Transmission

Fecal-oral transmission is the primary mode of transmission from an infected adult to the neonate. Most infections with M. avium subsp. paratuberculosis occur in the early neonatal period, often associated with the calf sucking the manure-contaminated teat and udder when ingesting colostrum.1013 Multiple-use maternity pens serve as focal points to spread the infection. An uninfected cow may lie on manure from a moderate or high shedder and contaminate her udder with the organisms. Approximately 25% of calves born to cattle with clinical signs will be infected in utero, but only 18% of calves born to asymptomatic cows are infected in utero.1014,1015M. avium subsp. paratuberculosis has been isolated from uterine flush fluids of infected cattle.1016

M. avium subsp. paratuberculosis may be passed through the colostrum and milk from cattle in the later stages of infection.1017,1018 Feeding pooled colostrum or pooled waste milk from several cows will serve to spread the infection from adults to calves during their most susceptible stage of life. Physical separation to calf hutches or better yet to another property such as a commercial heifer-raising facility decreases the risk of transmission to young calves. Although calves are most susceptible, older heifers and adult cattle can become infected from the ingestion of contaminated feed material. Feeding manger sweepings from the adult cows to older heifers has been shown to be a risk factor for spread of Johne’s disease. Semen from bulls kept in commercial bull studs represents a very low risk because these animals are tested twice yearly for Johne’s disease and must test negative. Although several species of wild animals may become infected with M. avium subsp. paratuberculosis, they represent a very low risk to spread the disease to calves.1019

GRASSLAND PASTURE

Some dairy herds use intensive grassland grazing of their adult milk cows. This system relies on moving milk cows to a new fresh growth of lush pasture each 12 or 24 hours on a rotational basis for 15 to 30 days. Typically heifers or steers follow the milking cows to graze the pasture closer to the ground, so the pasture will not need to be clipped or mowed mechanically. This leader-follower system has been used in New Zealand for many years and is an excellent way to provide less expensive lush pasture to the milking herd, negating mechanical harvest and greatly reducing the need to feed expensive concentrate rations. However, in herds that have Johne’s disease, the follower heifers or steers also are consuming M. avium subsp. paratuberculosis along with the lush grass left by the milk cows. Thus the follower cattle have a rather continuous uniform exposure to M. avium subsp. paratuberculosis over the months they follow the milking herd. Veterinarians need to be aware of this high-risk feeding practice, which perpetuates the transmission of M. avium subsp. paratuberculosis to younger cattle in the herd.

Prevalence

Johne’s disease is widely distributed throughout the world in many ruminant species. Reports suggest 7% to 18% of cattle from slaughterhouse surveys are infected.1020-1022 In Holland the true prevalence at cow and herd levels, based on an ELISA test sensitivity of 0.3 to 0.4 and a specificity that ranged from 0.985 and 0.995, was estimated to be 2.7% to 6.9% for cows and 31% to 71% for herds.1023 Herd prevalence based on bulk tank milk antibody showed that 70% of dairy herds in Denmark were positive.1024 A recent prevalence estimate, based on culture of ileocecal lymph nodes and ileum from dairy cows at slaughter in New Brunswick, Canada found 16.1% of cows positive, whereas 21.7% of cows from Maine were positive.1025 In 1998 the NAHMS survey indicated the dairy herd prevalence to be 30% to 50%.1026 More recent estimates of prevalence suggest 65% to 75% of dairy herds are infected in the major dairy states. Beef cattle have lower infection rates than dairy cattle.1027 Paratuberculosis is extensively distributed among other ruminants including sheep, goats, deer, bison, and many exotic ruminant species kept in zoologic gardens. The apparent prevalence seems to be increasing, but this phenomenon may be a result of an increased awareness by producers and veterinarians.

Treatment

No practical therapy for Johne’s disease is available. However, for cattle with significant genetic or sentimental value, several therapeutic agents have been used to effect remission of clinical signs. Isoniazid* given orally at 10 mg/lb daily, rifampin† at 10 mg/lb daily, and clofazimine‡ orally at 5 mg/lb daily have resulted in the amelioration of clinical signs facilitating collection of embryos and semen over an extended period of time.1028-1029 The drugs must be given daily, and if therapy is stopped clinical signs may reappear within a few weeks. No drug or combination of therapeutic agents has been shown to eliminate the infection. Treated animals continue to shed M. avium subsp. paratuberculosis in the manure, contaminating the environment, and have viable organisms in their tissues, indicating the possibility that semen and embryos from treated animals may be infected. If animals with Johne’s disease are treated with chemotherapeutic agents, the owners should agree with the prescribing veterinarian that milk or meat from that animal will never be used for human consumption. Drugs used to treat Johne’s disease are being used in an “extralabel” manner with an appropriate client-patient relationship but without any data regarding appropriate withdrawal times. For further information, refer to articles by Hoffsis and colleagues1028 and St-Jean and Jernigan.1029

Brumbaugh and colleagues1030 demonstrated a reduction in the number of CFU of M. avium subsp. paratuberculosis from the livers of experimentally infected mice treated with monensin compared with nontreated controls. Later, monensin was shown to either halt the progression of lesions or reverse the lesions in cattle with clinical signs of Johne’s disease.1031 Sections of tissues including liver, ileum, and adjacent mesenteric lymph node and a rectal mucosal biopsy were compared histologically with similar tissues obtained at necropsy after feeding 450 mg of monensin for 120 days. Taken together, the results of these two studies suggest that monensin may play a useful role both in the prevention of M. avium subsp. paratuberculosis infection in young cattle and in the treatment of established infection in adults.

