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Icterus in Foals

In the foal icterus is caused by increased levels of bilirubin in the blood caused by hemolysis, sepsis, or liver failure. Treatment of these diseases depend on the cause which can be separated out with description, physical exam, and laboratory evaluation. The most common cause of hemolytic disease is neonatal isoerythrolysis. Other causes of hemolysis are disseminated intravascular hemolysis, bacterial toxin induced hemolysis, and incompatible blood transfusions. Hyperbilirubinemia can also be caused by hepatobiliary disease, in the neonate the most common of is hepatocellular necrosis which can be caused by Equine Herpes Virus 1 infection, bacterial hepatitis secondary to sepsis, or hepatic dysfuction with asphyxia during birth. In the older foal liver disease is most commonly caused by necrotizing hepatitis seen with Tyzzers disease and by cholangiohepatitis caused by biliary stasis due to ulcers of the stomach and duodenum.

Pathophysiology of Icterus and Bilirubin

Icterus, a yellow tint to the body tissues, occurs when bilirubin exceeds 1.5 mg/dl in the plasma due to either hemolytic disease or hepatobiliary disease. Bilirubin is the major end product of hemoglobin degradation when red blood cells die and release their contents. Macrophages engulf the released hemoglobin and the heme ring of the hemoglobin molecule is opened. Biliverdin gets formed from this and is rapidly reduced to free bilirubin which is released from the macrophages into the plasma. This form is the unconjugated form. The free bilirubin from here combines with albumin and is transported in blood like this. It travels to the liver cells and gets released from the albumin and it then passes to the inside of liver cells. Here it is conjugated with glucuronic acid to form bilirubin glucoronide. From here it can be excreted in the bile. There are three mechanisms that cause icterus: prehepatic, hepatic, and post hepatic. Prehepatic is due to hemolytic disease. Hepatic is caused by diseases that affect the liver parenchyma. Post hepatic is due to obstruction of the bile duct. Prehepatic disease occurs when the liver gets overwhelmed because of hemolytic disease where red blood cells are rapidly hemolyzed such that the liver cant excrete bilirubin quickly enough so the free bilirubin concentration in the plasma exceeds normal levels. Also the rate of urobilinogen formation increases and much of it is absorbed in the blood to increase concentrations even further. This bilirubin will be unconjugated. Icterus can also be caused by hepatic disease where the liver can not conjugate the bilirubin because of the nonfunctioning hepatocytes or it can not excrete conjugated bilirubin into the bile. Thus the conjugated and unconjugated levels of bilirubin are increased. Biliary disease (post hepatic icterus) where the liver can not effectively excrete the bilirubin in the bile occurs because of obstruction of the bile ducts. Bilirubin still enters the hepatic cells and gets conjugated but then it leaks into the blood from ruptured bile canaliculi. This type of icterus can be distinguished from the hemolytoic type because the bilirubin will be conjugated only. Icterus is more pronounced with greater elevations in conjugated bilirubin.

