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equine liver

liver disorders

QuestionAnswer
Liver is regenerative 80 loss of function prior to development of clinical signs or abnormal blood work
Serum biochemical information Liver specific enzymes Sorbitol dehydrogenase (SDH) highly specific for hepatocellular disease
Present in cytoplasm of hepatocyte, released with cellular injury sdh
Short half life so good for evaluating acute ongoing disease sdh
Return to baseline in 3-5 days sdh
Used in large animal medicine as liver specific enzyme sdh
Non-liver specific enzymes indicative of hepatocellular injury Aspartate transferase (AST)
Present in liver and skeletal and cardiac muscle ast
Falsely increased with hemolysis and lipemia ast
Long half life ast
Enzymes indicative of biliary obstruction or cholestasis Alkaline phosphatase (ALP)
Variable isoforms present in body (GI / bone / placenta) ALP
Not liver specific / elevated with cholestasis ALP
Neonates with osteoblastic activity have high ALP levels
Gamma glutyltransferase (GGT) Present in biliary epithelium, pancreas, mammary gland, lung and kidneys (released in urine from kidney)
Liver specific for biliary tract disease / cholestasis GGT
Young animals have higher GGT because of colostral ingestion
In horses is most sensitive indicator of liver disease GGT
Liver Function Tests Evaluation of bilirubin
Hyperbilirubinemia leads to jaundice
Not a sensitive indicator of liver disease in horse bilirubin
Anorexic horses are often hyperbilirubinemic without underlying liver disease
In horses, free or indirect bilirubin is transferred from albumin to ligandin in the sinusoidal blood and is then conjugated with glucose (instead of glucuronic acid) within the hepatocyte
The half-life of ligandin is short and ligandin stores decrease rapidly with starvation, which is likely the cause of hyperbilirubinemia in anorexic horses
With fasting hyperbilirubinemia‖ only indirect or unconjugated portion that is elevated
Indirect (unconjugated) bilirubin can be increased by hemolysis
Evaluation of bile acids (BAs) Excellent screen for liver disease
Increase within 24-48 hours, but not specific for the type of liver disease bile acids
elevated bile acids does not yield diagnosis or prognosis, only that hepatobiliary function is abnormal
Elevated BAs do not differentiate primary hepatic from extrahepatic diseases
Fasting sample not necessary in horses
Horses do not have a gallbladder, bile is released continuously in this species
A jaundiced horse with hyperbilirubinemia is not always indicative of primary hepatic disease and BA testing may help differentiate
In horses, BAs more sensitive indicator of liver disease than bilirubin
Tests for protein synthesis / detoxification Failure of the liver to process ammonia into urea may result from chronic hepatocellular disease leading to hyperammonemia
Blood must be stored on ice and quickly processed due to NH3+ instability,Decreased BUN
Decreased production of coagulation factors Factor 7 has shortest half life (4 hours)
Extrinsic pathway prolonged PT
Tests of carbohydrate metabolism Hypoglycemia occurs with advanced liver disease
Tests of lipid metabolism Elevated serum TG’s are not specific for primary liver disease
Other diagnostic tests Hepatic Ultrasonography,Observed ventral to lung margins
On the left lung margins between 7th - 9th ICS
On the right lung margins between the 6th - 15th ICS
Liver should remain within costrochondral junctions
Use of hepatic echogenicity compared to echogenicity of other visceral organs (ie kidney and spleen) provides information on parenchymal architecture
Allows evaluation of hepatic vasculature and biliary tracts if dilated / tortuous, hepatic abscessation, and presence of cholelithiasis ultrasound
CT / MRI Not available for horses based on the size of the gantry
Endoscopy In the horse, use of gastroscopy allows visualization of the distal portion of common bile duct only
Hepatic Biopsy may be performed if a patient presents with clinical signs suspicious of liver disease which are further supported by abnormal function tests and confirmed by diagnostic evaluation (U/S, CT, etc)
A liver biopsy provides definitive diagnosis and allows the clinician to offer a prognosis based on histologic diagnosis
Hepatic biopsy is the only diagnostic tool that provides definitive diagnosis of the liver disease
