): 362-367.
  18. Saeed, M., Alagawany, M., Asif Arain, M., El-Hack, M.E.A., Dhama, K. (2017) Beneficial impacts of choline in animal and human with special reference to its role against fatty liver syndrome. Journal of experimental biology and agricultural sciences 5(5): 589-598.
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Necrotic enteritis and necro-haemorrhagic enteritis in broilers

Necrotic enteritis is a very important disease in broilers and turkeys, but is also found in layers and breeders. It is caused by toxins and enzymes produced by pathogenic strains of C. perfringens.
In the field, the disease is characterized by different clinical forms. A group of authors from the department of pathology, bacteriology and avian diseases of the faculty of veterinary medicine in Ghent (Belgium) recently published about the distinction of two clinical forms of necrotic enteritis (Goossens et al. 2020). In this article we will briefly present their conclusions.

Necrotic enteritis is characterized by necrosis of the small intestine. In 2019 we informed you about the toxinotypes of C. perfringens. The netB-producing toxinotype G was positioned as the most probable cause of necrotic enteritis in birds. You can find this article on our website.
There are however still research groups that isolate netB-negative toxinotype A strains from birds with this disease. When infecting other birds with these strains, they also develop disease, supporting that these strains are pathogenic. Re-isolation of these strains from the infected and diseased birds is however not reported. The postulates of Koch have therefore not yet been completely fulfilled.

Besides the fact that two different C. perfringens toxinotypes are isolated, there are two distinct presentations of disease on necropsy; a haemorrhagic and a non-haemorrhagic form, which are explained below.

Non-haemorrhagic necrotic enteritis

  • The non-haemorrhagic form is the best described and most commonly accepted form of necrotic enteritis.
  • This form also is often subclinical and associated with poor bird performance.
  • Lesions can be found mainly in the jejunum and ileum and are described as confluent mucosal necrosis, often covered by a pseudomembrane.
  • This form is caused by netB-positive toxinotype G strains.

Necro-haemorrhagic enteritis

  • The necro-haemorrhagic form of this disease is not so often described.
  • This form of necro-haemorrhagic enteritis is characterized by sudden death. Subclinical cases have not been described.
  • Lesions are also mainly found in the jejunum and ileum but in this case described as haemorrhagic; the mesentery is engorged with blood. When looking at the mucosa, the macroscopic lesions very much resemble those of non-haemorrhagic necrotic enteritis: confluent mucosal necrosis which is often covered by a pseudomembrane.
  • Necro-haemorrhagic enteritis seems to be linked with specific netB-negative perfringens type A strains. There is a resemblance with bovine necro-haemorrhagic enteritis which is caused by toxinotype A strains.

In the picture you can find the typical necropsy of a broiler with severe non-haemorrhagic (A) or necro-haemorrhagic (B) enteritis (Goossens et al. 2020).

Figure 1 Necropsy of a broiler with severe non-haemorrhagic (A) or necro-haemorrhagic (B) necrotic enteritis (Goossens et al. 2020)

Because of the confusion caused by the use of one single name for the description of these two syndromes, Goossens et al propose to rename the haemorrhagic disease entity to necro-haemorrhagic enteritis.


The different entities of necrotic enteritis can cause severe problems in farms. When treatment is indicated, it is advisable to use narrow spectrum antibiotics. As Dopharma we have the narrow spectrum penicillin Phenoxypen® WSP in our portfolio.

  1. Goossens, E., Dierick, E., Ducatelle, R., van Immerseel, F. (2020) Spotlight on avian pathology: untangling contradictory disease descriptions of necrotic enteritis and necro-haemorrhagic enteritis in broilers. Avian pathology DOI /10.1080/03079457.2020.1747593.

The withdrawal period; a guideline

For all veterinary medicinal products intended for food producing animals, a withdrawal period has been determined. This is however an advice rather than a period set in stone. In this article we will explain what a withdrawal period is and which factors can be of influence. Additionally, we will provide two examples to demonstrate the importance of a good understanding of this subject in everyday practice.