Common Mechanisms of Icterus in Foals

1. Mild physiological icterus This is type of icterus is very common in new born foals and it is usually transient. It should be evaluated but it is not cause for concern. It can be caused by small amounts of food intake due to milk feeding, destruction of red blood cells at birth, or prebirth loading of the hepatocytes. Mild icterus due to anorexia does not occur significantly in the foal. 2.Neonatal isoerythrolysis This type of icterus occurs when an older foal drinks colostrum with allo-antibodies from an Aa or Qa allo-antigen negative multiparous mare. These antibodies cause hemolysis and destruction of the red blood cells (isoerythrolysis) and resultant anemia and icterus. The mare develops allo-antibodies to the these antigens from a previous parturition. These antibodies develop in response to a previous foals blood because of foreign antigenic factors that are inherited from the stallion. The foal’s blood leaks into the mares during parturition and stimulates the immune response. The first foal will be unaffected. The subsequent foal, though healthy at birth, nurses and within 24-72 hours the foal develops neonatal isoerythrolysis: progressive icterus, anemia, pale mucous membranes, hemoglobinuria, weakness, tachypnea, and tachycardia. These signs can progress to death which occurs with lack of tissue oxygenation due to anemia. The hallmarks of the disease are anemia and hemoglobinuria which are caused by intravascular hemolysis. 4 criteria for an NI foal: 1. mare is negative for Aa or Qa	   2. stallion is positive for Aa or Qa	    3. foal inherits Aa or Qa	    4. mare produces antibodies against Aa or Qa because of previous foaling 3. EHV-1 This is icterus is severe and occurs immediately after delivery and before colostrum ingestion and is accompanied by markedly injected mucous membranes. Because it is caused by the Equine Herpes virus-1 abortion storms and premature/fading foals are seen with the disease. When foals do survive birth they die soon after death as the disease is fatal. Hepatic necrosis and interstitial pneumonia are two primary diseases associated with this virus in foals. The virus is passed through vertical transmission through the blood via placenta or through endothelial cells of the uterus and placenta. The virus travels in leukocytes. The foal is aborted or prematurely delivered either because of direct infection of the fetus or because of vasculitis or thrombosis of the placental or endometrial vessels. The mare often has precocious udder development and foals in addition to icterus and injected mucous membranes are weak, depression, progressive respiratory distress, and septic shock associated with multi-organ system failure. Aborted fetuses should be handled with care because they are highly infective fomites. Infected animals should be separated from the herd for at least 2 weeks because the virus is contracted via the respiratory route. 4. Tyzzer’s Disease This type of icterus is caused by acute bacterial hepatitis and necrotizing liver necrosis due to an infection with Clostridium piliformis, a spore forming, soil and manure born gram negative rod. This is a rare disease and effects of the disease occur rapidly with an acute onset of severe icterus, rofound depression, mucous membrane hyperemia, hypotension, diarrhea, shock and collapse in older foals (7-42 days of age). Uncontrolable seizures and coma can occur followed by death. Sudden death can occur within hours of being normal. It is often the best foals that are affected most likely because theses are the ones receiving the best nutrition and growing faster. Route of infection is most likely oral ingestion of the organism from feces of infected horses as well as investigation by foals of contaminated soil. After ingestion spores pass to the liver via the portal system. 5. Other 1. Sepsis Icterus that occurs with sepsis is caused by either biliary stasis, secondary bacterial hepatitis, or hemolyisis as occurs with DIC. Prepartum may see the mare driipping milk or vaginal distarge that would lead you to suspect septicemia. Clinical signs to look for are injected mucous membranes, progressive weakness, and depression accompanied by leukopenia, metabolic acidosis, and hemoconcentration 2. Hypoxia/asphyxia during birth- this type of icterus is occurs in foals showing other signs of hypoxic ischemic encephalopathy such as stupor, seizures,and abnormal mentation. This disease can occur in foals of dystocias or placental disease such as premature placental seperation, placental edema, and placentitis. Liver disease caused by hypoxia usually resolves when the primary problem resolves. 3. Gastro-duodenal ulcers- These occur commonly in foals especially with a prolonged diarrhea. Most ulcers are found in the glandular region of the stomach (adults get them along the margo plicatus) Icterus occurs with ulcers because of delayed gastric emptying due to stricture and bile stasis. It can also occur with ulcers because of internal bleeding and overwhelming of the liver with bilirubin. 4. Hepatoencephalopathy in Morgan weanlings- This type of icterus is associated with abnormal behavior, thriftiness, and poor growth after weaning. Affected foals show signs of hepatic encephalopathy such as dementia and depression. The disease is thought to be related to a deficiency in ornithine thats required for urine synthesis. The deficiency of ornithine is due to a defective mitochondrial transporter protein. Blood ammonia increases along with ornithine concentrations in the blood. There is no treatment. 5. Piroplasmosis- This type of icterus is caused by an infection with Theileria equi or Theileria caballi that are intracellular protozoa of redblood cells. T. equi is much more significant then T. caballi as a cause for disease in newborn foals. The neonatal form is born with a high fever, icterus, and profound anemia. Splenomegaly and hepatomegaly are present in these foals as well. T. caballi can cause weak foals that develop more obvious symptoms over the next 2 weeks. Infection occurs via the placenta to foals and is transferred via ticks in adults. Stress may be a risk factor for the disease in the mare and she can serve as a resevoir of infection for the fetus. 6. Excessive iron- This type of icterus can occur when iron supplements are fed to foals with in the 1st 3-5 days of life. It causes a necrotizing liver disease. Foals typically have high serum iron at birth so there is little reason to administer excess. Iron has a high absorptive capacity from the gut during the 1st few days of life. With supplementation transferrin can become overwhelmed and free iron will be delivered to the liver. The only warranted use of iron is in foals that are restricted to milk diets who dont get enogh iron and can develop anemia. Clinical signs include blindness, seizures, and other signs of hepatoencephalopathy. 7. Excessive copper- Due to inappropriate copper supplementation. Copper often gets supplemented becase it is found that ruminants grazing on the same pasture have decreased copper. Copper is stored in the liver and it is necessary for red blood cell production. Intravascular hemolytic anemia with hemoglobinuria and hematuria are seen and sometimes anterior abdominal pain and may be followed by sudden death. 8. hemorrhagic causes- 1. DIC- This type of icterus is due overwhelming hemorrhage and overload of the liver with bilirubin. It occurs due to the consumption of clotting factors and fibrinolytic proteins and platelets. 2. Internal hemorrhage- This can be due to retroperitoneal, intra-abdominal, intrathoracic hemorrhage. Icterus occurs because internal bleeding overwhelms the liver with bilirubin that can not be conjugated quickly enough.