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Neonatal calves fed 70 mg of monensin twice daily in their milk replacer suggested in a proof-of-concept study that monensin is efficacious in controlling M. avium subsp. paratuberculosis infection in the neonatal calf. The amount of monensin (70 mg) administered per day to calves in this study is higher than the amount that would normally be consumed by a neonatal calf in a calf starter formula. In experimental dairy calves, monensin greatly reduced (>60%) both the passive fecal shedding and systemic tissue uptake.1032 Monensin added to cattle rations at all phases of life, coupled with stringent implementation of biosecurity management practices at the farm level, offers new hope to help reduce the unyielding spread of this disease among the nation’s cattle herds. Monensin seems to offer cattle producers another potent weapon in their management armamentarium to reduce the spread of Johne’s disease within their herds. The costs are modest compared with many other management tools designed to reduce M. avium subsp. paratuberculosis bioburden within cattle herds. No other management technique evaluated to date has been shown to reduce M. avium subsp. paratuberculosis shed in manure of cattle and to reduce the tissue uptake of the organism to this extent.

Economic Losses Attributed to Paratuberculosis

Economic losses associated with Johne’s disease have been attributed to many factors, including decreased milk production, decreased fat and protein yield, increased susceptibility to other diseases, loss of genetic potential, loss of export market, increased medical costs, reduced weight at slaughter, premature culling, poor feed conversion, increased calving interval, and financial loss at auction sales if animals are designated “exposed to Johne’s disease.”1033-1042 In dairy herds where 10% or more of cull cows have clinical Johne’s disease, the estimated loss per cow exceeds $220 for each adult cow in the herd.1043

Biosecurity Practices and Herd Management Plans

The key to preventing, controlling, and eliminating Johne’s disease in a herd is by implementation of a rigorous herd management plan designed to reduce M. avium subsp. paratuberculosis exposure to young calves.1044 Factors such as finances, movement of cattle on the farm, maternity and sick cow pen locations, feed delivery to adult cattle, location and structure of feed bunks, and personnel issues are but a few of the specific issues that need to be reviewed with the final focus on how to best limit transmission of M. avium subsp. paratuberculosis to young calves. Farm managers should adopt two fundamental control principles: (1) prevent highly susceptible newborn calves and young animals from ingesting manure from infected adults, and (2) reduce total farm environmental contamination of M. avium subsp. paratuberculosis by culling infected animals shedding the highest concentrations of M. avium subsp. paratuberculosis. Calves should be separated from their dams at birth and fed single source colostrum from culture-negative and/or ELISA-negative cows. The same management factors that reduce the risk for Johne’s disease also reduce the risk of other fecal-oral diseases such as Salmonella, Cryptosporidium, E. coli, and Campylobacter infection.1045

Fecal culture testing of the whole herd followed by aggressive culling of infected animals is very effective in reducing the prevalence of paratuberculosis in the herd.1044 The risks of transmission of M. avium subsp. paratuberculosis within both dairy and beef herds have been compiled into three major documents, entitled “How to Do Risk Assessments for Johne’s Disease,” “Handbook for Veterinarians and Dairy Producers,” and “Handbook for Veterinarians and Beef Producers.” These documents are available at the national office of United States Animal Health Association (USAHA) and the National Institute for Animal Agriculture (NIAA) website.1046 A companion document entitled “U.S. Voluntary Johne’s Disease Herd Status Program for Cattle” is also available from the USDA website.1047-1049

In herds with low to moderate infection levels (1% or fewer clinical cases per year), wise use of a combination of testing, culling, and biosecurity measures may eliminate clinical disease within 1 to 3 years and most infected adults in 5 to 7 years, as the adult cattle are culled over time. Complete elimination of infected cattle is likely to take many years after clinical Johne’s disease is no longer apparent. Biosecurity measures should remain in place, or Johne’s disease is likely to recur. Herds at low risk for Johne’s disease need to be reminded that a major risk factor for Johne’s disease is the purchase of replacement cattle from herds of unknown Johne’s status. As herd owners continue to expand herd size with the acquisition of purchased animals, Johne’s disease is often included in the purchased cattle.1050

Herds with more severe, widespread infection require aggressive control programs and many years to eliminate clinical Johne’s disease. These herds should consider Johne’s vaccination as one serious alternative to control Johne’s disease. However, a practical control program and sound herd management can eliminate clinical disease in these herds and reduce the economic impact of Johne’s disease to a minimum. Feeding monensin to heifers and all adult cows should reduce the M. avium subsp. paratuberculosis bioburden on the farm and therefore reduce transmission to young susceptible calves.1032 Rather than focused attention to detect all M. avium subsp. paratuberculosis shedders, the diagnostic efforts should focus on elimination of those cattle shedding the highest concentration of M. avium subsp. paratuberculosis, that is super-shedders.980

In addition to the United States, with its well defined voluntary Johne’s disease herd status program,1049 Australia was one of the first countries to implement a national Johne’s disease control program. The National Johne’s Disease Market Assurance Program for Cattle was launched in 1996.1050,1051 Subsequently both Denmark and Holland1052 and more recently Canada have implemented voluntary Johne’s disease programs.1053

Vaccination

A killed Johne’s vaccine is available in several states through an accredited veterinarian with the approval of the state veterinarian required. The vaccine is effective at reducing the prevalence and delays the onset of clinical signs,1054,1055 but does not eliminate infection. Investigations with Johne’s vaccines in sheep and cattle provide the following insights: (1) most Johne’s disease vaccines reduce fecal M. avium subsp. paratuberculosis shedding by approximately 90% compared with nonvaccinated controls; (2) onset of fecal shedding is delayed approximately 1 year postvaccination in sheep; (3) Johne’s disease—vaccinated sheep have reduced mortality compared with nonvaccinates; (4) Johne’s disease vaccines stimulate both a humoral and a cellular immune response in the host, but the site of vaccination may progress to develop granulomas or draining abscesses; and (5) massive M. avium subsp. paratuberculosis challenge may overcome the protective immunity of the vaccine, resulting in clinical Johne’s disease in animals.1056-1062 On occasion in some flocks a vaccinated sheep will develop multibacillary lesions and excrete millions of M. avium subsp. paratuberculosis CFU per gram of manure and thus expose all other sheep in the flock. Thus some vaccinated sheep may serve as vectors if moved to flocks at low risk for Johne’s disease.1063