What is a withdrawal period?

The withdrawal period is the time period required after cessation of treatment to assure that drug residues in animal products are below the Maximum Residue Limit (MRL).

The advised withdrawal period is based on the use of veterinary medicines according to the product registration and was determined in healthy animals. The advised product withdrawal period is the minimal withdrawal period that should be applied. Veterinarians prescribing the treatment can advise to prolong the withdrawal period when they deem this necessary.

Which factors can influence the withdrawal period?

There are several factors that can influence the withdrawal period.


Several diseases can result in a slower elimination rate of medicinal products. Primarily liver and kidney disease are known risk factors; they might delay elimination and therefore prolong the withdrawal period.

Drug combinations

The pharmacokinetics of a veterinary medicinal product can be influenced by other medicines which are administered before, together with or after the veterinary medicinal product issued. Prolongation of the elimination period occurs in particular when you combine veterinary medicinal products that are excreted via the same elimination route.

Treatment repetition

When the treatment is repeated immediately or shortly after the first treatment period, this may result in accumulation of the active substance in the body.

Acidification of the drinking water

Acidification of the drinking water is sometimes used to increase the solubility and stability of veterinary medicinal products. It can however also increase the biological bioavailability of the drugs and therefore prolong the withdrawal period. Only when veterinary medicinal products already contain citric acid or another acid as part of their formulation, the marketing authorisation holder has taken this into account when determining the advised withdrawal period.

Contamination of the drinking water system

Medicinal residues can stick to contaminants in the drinking water system and when acids are then used post treatment, these residues can re-dissolve. This means that the animals are exposed to the active substances again after the treatment is supposed to have been ceased already.

Not completely emptying the bulk tanks

When bulk tanks are used it is important to empty the tanks completely before the water tap is opened again. This will prevent dilution of the product with clean drinking water and thus the exposure of animals for prolonged periods of time.

Cascade and off label use

When veterinary medicinal products applied via the cascade are used to treat other species than those mentioned in the registration, it is mandatory to maintain a withdrawal period of at least 7 days for milk and eggs and 28 days for meat. When veterinary medicinal products are applied for a different indication, but for a species mentioned in the registration, it is officially not needed to adjust the withdrawal period. A different off label indication can however influence the withdrawal period by altering/influencing the rate of elimination. In such cases it is advised to prolong the advised withdrawal period after all.

Veterinary medicinal products should be administered according to the product characteristics. When it is however needed to administer a veterinary medicinal product in a different dosage or via a different method in the context of Good Veterinary Practice, it can be needed to derogate from the registration. In these cases it can be needed to adjust the withdrawal period too. This is preferably done based upon trials in which the pharmacokinetics of the medicinal product in that dosage and for that route of administration are determined in the animal species treated.

Two examples

Below you can find two examples to demonstrate the importance of withdrawal periods in everyday life.

Acidification of the drinking water

Acids are often used to improve the solubility and stability of veterinary medicinal products, such as doxycycline containing products. Dopharma’s Doxylin® 50% WSP already contains citric acid and under normal circumstances it is not needed to add extra citric acid. However, when other doxycycline products are used, it is often necessary to use an acid as water conditioner. Some acids are also used on their own, such as Vitamin C.

The addition of acids to the pre-solution as well as the separate use of acids can influence the withdrawal period. When acids are used together with antibiotics, the biological bioavailability of the antibiotics administered can be increased. When acids are used after completion of the antibiotic treatment, they can re-dissolve residues of veterinary medicinal products that are present in the drinking water system. Animals will then be exposed again. Depending on the concentration of the residues in the drinking water and the period until slaughter this can result in residues.

Benzylpenicillins and the Delvotest

When the Delvotest is used to determine the presence of benzylpenicillin in milk, residues are sometimes found whilst the withdrawal period has been respected. False positive testing results can be the explanation for this. Please find below three factors that can cause false positive results when using the Delvotest.