Physical Exam/Laboratory Data

Physical Exam: The best way to assess icterus through clinical observations is via the sclera which should be examined in natural light. An icteric index can be obtained by comparison of the color of different samples of plasma using a potassium dichromate chart. A laboratory assessment should be used to support clinical observations. 1.Full physical exam with temperature, pulse, and respiration rate. Assess mucous membranes and CRT which should be < 2 seconds. 2.If anemia is also observed in the patient then intravascular hemolysis moves up on your diagnostic list. The best way to assess anemia is via mucous membrane color. 3.If concurrent hemoglobinuria is also present then neonatal isoerythrolysis is most likely present. 4.Severity of the icterus: bleeding disorders have a less severe yellow color then Tyzzers. 5.Concurrent nervous system signs with icterus indicate a hepatic encephalopathy 6.febrile icterus is indicative of infectious diseases such as Tyzzers, Herpes virus, or piroplasmosis. 7.Meconium staining is often mistaken for icterus and starvation icterus can occur in older horses. Neither of these are of any clinical significance Laboratory Data: 1. A full blood count profile should be performed. - Look for a blood red color (hemoglobinemia) of the plasma, this indicates intravascular hemolysis. Hemoglobinuria may also occur with intravascular hemolysis- Erythrocyte regeneration can be identified with increased MCV and increased RDW (but these values can take up to 2 weeks to elevate) and nucleated erythrocytes or reticulocytes. Blood culture should be performed on sick foals and must be performed before antibiotics are administered to assess bacteremia and sepsisFull Serum Chemistry Profile should be performed with particular attention to liver enzymes, bile acids, bilirubin and proteins (albumin, globulin, analysis, fibrinogen, and SAA) - EHV-1: elevated AST and SDC, hypoglycemia - Tyzzer's disease-elevated AST, SDH; severe metabolic acidosis, hypoglycemia - Gastroduodenal Ulcers-increased GGT. 2. Liver biopsy can be performed but only if the foal is not severely icteric as might be with a foal with a severely compromised liver. A clotting profile should be performed to assess function of the liver. 3. serologic testing for suspected cases 4. PCR test on feces for Tyzzers 5. Abdominal paracentesis can be performed to assess integrity of the bowel and if there is an infection. 6. Ultrasonography can be performed to assess liver consistency, liver size, and dilated ducts, - Increasing echogenicity indicating fibrosis 7. Gastroduodenoscopy can be performed to look for ulcers. 8. Radiography can be performed to assess liver size. 9. Bilirubin (conjugated and unconjugated) - both are increased with Tyzzers - increased conjugated with gastroduodenal ulceres - increased unconjugated with hemolyisis - increased unconjugated with EHV-1

Specific diseases:

1. Diagnosis of Tyzzers disease is based clinical signs and age, demonstration of Clostridium piliformis in areas of hepatic necrosis�on a Warthin-Starry stain. 2. Diagnosis of gastroduodenal ulcers with icterus is based on history of diarrhea in a foal and clinical signs of severe icterus and�elevated GGT. Occasionally can see retrograde movement of barium into the biliary ducts after oral administration or delay of�gastric emptying on radiographs. 3. Diagnosis of hepatic encephalopathy in Morgan breed is based on clinical signs of diminished growth rate and depression and�elevated liver enzymes, normal to elevated bilirubin and very high blood ammonia levels (>200 umol/L) shortly after weaning.�Terminal hemolytic anemia can occur occasionally. 4. Diagnosis of liver failure with neonatal isoerythrolysis due to intravascular hemolysis is from biochemical testing of affected foals�showing increases in liver enzymes and function tests becomin abnormal. Neonatal isoerythrolysis is diagnosed by history (<7�day old of a multiparous mare especially if the mare has received a previous blood transfusion, especially mule foals with icterus�and tachycardia. A cross match of the mares colostrum to the foals RBCs can be performed and monitored for an agglutination�reaction (jaundice foal agglutination test-JFA). A positive coombs test will confirm the reaction.  Urine is discolored, light red, due�to hemoglobinuria.  Measure the PCV to distinguish from other causes of sepsis because it will be < 20% .  Liver enzymes may be�altered.  To diagnose before parturition the mare should be tested for rising titers of antibodies in the last 3-5 weeks of pregnancy.  5. Diagnosis of icterus due to fasting or physiological icterus is based on finding normal liver enzymes and >90% unconjugated�bilirubin with total of < 11 mg/dl of bilirubin.  6. Diagnosis of hemolyisis or internal hemorrhage as a cause of icterus will all show normal liver enzymes and >90% unconjugated�bilirubin and a decreased PCV. If the hemolysisis is intravascular then hemoglobinuria will also be seen along with pink plasma�and a positive occult blood. Parasites such as Piroplasmosis can be diagnosed by giemsa stain of the parasite in the red blood�cells. This disease can also be diagnosed with serology: competitive ELISA, complement fixation, indirect fluorescent antibody�assays, PCR, splenomegaly and hepatomegaly can be seen on ultrasound, and these horses will typically have a fever. DIC can�be diagnosed with the following tests :fibrin degradation products - high; partial thromboplastin time (PTT) - high; platelet count - low; prothrombin time (PT) – high. The coombs test will be positive if the following immune mediated hemolytic diseases are present: neonatal isoerythrolysis, equine infectious anemia, Lymphoma, Clostridium perfringens, and Streptocpccal antigen induced hemolyisis. Coggins is diagnostic for EIA. 7. Equine Herpes Virus Type: diagnosis can be made identification of foals with severely injected icteric mucous membranes immediately after delivery and confirmed by virus isolation from the buffy coat or PCR of whole blood. Definitive diagnosis on necropsy is by identification of viral intranuclear inclusion bodies from immunoperoxidase stained liver, lymphoid tissues, ileum, lungs and adrenal glands. 8. Hypoxia/Asphyxia: diagnosis is based on history of a difficult birth and clinical signs of multi-organ failure:  neurological signs, renal signs, icterus, cardiac dysfunction, enterocolitis, pulmonary dysfunction, every organ can be affected.

Treatments:

For treating hepatic failure and hepatic encephalopathy give IV crystalloid fluid therapy (plasmalyte is preferred) supplemented with dextrose and potassium. Glucose is often decreased in foals with hepatic failure. Fluids with acetate are preferred over fluids with lactate. Plasma can be given because of in addition to crystalloids. With hepatic encephalopathy, if sedation is necessary, low doses of xylazine and detomidine can be administered. Dont use diazepam! Stress should be minimized and small amounts grain with branched chain amino-acids should be fed to decrease ammonia. Lactulose or neomycin can also be given to decrease ammonia. Metronidazole is also efective at decreaseing enteric ammonia production, it is antiendotoxin and antimicrobial against anaerobics. Mannitol can be given to decreased brain edema. Protect horses with hepatic disease from sunlight. DMSO can be diluted in fluid therap for horses with hepatic encephalopathy. Flunixin can be given as an anti-endotoxin. Vitamin E can be given as an anti-endotoxin. Parenteral nutrition should be used in foals with hepatic failure caused by acute disease. SAM-e can provide anti-oxidant properties to the liver. Acetylcysteine can be used an anti-oxidant in progressive acute liver disease. Prednisolone can be used for relapsing chronic active hepatitis and other hepatopathies. Pentoxifylline can be used for chronic progressive diseases. Always use antibiotics with acute liver disease.