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Animals must be younger than 35 days old when vaccinated. Reasons some oppose the use of vaccination for Johne’s disease include the following: (1) vaccinated animals will often have a positive skin test for tuberculosis; (2) injection site lesions may develop into granulomas, even abscesses that break and drain; (3) accidental injection of humans is a risk that has resulted in severe painful granulomas1064; (4) vaccination interferes with immunologic tests for Johne’s disease; and (5) some producers rely on the vaccine as the sole management tool for Johne’s disease and neglect herd management changes to reduce the risk of transmission.

Paratuberculosis and Crohn’s Disease

An increasing body of literature implicates mycobacteria as one of the causes of Crohn’s disease, a chronic smoldering inflammatory disease of the gastrointestinal tract of people.1065,1066 Abundant evidence suggests human exposure to M. avium subsp. paratuberculosis may occur from the milk or meat of infected cows and/or the water supply.1067 Many research publications suggest M. avium subsp. paratuberculosis is killed by pasteurization, whereas others provide evidence that M. avium subsp. paratuberculosis does survive pasteurization but in decreased numbers.1067-1072 More recently, retail pasteurized milk from three states was shown to harbor viable M. avium subsp. paratuberculosis in 2.9% of samples tested, with M. avium subsp. paratuberculosis genetic material detected in 64% of the 702 samples of milk tested.1073 Later the same group found M. avium subsp. paratuberculosis in samples of soft cheeses.1074 Because most metropolitan water is not filtered and is collected from rural areas, drinking water may also represent a major potential source of the pathogen. Intestinal cohabitation may change parasitism to clinical disease after a long latency period. Numerous cofactors such as genetic susceptibility, coexistence of other enteric diseases, hormonal factors, and other, poorly understood stress factors may enhance the likelihood of clinical disease after a long incubation period.1075-1078 An association between Crohn’s disease and paratuberculosis has been shown, but a causal relationship remains to be demonstrated. M. avium subsp. paratuberculosis isolates from humans with Crohn’s disease have been shown to be genetically similar to isolates from cattle with Johne’s disease.1079 Recent reports indicate an increasing number of patients with Crohn’s disease in whom M. avium subsp. paratuberculosis has been isolated from breast milk and from the peripheral blood.1080 One critical report defines the characteristics of Crohn’s disease that differentiate it from Johne’s disease, suggesting the two syndromes are in fact different disease processes.1081 For an unbiased review of a possible connection between Johne’s disease and Crohn’s disease, see the report entitled “The Diagnosis and Control of Johne’s disease” by the National Academies of Science.1082

COPPER DEFICIENCY IN RUMINANTS

John Maas

Bradford P. Smith

Definition and Etiology

Copper deficiency occurs when the diet contains an abnormally low amount of copper (primary copper deficiency) or when copper absorption or metabolism is adversely affected (secondary copper deficiency). If inadequate amounts of copper are available to tissues in the form of essential metalloenzymes, the signs of copper deficiency (hypocuprosis) may occur. Clinical signs in ruminants include diarrhea, decreased weight gain, unthrifty appearance, anemia, changes in coat color (achromotrichia) or wool quality, anemia, spontaneous fractures, lameness (epiphysitis), and demyelinization (enzootic ataxia of sheep and goats, or swayback). One of these syndromes usually predominates in a given herd.

The minimum recommended dietary copper concentration (dry matter basis [DMB]) is 4 to 10 ppm (mg/kg) for cattle,1083,1084 5 ppm for sheep,1085 and 7 ppm for merino sheep.1085 Young animals and fetuses are more susceptible to copper deficiency than mature animals, and cattle are more susceptible than sheep. Secondary copper deficiency is associated with high dietary levels of molybdenum, sulfates, zinc, iron, or other compounds. Secondary copper deficiency often manifests with clinical signs of diarrhea and weight loss or unthriftiness. It has been called teart, peat scours, renguerra, pine, and salt lick disease.1086 Salt sickness in Florida appears to be the result of combined copper and cobalt deficiencies. The cause of copper deficiency in clinical cases is often multifactorial and can be difficult to quantify. In addition, unknown factors cause clinical expression of copper deficiency in ruminants to be manifested as a variety of syndromes.

Clinical Syndromes and Differential Diagnosis

Profuse watery diarrhea with poor weight gain and/or weight loss is a common syndrome seen in ruminants with copper deficiency.1086 When it occurs in animals on boggy pastures that contain high concentrations of molybdenum, it has been referred to as teart.1086 Decreased weight gain or weight loss as a herd problem can have many other causes, including parasitism, trace mineral deficiencies (selenium, cobalt), protein calorie malnutrition, and Johne’s disease. A syndrome characterized by epiphyseal enlargement, stiffness, and unthriftiness is seen in young ruminants as a result of copper deficiency1087 and is sometimes called pine.1086 Copper deficiency can cause spontaneous fractures in ruminants. Enzootic neonatal ataxia (swayback) of lambs and kids is characterized by progressive incoordination and recumbency that begins with the hindlimbs and progresses to the forelimbs. It has also been reported in deer and pigs. Inadequate keratinization of wool and achromotrichia are the result of imperfect oxidation of free thiol groups during hair growth and keratinization. Subsequently the wool fibers do not crimp normally, and they appear to be “stringy” or “kinky.” A copper-containing enzyme, tyrosinase (polyphenyloxidase), is needed to convert L-tyrosine to melanin. With copper deficiency, this conversion is slow and hair is lighter in color than normal (achromotrichia). Loss of wool crimp and pigmentation changes in sheep or cattle, respectively, occur late in the course of copper deficiency. In addition to the described clinical syndromes, which may occur alone or jointly, copper deficiency may be associated with anemia1088 (altered iron metabolism) or infertility.1089 Infertility is probably multifactorial and may not respond to an increase in copper intake alone. Copper deficiency also seems to result in decreased immune function in ruminants.1090,1091