To perform a liver biopsy in the horse Using ultrasound-guided technique is quite easy
Typically performed on the right side liver biopsy
Between the 11th-14th ICS, appropriate site confirmed with U/S liver biopsy
Liver biopsy Aim cranio-ventral to avoid diaphragm and lung
Liver biopsy Collect samples using biopsy punch (Tru-cut)
Submit tissues for both histology and culture liver biopsy
Hemostasis,Even with documentation of abnormal coagulation parameters, horses rarely experience hemorrhage following biopsy
A biopsy should be cautioned in a patient with clinical bleeding diatheses
Indicators for poor prognosis in horses with liver disease Hypoalbuminemia <2
5 g/dl,Increased globulin level,Prolongation of prothrombin time (PT) by 30pct,Chronic severe elevation of GGT,Bridging fibrosis of liver lobules on histopathology
Terminal clinical signs of liver disease include development of hemolytic crisis and marked hepatoencephalopathy in the patient with a fibrotic liver
Prognosis is generally poor for horses with liver disease and severe hepatoencephalopathy or hemolysis or severe acidosis or diarrhea
Clinical Signs of Liver Disease in the Horse Jaundice / Icterus,The most classic sign of liver disease
Yellow oral mucous membranes, sclera, aural / vaginal mucosa Occurs with failure to excrete bilirubin
In horses, anorexic hyperbilirubinemia may cause jaundice without primary liver dysfunction
Neurologic disease / Hepatic encephalopathy Occurs when the liver fails to excrete nitrogenous wastes (ammonia)
In horses, not specific for primary liver disease as can be elevated with GI-induced ammonia that temporarily overwhelms the ability of the liver to detoxify the compound hyperbilirubinemia
Clinical signs of hepatic encephalopathy Abnormal mentation, cortical dysfunction,Alterations in behavior,Wandering aimlessly,Circling / head-pressing,Inspiratory stertor,Yawning
Dermatitis / Photosensitization Failure of the liver to excrete phylloerythrin
Instead of excretion through bile, phylloerythrin is transported to the skin where the molecule reacts to UV radiation in sunlight
Phylloerythrin acts as a photodynamic agent in the skin leading to necrosis and sloughing
Primarily affects non-pigmented skin,Diarrhea phylloerythrin
Failure of the liver to recirculate bile acids leads to poor digestion of fat and subsequent diarrhea
Mechanism not fully understood,Lethargy / weight loss failure to recirculate bile acids
Failure of the liver to metabolize carbohydrates, fats and protein leads to weight loss and ill-thrift
Ascites / Peripheral edema,Peripheral edema occurs when the liver fails to produce the primary plasma protein albumin
Lack of albumin causes plasma oncotic pressure to drop allowing fluid to leak into the interstitium leading to edema formation
Hypoalbuminemia leads to distal limb / ventral / inter-mandibular edema, but rarely to ascites
Ascites in the liver patient most likely occurs due to portal hypertension and increased hydrostatic pressure along the sinusoidal channels increases lymph production
Hepatic lymph is high in protein and leaches into the peritoneum and according to Starlings law, fluid follows the protein-rich lymph into the peritoneal cavity
Bleeding diatheses Failure of the liver to synthesize clotting factors may lead to bleeding tendencies, typically an end-stage clinical sign
TREATMENT FOR LIVER DISEASE in HORSES For the most part, treatment of horses with liver disease and/or hepatic failure centers on medical therapy, although surgery may be indicated several instances
There are very few cases of liver disease in the horse with specific antidotes therefore therapy is generalized and targeted towards clinical signs the patient exhibits and is based on the severity of the disease
Unfortunately, given the regenerative properties of the liver, many horses fail to demonstrate early clinical signs of disease and may not be diagnosed until late in the course of disease when >80% of the liver fails
As a result, medical therapy may not be possible
Medical therapy is indicated in patients with acute hepatic failure that have no evidence of chronic fibrosis as these horses have the best chance for long-term regeneration of the liver
The primary clinicopathologic abnormalities of equine liver disease are by most appropriate therapeutic interventions available to the equine patient These are generalized therapies and are administered on an individual case basis depending upon severity of clinical signs and disease process