Specific diseases:

1. Tyzzers disease: give antibiotics, broad spectrum: penicillin, gentamicin, metronidazole. Aggressively manage septic shock. Give hyperimmune plasma. Give pentoxifylline should be used as an anti TNF agent and oxygen should be administered. Give parenteral nutritional support and supportive care for liver failure as discussed above. 2. Gastroduodenal ulcers: transposition of the bile duct of gastrojejunostomy or duodenostomy 3. Neonatal Isoerythrolysis: antioxidant therapy and anti-inflammatory treatments (Vitamin E, selenium, SAM-e, DMSO, pentoxifylline). NI foals can be prevented by organizing breedings. Aa and Qa negative mares should not be bred to Aa positive and Qa positive stallions. 4. Theileria equi: Imidocarb-dont treat with the high dose in donkeys. 5. Neonatal Isoerythrolysis: if it is discovered that the mare has the antibodies to the foals blood, and the foal is <48 hours dont allow it to nurse the mare if unless the colostrometer value is of <1.03. Use a muzzle but do not stress the foal. For peracute cases with PCV <20% within 24 hours, perform transfusions for horse foals from Aa and Qa negative donors. A cross match is ideal but if a cross match isnt possible then a negative donor is usually safe and effective. The own mares blood can be used but must be washed of plasma 3 times and suspended in saline before each transfusion. The stallion is the least desirable donor. Oxyglobin can be administered as an alternative. It is polymerized bovine hemoglobin in modified lactated ringers solution. It increases the total arterial oxygen content and oncotic pressure. Neonatal isoerythrolysis is common in mule foals and female donors should not have been previously breed to a donkey. Intravenous fluid shoud also be administered at maintenance rates and is expected to slightly decrease PCV but not total RBC count and actually improves oxygen delivery. Administeration of dexamethasone if compatibility with donor blood is uncertain. Administer nasal oxygen to an anemic foal. Administer antibiotics to minimize sepsis of broad spectrum. Administer anti-ulcer medications. Provide supportive care (keeping the foal warm). Provide nutritional support through milk replacer. Do not be surprised by a second decline in PCV after transfusion. *Dont ever let a newborn foal nurse the mares colostrum if she has ever had a whole blood transfusion. 6. Equine Herpes Virus 1-administer acyclovir and therapy for acute sepsis. 7. Asphyxia syndrome: administer diazepam, potassium bromide for longterm seizure control, magnesium sulfate for ameliorating secondary neuronal cell death after hypoxia, mannitol or DMSO for cerebral edema, protection from self trauma, maintain cerebral perfusion through fluid therapy.

New Research:

Neonatal Isoerythrolysis can be associated with failure of passive transfer. It is theorized that this is because lower concentrations of other antibodies (ie IG antibodies) may be required in order to cause red blood cell destruction due to anti-erythrocytic antibodies. Liver disease in NI foals is due to low oxygen content in the blood because of concurrent anemia. Evidence of tissue oxygenation with an increase in Hct, PcvO2, and hemoglobin concentration showed blood transfussions are warrented in certain foals. In other foals tissue oxygenation can be improved by supplying colloid or crystalloid therapy as evidenced by an increased survival rate in treated foals. 1 study showed that Dg, Qb, and Qc were just as prevalent as Aa and Qa.

Kernicterus is bilirubin encephalopathy and can result from increased levels of unconjugated bilirubin (>18mg/dl). Unconjugated bilirubin can enter the brain and cause nerve cell death. It is opisthotonus, rigidity, lethargy, a high pitched cry, and convulsions. Phenobarbital can stimulate conjugation of bilirubin and exposure to sunlight can convert unconjugated into a version that cant be taken up by neurons. Frequent milk feedings can decrease absorption of unconjugated bilirubin in the gut.

Development of a vaccine for C. piliformis to prevent Tyzzers disease has been discussed and is likely feasible due to the existence of vaccines against other clostridial diseases. Also studies have revealed that isolates of C. piliformis from different sources share common antigens but that they have diverse protein profiles and antigens. This may make development of a vaccine more difficult. Serologic tests have found 2 strains that horses are susceptible to.

References

1. Knottenbelt, Derek; Holdstock, Nicola; Madigan, John E ; Equine Neonatology London, UK Saunders Elsevier, 2004: 202-219

2. Orsini, James A.; Divers, Thomas J.; Equine Emergencies: Treatment and procedures. 3rd ed. St Louis, MO: Saunders Elsevier, 2008: 237-251

3. St. Denis, Kelly A; Waddell-Parks, Nancy; Belanger, Morris; “Tyzzer's disease in an 11-day old foal” Can Vet J 2000: volume 41 491-492

4. Loynachan, Alan T., Williams, N.M., and Freestone, J.F.; “Kernicterus in a Neonatal Foal” Journal of Veterinary Diagnostic Investigation Vol. 19 Issue 2, 209-212