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Pathogenesis

A frank dietary deficiency of copper results in hypocuprosis and eventual clinical signs. Also, a variety of conditions can decrease copper absorption from the gastrointestinal tract (large intestine in sheep and small intestine in cattle). The interactions among dietary copper, molybdenum, and sulfates (or sulfur) are important (Fig. 32-106). Excess dietary molybdenum can lead to the formation of sparingly soluble cupric molybdates in the rumen that are not absorbed from the intestine. The addition of excess sulfur or sulfates in the diet and/or water can result in the formation of insoluble copper thiomolybdates in the rumen. The interactions among these three elements are complex.1092 The infertility seen with secondary copper deficiency may be a result of excess circulating oxythiomolybdates, which interfere with the release of luteinizing hormone.1093 It is important to note that at low sulfur concentrations in the diet excess molybdenum has a minimum effect on decreasing copper absorption. Even when no dietary molybdenum or sulfates are present, only about 5% of ingested copper is normally absorbed. Excessive calcium in the diet, particularly in the form of limestone, decreases copper absorption. Excessive iron, 30 mg/kg of body weight or 1200 ppm in the diet of calves, reduces copper absorption.1094 Overgrazing, with the subsequent ingestion of excess soil, also decreases copper absorption. In addition, excess cadmium (3 to 7 ppm) or excess zinc (100 to 400 ppm) reduces hepatic copper concentration, probably through the combined effects of decreased absorption and competition with copper for hepatic metallothionein.1095,1096 It had been suggested that excess dietary selenium might interfere with copper absorption and/or usage; recently this was shown not to be the case.1097 Copper is an essential component of a number of mammalian enzymes. Some of the medically important copper-containing enzymes are (1) the cytosol form of superoxide dismutase (copper and zinc), (2) cytochrome oxidase (c and aa3), (3) lysyl oxidase, (4) ascorbic acid oxidase, and (5) ceruloplasmin.1098 In addition, normal copper nutrition appears essential for iron absorption and transportation of iron to the liver and reticuloendothelial system and is therefore necessary for normal hemoglobin formation. The precise pathophysiology of most of the copper deficiency syndromes is not known. However, the central role of copper in preventing cellular oxidative damage and its role in iron and sulfur metabolism are probably important.

image

Fig. 32-106 Estimating the availability of copper in herbage from its molybdenum and sulfur concentration. The difference of 3 mg of molybdenum and 0.5 g of sulfur per kilogram of dry matter between pastures A and B is sufficient to reduce availability from 2.6% to 1.3%, doubling the grazing animal’s requirement of copper from the pasture.

From Suttle NF: Copper deficiency in ruminants; recent developments, Vet Rec 119:519, 1986.

Epidemiology

Copper deficiency can occur when diets are inadequate in copper or contain excess amounts of interfering substances, particularly sulfates and molybdenum. This occurs in many parts of North America. Forages and water can be sources of molybdenum, sulfur, and sulfate. To avoid primary copper deficiency, pasture (dry matter) should contain over 5 ppm of copper, with 3 to 5 ppm considered marginal, and less than 3 ppm deficient. Soil copper concentrations are generally slightly lower than those of the harvested forage. Molybdenum adversely affects plant uptake of copper. Forage molybdenum concentrations greater than the copper concentrations often lead to secondary copper deficiency, even when forage copper is adequate. Because copper content in grasses and legumes can be different, forage samples must be randomly selected to reflect dietary intake. Forage copper concentrations as high as 12 to 27 ppm have been associated with copper deficiency when molybdenum levels are high.1086 The critical ratio of copper to molybdenum in feeds is 2:1, with 5:1 recommended for sheep and 5:1 to 10:1 for grazing cattle.