Hepatoencephalopathy (HE) is a metabolically induced but potentially reversible disorder of the brain
Complex interactions between excitatory and inhibitory neurotransmitters determine whether the patient is manic or depressed
Horse owners may recognize a typically docile animal becomes aggressive and/or difficult to manage, or the reverse may occur (a high-spirited horse may become uncharacteristically docile)
Although the exact mechanism of CNS dysfunction is unknown, the disorder most likely results from abnormal protein metabolism by the diseased liver
Blood ammonia levels rise and are toxic to the CNS and result in a myriad of abnormal behaviors and mentation (wandering, circling, ataxia, head-pressing, yawning, depression, stupor, and coma)
Initial therapy for HE is aimed at abolishing abnormal behaviors to prevent the horse from endangering itself and others
If the animal is extremely agitated or convulsing, sedation should be administered first and foremost prior to attempting treatment
When dealing with a liver disease patient, it is important to remember the pharmacodynamic and metabolic properties of any medication administered to avoid further imposition upon the failing liver
Unfortunately, most sedatives and tranquilizers are metabolized by the liver
The use of benzodiazepines (ie valium) should be avoided because of the effect of GABA on inhibitory neurons, as the drug may actually worsen signs of HE
In humans, the use of benzodiazepine-receptor antagonists like flumazenil has been reported to lessen the signs associated with HE with variable success, but has rarely been used in the horse
In horses with liver disease, the drug of choice for sedation to counteract severe neurologic behaviors associated with HE is detomidine, an alpha-2 agonist
Administered IV or IM, deep sedation is easily achieved but should be used cautiously to avoid oversedation causing deep respirations and the horse to lower its head very low to the ground detomidine
Additional therapies for liver disease are aimed at reducing the amount of ammonia formed within the GI tract to ultimately decrease the amount absorbed into the portal circulation
These therapies which alter colonic microbial population remain questionable in the minds of many clinicians
The use of oral neomycin with or without added oral lactulose and acetic acid (vinegar) may be used to decrease the ammonia level within the GI tract
Neomycin should be used initially only, as prolonged use may be toxic to intestinal enterocytes, causing severe diarrhea in some horses
Vinegar and lactulose act to decrease colonic pH and subsequently decrease the amount of ammonia produced by enteric microbes
If oral medications are to be administered via nasogastric tube, extreme caution should be utilized to avoid trauma to the nasal cavity, esophagus or stomach, as prolonged and severe hemorrhage may result in swallowing of blood and worsening signs of HE
Most clinicians rely on diet and additional supportive therapies rather than alteration of colonic flora in treatment for liver disease
Hypoglycemia: Although few adult horses with liver failure are hypoglycemic, the administration of dextrose is necessary for several reasons
Administration of dextrose provides partial parenteral nutrition to a horse that is likely anorexic, but it also decreases ammonia concentration in the blood, reduces the reliance on catabolic gluconeogenesis, decreases protein catabolism and spares hepatic energy consumed in hepatic gluconeogenesis
Dextrose should be administered via constant rate infusion to avoid inadvertent iatrogenic hyperglycemia
Blood glucose concentrations are easily monitored stall-side and should be maintained tightly between 80-120 mg/dl
Excess blood glucose reaches urinary threshold between 180-200mg/dl, at which point a urine dipstick is a quick and non-invasive way to measure for hyperglycemia
Diet: alterations in diet are critical in those horses that maintain an appetite and important in the recovery of horses with acute liver failure, as well as for prolonging the life of a horse afflicted with chronic liver disease
Energy and protein requirements should be met, with the focus on branched-chain amino acids and very low protein fiber
Diets centered around oat and grass hay, but avoidance of alfalfa due to its higher protein content, are important