The detection level

The MRL of benzylpenicillin in milk is 4 μg/kg (4 ppb). The detection level of the Delvotest is however much lower than this. The Delvotest detection level for benzylpenicillin appears to be roughly 1 ppb, which is only one fourth of the MRL.

Research at Dopharma’s laboratory showed that the Delvotest showed positive results on some samples which did not contain any antimicrobials. These false positives were the result of contamination. Despite all precautions (use of new materials, clean working environment, etc.) contamination resulted in false positive results. This even occurred under laboratory conditions. It can therefore be concluded that the Delvotest is very sensitive to contamination.

Natural inhibitors

The product description of the Delvotest mentions that milk can contain some natural inhibitors such as lactoferrin or lysozymes. These molecules can also result in false positive test results.

The Delvotest does not seem to be sensitive to the presence of disinfectants in the milk. One disinfectant that can be used to disinfect the udder after milking has been studied in our laboratory: 4XLA.

The Delvotest is a non-specific, qualitative test and a correct and reproducible quantification of benzylpenicillin in milk to determine if this exceeds the MRL is therefore not possible. The Delvotest appeared to be extremely sensitive to contamination and all precautions should be taken to avoid contamination when using this test.

When the result of the Delvotest is positive it is advised to do a confirmatory re-test. The milk can be heated (a few minutes at 80˚C) to neutralise some contaminants. The milk that has to be tested can also be diluted with milk from the tank (in a ratio of 1:3) to decrease the sensitivity of the test to the level of the MRL.

The Delvotest appears to be the most commonly used test, but there are several other similar tests on the market. Dopharma has not performed any laboratory tests with those tests. However, looking at the specifications of several other tests, the same problems are to be expected. The sensitivity of most tests is at or below the MRL which means that you can expect positive test results whilst the level of the antibiotic(s) examined is still below the MRL.


  • Huyghebaert, A. (2006), Advies 42-2006 (Wetenschappelijk Comité van het Federaal Agentschap voor de Veiligheid van de Voedselketen, Brussel).
  • Dutch legislation: Wet dieren, Besluit diergeneesmiddelen en Regeling diergeneesmiddelen.
  • European legislation: Directive 2001/82 and Regulation EEG nr 37/2010.
  • Reference picture: Different kinds of meat, eggs and two bottles of milk — Image by © Imagemore Co., Ltd./Corbis

Gastric ulcers in horses; ECEIM consensus statement

In 2015 the “European College of Equine Internal Medicine (ECEIM)” published the new “consensus statement” regarding gastric ulcers in adult horses.

This “consensus statement” is written by B.W. Sykes, M. Hewetson, R.J. Hepburn, N. Luthersson and Y. Tamzali. It was published in the “Journal of Veterinary Internal Medicine” (29: 1288-1299) and available as “open access” article. Below you can find a summary.


“Equine Gastric Ulcer Syndrome” (EGUS) is the general term used for all erosive and ulcerative diseases of the horse stomach. Based upon the affected regions in the stomach, two categories can be distinguished: “Equine Squamous Gastric Disease” (ESGD) and “Equine Glandular Gastric Disease” (EGGD).

ESGD is further divided into primary ESGD and secondary ESGD. Primary ESGD affects horses with normal gastric emptying, while secondary ESGD occurs in horses with delayed gastric emptying due to underlying pathology such as pyloric stenosis. EGGD is specified further based upon the anatomical location and the appearance of the lesion.


The prevalence of gastric ulcers varies with breed, use and level of training. There is also a difference in prevalence between ESGD and EGGD. ESGD has the highest prevalence in thoroughbred racehorses. The prevalence of EGGD is less well understood. Most lesions of EGGD are found in the antrum pyloricum.


Several studies show that there is a correlation between the presence of ulcers and the breed. The influence of age and gender is inconsistent which suggests that other factors, such as intensity and duration of training, are more important. Other factors, of which it has been described that they are a possible risk factor, are described below.