Clinical Pathology and Diagnosis

The primary site of copper reserves is the liver, and the copper concentration in the hepatic tissue is the best indicator of copper status (Fig. 32-107). The reference range for hepatic copper concentrations in cattle is approximately 90 to 200μg/g (ppm) and in sheep 90 to 250μg/g on a dry weight basis (DMB).1086,1099,1100 Hepatic copper concentrations as high as 250μg/g DMB are not unusual in supplemented ruminants (even over 350μg/g DMB in sheep). Blood copper concentrations can be maintained near normal until hepatic copper concentration falls to 35ppm DMB or less, at which time the serum copper concentration invariably begins to decrease.1101 When using blood samples for copper determination, serum or plasma is normally preferred. Plasma copper concentration is usually about 5% greater than an identical serum copper concentration.1102 Normal serum copper is 0.7 to 1.2ppm (μg/mL).1086,1098 Serum or plasma copper concentrations of 0.4ppm or less are considered evidence of frank deficiency. Values of 0.4 to 0.7ppm are marginal, and it is difficult to estimate the actual liver copper concentration. Approximately 50% to 90% of the copper in serum or plasma is present in ceruloplasmin. The remainder is bound to albumin or amino acids. The correlation between serum copper and serum ceruloplasmin was found to be weak (0.50)1102; therefore ceruloplasmin is not commonly used to aid in diagnosing copper deficiency. Hepatic copper concentration is the preferred diagnostic sample and is easily secured at necropsy. Hepatic copper values less than 35ppm DMB are considered deficient.1086,1099-1101 However, surgical biopsy is necessary for live patients, and because laboratories generally require 100mg or more of tissue, a biopsy instrument with an internal diameter of 3 to 5mm is necessary.1103 The biopsy procedure in cattle is performed by locating the tenth intercostal space on the right side of the animal along a line from the tuber coxae (point of the hip) to the point of the shoulder.1103 This site is surgically prepared and blocked with lidocaine (12mL of 2% lidocaine), and a stab incision is made. The biopsy instrument is directed slightly ventrad and craniad and advanced through the intercostal space and the diaphragm to enter the liver, where the biopsy sample is obtained.1103 The liver biopsy can place the patient at increased risk for black disease or bacillary hemoglobinuria in some areas of the United States. This risk should be decreased by prior vaccination and a single dose of procaine penicillin G (4 million I.U. SC) administered at the time of the biopsy.1103 This technique has been shown to be safe and effective.1103 The tissues of young animals (neonates) contain variable amounts of copper compared with adults of the same species. In sheep, serum and liver copper concentrations are the same for lambs (1 week of age) and adults.1104 The plasma copper levels in lambs are low at birth but rise to adult values by 1 to 7 days of age. Plasma copper levels in the bovine neonate are lower than in mature cattle.1105 In the bovine neonate hepatic copper concentration changes little from birth to maturity; however, copper distribution in the liver is quite variable in the neonate.1100,1105 Because of these differences, interpretation of neonatal serum copper concentrations is difficult. Milk is a poor source of copper, containing only 0.2 to 0.6ppm in normal ewes and 0.01 to 0.02ppm in severely copper-deficient ewes or cows. Milk copper in cattle is 0.05 to 0.2ppm. To make matters worse, molybdenum is concentrated in milk.1106

image

Fig. 32-107 Relationship between the serum and hepatic copper concentrations in ruminants.

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Treatment and Control

Treatment of copper-deficient animals is usually possible, and the prognosis is guarded to good, depending on the severity of the deficiency and the associated syndrome(s). When excess molybdenum, sulfate, and other factors leading to secondary deficiency are present, they can be overcome to some extent by increasing dietary copper or by injecting copper glycinate. Copper glycinate must be prescribed by the attending veterinarian and dispensed by a compounding pharmacy because no commercial over-the-counter products are currently available. Injectable copper glycinate (30% copper by weight) is given to adult cattle at the rate of 400mg (120mg of copper) SC. Calves are given 100 to 200mg of copper glycinate (30 to 60mg of copper), depending on their age. One injection may be effective as a treatment or supplement for up to 4 to 6 months in cases of primary copper deficiency. However, in cases of excess molybdenum, sulfates, and/or sulfur, repeat injections may be necessary. Injections of copper glycinate frequently result in large swellings, granulomas, or abscesses and may be cosmetic considerations for some cattle. The reactions can be minimized by using sterile technique and using the subcutaneous tissue of the brisket as the injection site. Acute deaths can occur in calves after the use of copper glycinate injections. In some countries copper disodium edetate (copper EDTA) solutions are used as injectable copper supplements. The dose of copper is usually the same as that recommended for copper glycinate solutions. However, acute deaths can also occur after use in cattle.1107 Copper can be supplemented to cattle in salt-mineral mixes in situations in which adequate consumption (1 to 2oz [28 to 56g]/cow/day) of the salt-mineral mix occurs. These mixes are usually 0.2% to 0.6% copper. Feed-grade copper sulfate (CuSO4-5 H2O) is 25% copper on an as-fed basis (40% copper DMB). Feed-grade copper oxide is usually 50% copper as fed (80% copper on 100% DMB). To make a 0.4% copper salt mixture, add 7.2g of CuSO4 or 3.6g of CuO to each 454g (1lb) of salt. For large batches add 32 ob of CuSO4 or 16lb of CuO per ton of salt. Salt mixtures for copper-deficient sheep should usually contain only 0.0625% to 0.13% copper (0.25% to 0.5% copper sulfate). Copper supplements can be added to a TMR easily in the form of trace mineral—vitamin premixes or premix-containing pellets. Copper sulfate can be added to molasses or other sweet feed at 0.363g/head/day for mature cattle and correspondingly less for calves. This would supply approximately 91mg of copper to a 450-kg (1000-lb) cow per day or 10ppm of the total diet (20lb [9.1kg] of dry matter). The copper in CuSO4 is more available than that in CuO. Another method of copper supplementation involves the oral administration of copper oxide needles (fine rods, 1 to 10mm long) placed in gelatin capsules, which dissolve in the reticulorumen and liberate the CuO wires. These wires reside in the reticulum and abomasum and slowly release copper for absorption. These boluses are currently available in the United States (Copasure) and contain either 25g or 12.5g per bolus. The usual recommended dose is 25g per animal 500lb or heavier. One 12.5-g bolus is recommended for calves, and the usual dose is 2 to 4g for ewes and does,1086,1108,1109 which is an extralabel recommendation for sheep and goats. The copper oxide needles are thought to provide copper supplementation for 4 to 12 months. Sheep are particularly susceptible to copper toxicity, and appropriate care is necessary when supplementing them. Sheep can easily be intoxicated when consuming cattle supplements or feeds. Continued monitoring of hepatic copper concentration from slaughtered animals or via liver biopsy is an important tool in evaluating copper supplementation methods in cattle and sheep. Lambs can be given 35mg of copper sulfate per head twice weekly to prevent swayback in endemic areas. The usual recommendation by the National Research Council is 10ppm (10mg/kg) of the total diet DMB for cattle. However, diets of 20ppm are commonly fed to lactating dairy cattle. The most important goal of copper supplementation is to provide adequate dietary amounts without oversupplementing or risking toxicity.