Other supplemental fiber includes milo, beet pulp and sorghum
In horses that refuse to eat, force feeding may be necessary, in addition to parenteral nutrition in the initial stages of therapy
The bottom line: in a horse with liver disease, it is important for them to eat something / anything, even if it is not one of the low-protein diets discussed above
Antimicrobial therapy: there are some cases of liver disease in the horse which may warrant antibiotic therapy
Chronic active hepatitis (CAH) may have a suppurative focus as well as cases of cholangiohepatitis, in which ascending biliary tract infections from the GI tract result in liver disease
The most common infection of the liver is Gram negative bacterial infections (enteric organisms), unless the infection occurs hematogenously, which is rare in adult horses
The use of antimicrobials in horses with liver disease is indicated following liver biopsy and histopathologic results of inflammatory infiltrates or positive results of biopsy tissue culture and sensitivity
Although the results of bacterial sensitivity will indicated therapeutic options, it is important to keep in mind choice of antibiotic should include those that concentrate within the liver or biliary tract
Examples of useful antimicrobial are penicillin / gentamicin, enrofloxacin, chloramphenicol and trimethoprim-sulfa drugs
If an anaerobic bacterial infection is determined, additional use of metronidazole will be necessary
Anti-inflammatory / Anti-oxidant therapy: equine patients with liver disease should receive flunixin meglumine (Banamine®) as well as pentoxifylline as anti-inflammatory therapies
The use of S-adenosylmethionine (SAMe) appears to have protective effects against oxidative hepatic injury and may be useful for horses with liver disease
Dimethyl sulfoxide (DMSO) may provide additional antioxidant support as a free radical scavenger
Corticosteroid therapy there are very few hepatic diseases in which steroid therapy is indicated
Suspect autoimmune disease or overzealous inflammatory infiltrates may warrant corticosteroid therapy
Additional therapies: DMSO may be useful for dissolving small biliary stones or sludge within the biliary tract (1-3 day course of therapy)
Colchicine may be used for its anti-inflammatory effects (mechanism unknown) but therapeutic effects in horses are variable
The drug ursodeoxycholic acid, Actigall®, is a commercially prepared bile acid which is used for a variety of biliary disorders in humans and small animals to achieve choleresis, or the secretion of bile by the liver into the gallbladder
The drug has not been proven in horses and safety is a concern as ursodeoxycholate acid is metabolized into toxic bile acids in rabbits, which have a GI tract similar to that of horses actigal
In cases of cholelithiasis where there is an obstruction visible in the distal bile duct and when no fibrosis is present surgery is indicated
Additional surgical procedures may be necessary in foals or calves suffering liver failure from duodenal strictures or portosystemic shunts
ACUTE HEPATITIS in HORSES,Idiopathic acute hepatic disease (IAHD) is the most common cause of acute hepatitis and acute liver failure in horses
It is also known as Theiler’s disease, serum hepatitis and post-vaccinal hepatitis IAHD
It is primarily a disease of adult horses and is most often associated with administration of equine biologic products such as tetanus antitoxin (TAT) and/or commercial equine plasma IAHD
The mechanism of hepatic failure associated with IAHD is unknown, but has been proposed to be a Type III immune-mediated disorder (immune-complex / Arthus reaction)
Clinical signs of IAHD are consistent with liver failure in other species and include depression, jaundice, inappetance, pica, yawning, photoactive dermatitis and hepatic encephalopathy
Fever is absent or rare liver disease in horses
Although the disease is highly fatal, there are reports of some horses developing evidence of liver dysfunction without developing clinical signs
This evidence suggests that disease severity may vary IAHD
Diagnosis of IAHD is largely determined by anamnesis, or medical history of the patient, with concurrent clinical signs, and documentation of abnormalities on serum chemistry profile, liver biopsy and necropsy
Hepatic necrosis in horses is identified on serum chemistry profile by elevations of both hepatocelluar enzymes (SDH and AST) and cholestatic enzymes (GGT and ALP)