  • Grazing is shown to decrease the risk of gastric ulcers, but supporting evidence is contradictory.
  • Unlimited/frequent access to roughage is considered to reduce the risk on EGUS, but supporting evidence is not available. Besides, findings suggest that the impact of roughage without reduction of other risk factors might be less than expected. The occurrence of ESGD is more likely when straw is the only form of roughage provided. This suggests that also the type of roughage influences the prevalence of ESGD.
  • An increased interval (> 6 hours) between roughage meals increases the risk on ESGD, when compared to more frequent (< 6 hours) roughage supply.
  • An increased starch intake is consistently associated with an increased risk on ESGD in animals trained at different levels.
  • Intermittent water access increases the risk on EGUS.
  • Fasting is an often described risk factor for ESGD; intermittent fasting causes ESGD and increases its severity.

More large-scale research is needed to understand the epidemiology behind EGUS, especially behind EGGD.

Clinical symptoms

Stomach ulcers in adult horses are associated with a broad range of clinical symptoms: a decrease in appetite, slower eating, poor body condition score or weight loss, chronic diarrhoea, a bad coat condition, teeth grinding, behavioural changes, acute or recurring colic and bad performance. There is however no strong epidemiological evidence for the correlation between the presence of these clinical symptoms and the occurrence of gastric ulcers.

A broad range of clinical symptoms can occur in individual EGUS cases. On population level the different gradations of a decreased appetite and a poor body condition score are most common. Behavioural changes, including stereotypes, are inconsequent, but not unusual. EGUS can also contribute to bad performance, but considering the number of factors that can contribute to this, other factors should also be taken into account. Differences in clinical symptoms occurring with ESGD or EGGD are currently not known. Despite the large variety of possible symptoms, all these symptoms are badly correlated to the presence of EGUS. Diagnosing EGUS based on the presence of “typical clinical symptoms” should thus be avoided.


Gastroscopy remains the only reliable ante-mortem method to determine accurately if a horse has gastric ulcers. The entire stomach, including pylorus and proximal duodenum, should be included because lesions in one of these regions are easily missed.

There is no correlation between the presence of ESGD and EGGD. The presence of one cannot serve as an indication for the presence or absence of the other.

There are currently no reliable haematological or biochemical markers that can be helpful in diagnosing gastric ulcers.

Ulcer grading

The 0 – 4 “Equine Gastric Ulcer Council” system is recommended as a standard scoring system for ESGD.

Due to a lack of data to support the validity of the hierarchical grading system for EGGD, the use of this type of grading system is not recommended. For EGGD it is recommended to describe the lesion based on the presence or absence, anatomical location, distribution and appearance.

The biggest challenge is to determine the clinical relevance of the individual lesions found. There is little evidence that the presence and grading of the lesions correlates with the presence of clinical symptoms. The clinician should try to interpret the results of the endoscopy in relation to the complete clinical picture, history, etc.


ESGD is caused by an increased exposure of the squamous mucosa to acids. The relation between exposure of the squamous mucosa to gastric content and fasting and training has been described clearly. During gaits faster than a walk, the acid gastric content will be pushed up to the squamous mucosa by the increased intra-abdominal pressure.

The pathophysiology of EGGD, on the contrary, is poorly understood. The glandular mucosa differs fundamentally from the squamous mucosa by the fact that it is exposed to gastric acid in physiological conditions. For this reason it is thought that EGGD is caused by failure of the normal defence mechanisms that usually protects the mucosa against the acid gastric content. There is still no evidence that bacteria are the direct cause of EGGD.

NSAIDs have the potential to induce EGGD in individual animals, but on population level they do not contribute significantly to the prevalence of EGGD. The ulcerogenic capacity of some NSAIDs has been shown when dosages were administered that are 50% higher than the recommended dosages. When the recommended dosages are administered, phenylbutazone and suxibuzone however do not induce gastric ulcers.