COBALT DEFICIENCY IN RUMINANTS

John Maas

Definition and Etiology

A number of syndromes occur in ruminants as a result of a primary cobalt (Co) deficiency in their diet. These include ill thrift or enzootic marasmus and anemia. These conditions are characterized by decreased growth, weight loss, diarrhea, decreased feed efficiency, unthrifty appearance, anorexia, and anemia. Recently, a Co deficiency syndrome referred to as ovine white liver disease has been described in sheep.1110-1112 This syndrome is also characterized by ill thrift, weight loss, serous ocular discharge, and occasionally photosensitization.1110-1112 Histopathologic lesions of this syndrome included accumulation of lipid droplets and lipofuchsin particles, dissociation and necrosis of hepatocytes, and sparse infiltration by neutrophils, macrophages, and lymphocytes.1112

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Clinical Signs and Differential Diagnosis

Co deficiency in ruminants is associated with the nonspecific signs of decreased growth, weight loss, diarrhea, ill thrift, pica, emaciation, pale mucous membranes (anemia), and lacrimation. Clinical disease is more common in young, growing animals. Sheep are apparently more susceptible to Co deficiency than cattle. Primary differential diagnoses include helminthic parasitism; protein-calorie malnutrition; coccidiosis; Johne’s disease; nutritional deficiencies of selenium, copper, or vitamin D; and other causes of chronic disease that may be associated with weight loss.

Co-deficient ruminants are commonly anorectic and fail to thrive on lush pasture or high-quality feeds. Anemia with cobalt deficiency is characterized as normocytic normochromic and must be differentiated from other causes of anemia. Co-deficient cattle are more susceptible to infestation with Ostertagia ostertagi and to the effects of parasitism.1113 The primary differential diagnosis when considering Co deficiency is invariably internal parasitism.

Clinical Pathology and Diagnosis

Because the role of Co in ruminant nutrition is tied to the formation, absorption, and use of vitamin B12, the most significant clinical chemistry analysis is tissue vitamin B12 concentration. However, the effects of starvation tend to increase vitamin B12 concentrations in liver and kidney.1114 If Co deficiency occurs with other conditions that cause anorexia, the tissue vitamin B12 concentrations may appear falsely normal. Criteria used for sheep1115 (and by extrapolation for cattle) are found inTable 32-24.

Table 32-24 Criteria Used to Determine Cobalt Deficiency in Sheep

Condition of Animal (Co or B12 status) Concentration of Vitamin B12 (mcg/g of Fresh Liver)1115
Severe cobalt deficiency <0.07
Moderate cobalt deficiency 0.07–0.10
Mild cobalt deficiency 0.11–0.19
Cobalt sufficiency >0.19

Serum vitamin B12 analysis is advantageous in many clinical settings. Serum or plasma vitamin B12 levels exhibit a marked diurnal variation.1116 Serum vitamin B12 concentration more closely reflects short-term Co intake and can be decreased when adequate liver reserves of vitamin B12 remain. In normal, Co-sufficient ruminants, serum vitamin B12 values are usually 1 to 3ng/mL. When serum vitamin B12 values decrease to 0.3ng/mL, the threshold for clinical signs has been reached; when serum vitamin B12 values of 0.2ng/mL or less are reached, marked signs of Co deficiency are evident.1117

Severe Co deficiency in ruminants results in the excretion of methylmalonic acid (MMA) and formiminoglutamic acid (FIGLU) in the urine.1118 Urinary FIGLU levels of 0.08 to 0.2μmol/mL would be presumptive evidence of Co deficiency, and the urinary FIGLU level should return to zero after vitamin B12 administration. Use of urinary MMA for diagnosis is best accomplished by loading the rumen with propionate and then comparing the urinary excretion of MMA with and without vitamin B12 supplementation. The fact that urinary MMA and FIGLU excretion occur very late in the course of Co deficiency limits the routine use of these methods for diagnosis.

Pathophysiology

Co deficiency in ruminants induces a deficiency of vitamin B12 (cyanocobalamin). It is the lack of vitamin B12 that is thought to cause the majority of clinical signs and clinicopathologic abnormalities observed. Monogastric species need to ingest vitamin B12 preformed, whereas ruminants can manufacture adequate vitamin B12 if the ruminal microorganisms are supplied with adequate Co in the diet. The ruminal microorganisms incorporate Co into vitamin B12 and a number of physiologically inactive vitamin B12-like compounds. The production of vitamin B12 from dietary Co was estimated in one study to be about 15% in Co-deficient sheep and only about 3% in Co-sufficient sheep.1119 About 50% of the vitamin B12 produced is absorbed in normal animals, but only 3% to 5% of vitamin B12 is estimated to be absorbed by Co-deficient sheep.1120 Although the absorption of vitamin B12 formed in the rumen is not particularly efficient, with normal dietary Co there are usually no clinical problems, and interference by other dietary components does not appear to be important.

Ruminants use the VFAs acetate, propionate, and butyrate as their primary energy source. Propionate produced in the rumen is the precursor of glucose for ruminant metabolism. The general metabolic steps for conversion of propionate to glucose are shown1121 (Fig. 32-108).

image

Fig. 32-108 Pathway for conversion of proprionyl CoA (from proprionate) to succinyl CoA.

A primary defect in Co-deficient ruminants is the inefficient metabolism of propionate at the point in the pathway at which methylmalonyl-CoA mutase, a vitamin B12-requiring enzyme, catalyzes the conversion of methylmalonyl-CoA to succinyl-CoA.1122 As Co deficiency becomes severe, the rate of propionate clearance from the blood decreases, and the intermediate metabolite methylmalonyl-CoA accumulates.1123 With severe Co deficiency, the amount of MMA excreted in the urine increases.1118 As the half-time for propionate clearance increases, the voluntary feed intake of Co-deficient sheep decreases.1123 These changes correlate with the degree of anorexia and weight loss observed in severely Co-deficient sheep.