It is most likely that a combination of different factors contributes to the development of EGGD in horses.


Treatment and prevention

The therapy of both ESGD and EGGD focuses on adequate suppression of acid production. The proton pomp inhibitor omeprazole is the first choice treatment. Omeprazole is superior to ranitidine.

The duration of acid suppression needed to heal ESGD and EGGD has not yet been described. Clinical studies suggest that a period of 12 hours during which the acid production is suppressed may be sufficient for the treatment of ESGD. GastroGard gives a consistent healing rate of 70-77% when administered at the registered dose of 4 mg/kg per os, once daily, during 28 days. A lower dosage and/or shorter period of administration can however be taken into consideration based on the evidence available.

The success rate of EGGD treatment is only 25%. The reason for this poor response is unknown. A longer duration of treatment may be indicated in the case of EGGD. Bacteria might also play a part. In the absence of evidence to support this theory and in the context of responsible antibiotic use, it is however not recommended to use antimicrobials in the routine treatment of EGGD.

Considering the role of mucosal defence mechanisms failing in the pathogenesis of EGGD, protecting the mucosa as part of the therapy seems legit. Sucralfate is best studied for this indication. The combination of omeprazole (4 mg/kg PO once daily) and sucralfate (12 mg/kg PO twice daily) improves the success rate of EGGD when compared to omeprazole only.

The pharmacological approach of the prevention of ESGD is comparable to the treatment. Omeprazole is used as prevention in a dosage of 1 mg/kg per os, once daily. The efficacy of omeprazole as prophylaxis for EGGD is unclear, but so far there is no difference in the prevention strategy of both.

Nutraceuticals are attractive because of the ease of use and their availability. Pectine-lecithine complexes have been shown to increase the total mucus concentration in gastric juice. Antacids seem to provide some symptomatic relief, but their effect is short-lived.

There is no strong evidence to support a specific nutritional advice. There is only little evidence for the role of the diet in the occurrence of EGGD and therefore the recommendations are primarily based on the well-known risk factors of ESGD. Continuous access to a good quality grass pasture is considered ideal. Unlimited or frequent (4-6 times daily) access to hay (at least 1.5 kg (DM)/100 kg bodyweight/day) can be an appropriate alternative. Straw should not be the only type of roughage, but it can be included safely in the diet with a maximum of 0.25 kg (DM)/100 kg bodyweight. Concentrates should be used as cautiously as possible. Sweet feed should be avoided. The diet should not contain more than 2 gram starch per kg bodyweight per day, or no more than 1 gram starch per kg bodyweight per meal. The interval between feeding concentrates should be at least 6 hours. Maize oil could help to decrease the risk of EGGD development. Water should always be available. When pastes with electrolytes are given orally, they should be diluted in water first, or mixed with the feed.

EMA advice on the withdrawal period of lidocaine in food producing animals

The EMA recently published a report on the withdrawal period of lidocaine for milk. In general, when veterinary medicinal products are used through the cascade, the minimal withdrawal period for milk is 7 days. Based on the EMA advice, the withdrawal period for lidocaine should be extended to 15 days.


The cascade

In the Netherlands lidocaine is only registered for use in dogs and cats. Lidocaine can only be used in food producing animals when the cascade is applicable. Lidocaine is mentioned on the list of active ingredients belonging to regulation (EU) no 37/2010. This is a prerequisite for the application of the cascade in food-producing animals. Other conditions are the need for treatment, particularly to avoid suffering in the animals, and the lack of a registered veterinary medicinal product for the species and indication concerned.

For equines, no MRL (Maximum Residue Level) is needed as long as the product is used for local or regional anaesthesia. For the other food producing species no MRL has been determined. When using a product through the cascade, the minimal withdrawal period should be at least as long as the withdrawal period mentioned in the SPC for the species concerned. When there is no withdrawal period mentioned for the species concerned, the withdrawal period must be at least 7 days for eggs and milk and 28 days for meat.

New insights

The MEB (Medicines Evaluation Board) in the Netherlands has requested the EMA in December 2012 to provide a scientific opinion on the usage of lidocaine in food producing animals. This request was made as a result of recent research studies in which it was shown that 2,6-xylidin is one of the most important metabolites of lidocaine in cattle and pigs. This metabolite is considered carcinogenic and genotoxic.

Besides the possible effects of exposure to the metabolite 2,6-xylidin, the MEB was also concerned about exposure to the active ingredient lidocaine. Humans are also capable of producing this carcinogenic and genotoxic metabolite of lidocaine.

What did the EMA think?

The CVMP (Committee for Medicinal Products for Veterinary Use) of the EMA concluded that 2,6-xylidin has indeed got a potential genotoxic effect, but that the conclusions drawn in different studies differ largely. A carcinogenic effect was however clearly shown according to the CVMP. Changes in the DNA could be a possible mode of action for this carcinogenic effect.

The CVMP recognised the potential risk of exposing people to lidocaine and therefore the possible formation of potentially carcinogenic and genotoxic metabolites. But it was also pointed out that, on the other hand, lidocaine is also registered for human use as a short-term oral or topical treatment. However, they did comment that the benefit-risk assessment done for the approval of lidocaine as human medicinal product also factors in the positive effects of treatment which do not count when consuming residues through animal products.


The MEB mentioned that when it was decided that no MRL was needed for equines, it was taken into consideration that the metabolite 2,6-xylidin is not produced in horses. The CVMP contradicts this and states that this metabolite is produced in horses, but to a lesser extent than in other animal species.

The CVMP did conclude that with the available information, there is no need to change the MRL for equines as mentioned in Regulation EU No 37/2010.


Previously, it was not known if cattle were able to produce the metabolite 2,6-xylidin. Based on this it was decided not to allow a MRL for use in cattle.

Recent research has shown that 2,6-xylidin is the most important metabolite that is formed in hepatocytes and microsomes extracted from livers of cattle and pigs when exposed to lidocaine. This was an in vitro study. The metabolite was however also found in the urine of cattle and pigs after the intravenous administration of lidocaine.

Hoogendoorn et al have recently published a study in which the pharmacokinetics of lidocaine and its metabolite 2,6-xylidin were described in 8 dairy cows. In these animals lidocaine with adrenaline was injected subcutaneously and intramuscularly as is done for a caesarean. Five times 30 ml was used. This study group showed that both lidocaine and 2,6-xylidin can be found in plasma, milk, muscles and kidneys.

The CVMP has calculated values below which, in theory, there should be no risk for public health. This had to be done because there is no MRL available. Based on the studies done by Hoogendoorn et al a termination half-life of 17.7 hours was used. When a two-compartment model with a rapid elimination phase is used, the advised withdrawal period for meat would have to be at least 11 days. When the same method is used, the minimal withdrawal period for milk should be 15 days.

Based on these studies and the calculations made by the CVMP, the EMA concluded that a withdrawal period of 28 days for meat is sufficient. It was however advised to extend the withdrawal period for milk to 15 days.


When it was determined that no MRL was required for equines, there was also no information available about the metabolism in pigs. Recent reports do not include information about the metabolism of lidocaine in pigs either. The metabolism in pigs is however similar to that of cattle. It can thus be concluded that the withdrawal period of 28 days for meat is also sufficient to ensure public health. For pigs, it was also taken into account that lidocaine is primarily used during castration, which is usually done within the first week of life, resulting in a long period between the administration of lidocaine and slaughter.