The decreased growth, weight loss, unthrifty appearance, and anorexia are closely correlated to the observed abnormalities of carbohydrate metabolism. The diarrhea commonly observed with Co deficiency is not well explained; however, an increase in susceptibility to parasitism1110 might explain a portion of this clinical observation.

The anemia that is associated with Co deficiency occurs late in the development of the syndrome and is characterized as normocytic normochromic.1124 Cobalt deficiency results in the depression of the vitamin B12-containing enzyme 5-methyltetrahydrofolate homocysteine methyltransferase.1125 This interference with the recycling of methionine has a marked influence on folate metabolism. In addition to potentially resulting in anemia through inefficient folate metabolism, the decreased activity of this methyltransferase could lead to a deficiency of methionine; this is a possible reason for nitrogen retention and decreased body growth and wool growth observed.

Epidemiology

Co deficiency in ruminants occurs in selected regions throughout the world and in association with a variety of soil types. Clinically recognizable Co deficiency is reported in New Zealand, Australia, Brazil, the United Kingdom, Ireland, Scandinavia, and North America. In the United States, Co deficiency is most commonly seen in Florida, in the Northeast, along the eastern seaboard, in the upper Midwest, and around the Great Lakes.1126 Although various soil types are associated with Co deficiency, heavy fertilization with limestone reduces the Co available to plants and animals.1127

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The dietary intake of Co by ruminants is generally recommended to be 0.1mg/kg of dry matter (DM) of the complete ration.1128-1130 The Co requirement of young, rapidly growing lambs is thought to be 0.2mg/kg of DM of the diet.1131 When pasture Co concentrations are less than 0.07mg/kg of DM or 0.04mg/kg of DM for sheep and cattle, respectively, signs of deficiency can be expected to develop. On a practical basis, diets with 0.1mg/kg of DM are considered to be adequate. Legumes have relatively high Co concentrations. Rapidly growing grasses have much lower Co concentrations, and cereal grains are poor sources of Co.1128 Oilseed meals are generally good sources of Co.

Treatment and Control

Treatment is best accomplished in the short term with vitamin B12 injections. Ruminants poorly absorb oral vitamin B12; therefore injections are more efficient. Lambs receiving 100μg of vitamin B12 per week or 150μg of B12 every other week show remission of clinical signs.1132 Sheep receiving injections of 300μg of vitamin B12 weekly or cattle receiving 2000 to 3000μg of vitamin B12 weekly would also be expected to regain normal status.

Rations with 0.1 to 0.2mg of DM Co per kilogram (ppm) would be expected to prevent Co deficiency in ruminants. Salt-mineral mixes containing 0.1% Co also provide adequate supplementation. 0.1% Co in salt can be made by mixing cobalt carbonate (which is 46% cobalt) at the rate of 4.35lb/ton of salt, or 1g of cobalt carbonate per pound of salt.

Cobalt sulfate as a top dressing for pastures (1.5kg/hectare every 3 to 4 years or 0.3kg/hectare every 1 to 2 years) has been used to increase Co concentration of pasture forage. Heavily limed pastures1127 and soils high in manganese oxide1133 decrease Co availability, and Co top dressing of the pastures or Co (B12) supplementation to the animals should be considered.

A variety of ruminal pellets containing Co are used to supplement grazing ruminants. These pellets have been successful in maintaining normal Co status in animals.1131-1134 The pellets are not commercially available in the United States at this time.

The perennial grass, Phalaris tuberosa, can cause a syndrome in ruminants that is referred to as “phalaris staggers.” Co supplementation can aid in prevention of this syndrome because it inactivates or decreases absorption of the neurotoxin contained in P. tuberosa, Phalaris minor (canary grass), or Phalaris hybrids (ronpha).1135 The increased level of Co in the rumen is the important factor in preventing this condition; administration of oral or parenteral vitamin B12 is not effective.1135 Treatment of clinical phalaris staggers with Co is not effective, however.

Because Co is poorly absorbed, toxicity is an uncommon problem, and diets in excess of 30mg/kg of DM are necessary for toxicosis to occur in most cases.1128-1130

RECTAL PROLAPSE IN RUMINANTS AND HORSES

Spring K. Halland

Definition and Etiology

Rectal prolapse is the protrusion of the rectal mucous membranes through the anus. This evagination may be extensive and may include part of the small colon. Rectal prolapse occurs in all domestic animals, with the highest incidence in cattle, sheep, and swine. The age at which prolapse most commonly occurs is 6 to 12 months in sheep, 6 months to 2 years in cattle, and 6 to 12 weeks in swine.1136 Rectal prolapse is much less common in horses and occurs more often in mares than in males.1137

Rectal prolapse generally is the result of an increase in the pressure gradient between the abdominal or pelvic cavity and the anus. Factors that cause the increased pressure gradient can be divided into four categories: (1) factors that result in increased abdominal fill (e.g., excess fat, bloat, and large or multiple fetuses); (2) factors that cause tenesmus (e.g., enteritis, colitis, intestinal parasitism [coccidiosis], liver disease, constipation, proctitis, urinary obstruction, dystocia, aftermath of rectal examination, and false copulation); (3) conditions that result in chronic or excessive coughing (e.g., pneumonia, parasitism, and adverse environmental conditions); and (4) miscellaneous conditions (e.g., use of growth implants, space-occupying lesions, congenital or acquired sphincter tone problems, and short tail docking [especially noted in sheep]). One study strongly revealed that sheep with short docked tails (as close to the body as possible) had a 7.8% higher incidence of rectal prolapse when finished on a high concentrate diet.1138 Certain toxicities such as from lead, fluoride, estrogen, and zinc have been implicated as playing a role in rectal prolapse.1139 Any combination of factors may precipitate a rectal prolapse. Identification of predisposing factors becomes important in management of the case.