  1. Thuesen, L.R., and Friis, C. (2012) In vitro metabolism of lidocaine in pig, cattle and rat. Poster presentation EAVPT Congress 2012, The Netherlands.
  2. F. Verheijen, Medicines Evaluation Board Agency (2012) Request for a scientific opinion.
  3. European Medicines Agency (EMA), Committee for Medicinal Products for Veterinary Use (CVMP) (2015) CVMP assessment report regarding the request for an opinion under Article 30(3) or Regulation (EC) No 726/2004.
  4. European Medicines Agency (EMA), Committee for Medicinal Products for Veterinary Use (CVMP) (2015) Opinion of the Committee for Medicinal Products for Veterinary Use regarding a request pursuant to Article 30(3) of Regulation (EC) No 726/2004.
  5. European Medicines Agency (EMA), Committee for Medicinal Products for Veterinary Use (CVMP) (1999) Lidocaine Summary Report.

Clostridium assaults the intestines of poultry

In many flocks of laying hens the bacteria Clostridium perfringens causes a large amount of damage to the intestines. Other problems, like coccidiosis or worm infestations, facilitate the problems caused by clostridium.

“In one out of every four post mortems performed on chickens intestinal problems were the underlying reason for referral to the GD”, knows Noami de Bruijn, poultry vet and pathologist at the GD Animal Health Service. “And in one out of every three post mortems done, we actually did find enteritis”, she explained at the Poultry Relation Days held in Barneveld.


Acute intestinal problems are often caused by Clostridium perfringens. This bacterium is a natural inhabitant of the intestines and is always present. It is not exactly known yet why the bacterium sometimes suddenly turns pathogenic. “In practice, preventing stress is one of the most important preventative management measures that can be taken to minimize intestinal damage”, says poultry vet Pim Eshuis. “And that already starts in the rearing period”.


Go and visit the rearer to discuss deworming and minimising the transition to the laying farm, advised Eshuis. “Give the hens a lot of attention, especially at the start of each new round”.

Research done at the GD Animal Health Services shows that in chickens with intestinal problems caused by Clostridium perfringens, coccidiosis often plays a part as well.`

Source: De Nieuwe Oogst.

Responsible use of veterinary medicines

Lately there has been a broad societal interest in the use of veterinary medicines and specifically the use of antimicrobials. The use of antibiotics and the need to reduce their usage are in the news regularly. Also the induction of resistance and the occurrence of zoonosis are discussed often.

Mitigate risks

Every time micro-organisms are exposed to antibiotics there is a certain risk for the development of resistance. Prolonged exposure, especially in low doses, can result in the selection of resistant bacteria. Theses resistant bacteria can be transferred to humans and thus pose a threat to public health.

Applying the advised withdrawal period is important. Residues of veterinary medicines in meat, milk or eggs can pose a potential threat to public health. To minimize the risks the usage of veterinary medicines could pose to public health, it is essential to increase awareness of the risks among veterinarians and farmers and to encourage preventative measures to avoid diseases and infections. Personal protection is an easy way to reduce direct contact with antimicrobials and the possible risks. Dopharma therefore has dust masks and latex gloves in their assortment.

Responsibility - street sign illustration in front of blue sky with clouds.


The Dutch society for Veterinary medicine and the FIDIN (board for manufacturers and distributors of veterinary medicines) have developed the following recommendations on the responsible use of veterinary medicines:

  1. A good treatment starts with the correct diagnosis: determine which causative agent is responsible for the disease and focus your treatment on this micro-organism specifically.
  2. Use registered veterinary medicines: check the registration number, read the label and, if applicable, the leaflet. Consult your veterinarian regarding the right treatment.
  3. Use the recommended dosage.
  4. Do not change the method of administration (e.g. injection, intramammary treatment, treatment via drinking water or feed or topical application).
  5. Complete the treatment, even though the animals seem to already have recovered. This is important to prevent re-occurrence of the disease and development of resistance.
  6. Do not combine veterinary medicines unless this is advised by your veterinarian.
  7. Think about your own safety.
  8. Avoid exceedance of the maximum residue levels (MRLs) in animal (by-) products.
  9. Document the important details of the veterinary medicines used.
  10. Evaluate the treatment on a regular basis with your veterinarian. Always report adverse events.
  11. Read the storage conditions as mentioned on the package and always apply them.