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Clinical Signs

Four categories have been used to described rectal prolapse: type I, mucosal prolapse; type II, complete prolapse; type III, complete prolapse with invagination of the colon; and type IV, intussusception of the peritoneal rectum or colon through the anus (Fig. 32-109).1140 Types I and II are much more common and more amenable to correction. On physical examination, types I, II, and III are continuous with the mucocutaneous junction of the anus, whereas with type IV a protrusion with a palpable trench inside the rectum is seen.1140 Chronic cases can be seen and usually are type I or II. Types III and IV often cause loss of vascular integrity to the rectum or small colon and require more immediate intervention. Types III and IV may accompany dystocias in mares.1141

image image image image

Fig. 32-109 A, Type I rectal prolapse. Mucosal prolapse, involving only mucosa and submucosa of the rectum. B, Type II rectal prolapse. Complete prolapse, involving full wall thickness of the rectum. C, Type III rectal prolapse. Complete prolapse plus intussusception of peritoneal rectum or small colon. D, Type IV rectal prolapse. Intussusception of the peritoneal rectum or small colon or both.

From Robinson NE, ed: Current therapy in equine medicine, ed 2, Philadelphia, 1987, Saunders.

Treatment and Prognosis

The first aim of therapy is identification and alleviation of the cause if possible. Early identification and correction of the prolapse is essential to saving tissues and the animal. The animal’s value and intended use and the affected tissue’s viability need to be considered when deciding on conservative or surgical options. The color of the membranes is a good parameter for determining if the tissue is salvageable. In general, the rectum is a forgiving structure, and attempts should be made to salvage the prolapsed tissue unless it is obviously cyanotic, necrosed, and devitalized.1136 To prevent further damage, animals should remain standing and restrained in a small area until the prolapse can be corrected.

Types I and II usually are treated conservatively. A caudal epidural is necessary to reduce straining and facilitate correction of the prolapse. Sedation may also be necessary, depending on the individual animal. Effective conservative therapy includes thorough cleansing of the prolapse with warm water and mild soap to remove all debris. This allows evaluation for trauma, tears, necrosis, or sloughing. Edema can be removed by gentle kneading combined with topical application of glycerin or sugar. Generous lubrication and massage allow for reduction of the mass into the rectum. To ensure that the rectum is maintained in place, purse-string sutures using umbilical tape or other nonabsorbable suture are placed circumferentially around the anal sphincter, with care taken not to enter the rectum. The purse-string should not be so tight as to prohibit the passage of feces. If necessary, it should be loosened daily to expedite removal of accumulated fecal material. The purse-string should be removed in 3 to 4 days. In addition to purse-string sutures, counterirritants such as Lugol’s iodine are often used.1136 Two to 3mL of these irritants are injected with a 7.5-cm needle at the 4, 8, and 12 o’clock positions around the rectum. The counterirritants create an inflammatory response that results in scar formation, which retains the prolapsed tissue after the purse-string has been removed. Broad-spectrum antimicrobial drugs should be administered if tissue compromise is a factor. When indicated, stool softeners and enemas may be used to ease the passage of feces through the rectum.

Surgical intervention often is necessary if type I or type II prolapse cannot be reduced, if tissue necrosis is extensive, or if prolapse recurs after conservative therapy.1140 Submucosal resection, amputation, or the use of a prolapse ring are all accepted surgical options. Prolapses of types III and IV that cannot be manually reduced often require a celiotomy for surgical reduction of the intussusception or resection or both. An important fact to remember is that even with manual reduction of a type IV prolapse, significant vascular compromise may have occurred, resulting in bowel leakage and peritonitis. Vascular damage encountered by the colon may necessitate a colostomy.1486 Broad-spectrum antimicrobial drugs should be administered in these cases.

Unique problems are encountered when conservatively managing equine rectal prolapse versus ruminant prolapse. Equine patients may experience more hindlimb ataxia with caudal epidurals, which can be prevented by using different combinations of xylazine, lidocaine, detomidine, morphine, and/or mepivacaine in the epidural. Placement of an epidural catheter can facilitate long-term therapy if needed.1142 Another problem encountered is that horse feces often are too large and dry to readily pass through the purse-string in the anus. The use of enemas and stool softeners offers some assistance. The sutures tend to cause greater anal irritation than is seen in ruminants, causing the horse to strain against them.

The common complications after rectal prolapse include prolapse recurrence, rectal strictures, obstipation, formation of a pararectal abscess, and peritonitis. The prognosis for all types of rectal prolapse depends on early identification and reduction of the prolapse. Prolapses of types I and II that can be managed conservatively have a favorable outcome. Surgical correction of types I and II also carries a good prognosis but with a higher incidence of postsurgical complications. Because of the cost of surgical repair, market animals often are slaughtered if conservative management fails. Rectal prolapses of types III and IV carry a fair to guarded prognosis, which depends on the extent of tissue involvement and viability, the surgeon’s skill, and postsurgical complications.

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473 Deleted in proofs

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808 Lloyd K, Hintz HF, Wheat JD, et al. Enteroliths in horses. Cornell Vet. 1987;77:172.

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817 Johnston JK, Freeman DE. Diseases and surgery of the large colon. Vet Clin North Am Equine Pract. 1997;13:317.

818 Hackett RP. Nonstrangulated colonic displacement in horses. J Am Vet Med Assoc. 1983;182:235.

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