Confirmation of IAHD requires biopsy or necropsy examination of the liver
The histologic changes within the liver are typically more pronounced than the degree of clinical signs would indicate
Widespread hepatocellular necrosis is most severe in the centrilobar regions (tissue nearest the central vein within each lobule) with the few remaining living cells situated nearest the portal vein
Treatment for IADH is non-specific and impossible in many cases due to the advanced stage of failure at the time clinical signs are observed
Supportive therapy is aimed at supporting liver function and controlling abnormal behavior
Dietary adjustments are important and consist of reducing the quantity of protein in the diet while increasing the carbohydrate intake
Aromatic amino acids may potentiate signs associated with hepatic encephalopathy and therefore, diets with higher proportions of branched-chain amino acids should be fed (ex
Sorghum, milo, beet pulp)
The administration of mineral oil, lactulose and oral neomycin has been reported to decrease ammonia absorption from the GI tract
Horses with severe signs of hepatic encephalopathy may require sedatives (alpha-2 agonists xylazine or detomidine) to prevent self-trauma
In addition, IV administration of polyionic fluid and dextrose CRI may reduce the workload of the liver while providing maintenance requirements of fluid and electrolytes
Caution should be noted when administering total parenteral nutrition to patients with hepatic encephalopathy: avoid the use of amino acids to reduce the risk of exacerbating clinical signs
The observation of prolonged bleeding at sites of venapuncture or self-inflicted injury should prompt administration of plasma to provide additional clotting factors
Hemorrhagic diatheses are common late stage events and typically occur as a terminal event
Although IADH was first recognized in horses in South Africa following vaccination for African horse sickness with combination live virus and hyperimmune equine serum, in the US, IADH is most commonly reported in brood mares
The precise association between IADH and brood mares is unclear, but most likely related to the frequency with which TAT is used in this population of mares following parturition
It is now well understood the use of TAT is not without risk, and its use in brood mares has been strongly discouraged
The focus for tetanus prophylaxis should be centered around the use of tetanus toxoid for immunoprophylaxis
The use of TAT should be reserved for cases in which immediate passive immunity against tetanus in horses is necessary, for example, a deep penetrating wound in a horse with unknown vaccination history with tetanus toxoid
The risk of post-vaccinal IAHD should be addressed with any horse owner prior to administration of TAT
While it is uncommon, the administration of commercial equine plasma has been associated with development of fatal cases of IADH
IADH has also been reported to occur both sporadically and in groups of horses
Screening of herds following identification of IADH in one horse should include routine serum biochemical profiles, as it is now known that cases of subclinical IADH may occur
PYRROLIZIDINE ALKALOID TOXICITY in HORSES,Pyrrolizidine alkaloid (PA) toxicity results in delayed onset of chronic, progressive failure of the liver that results from consuming plants containing PAs
While there are literally thousands of plant species that contain PAs, they uniformly result in the same manifestations of liver failure
The clinical signs of horses with PA toxicity are those consistent with liver failure and may not become evident for 4 weeks to one year following consumption of PA containing forage
The most common clinical signs of PA toxicity are weight loss, slight to moderate icterus and sign of hepatic encephalopathy (ie wandering and ataxia), but photosensitization and diarrhea may be observed
Mares have aborted fetuses following ingestion of sublethal doses of PAs
Consumption of the plant at 2-5% of horses body weight ingested all at once or over a period of days may result in acute toxicity
Because the effects of PA are cumulative, toxicity typically occurs following chronic, low-level ingestion
The PA plants are not palatable and are typically ingested as a last resort in pastures
The most common PAs in the US are the Senecio ssp
(Tansy ragwort, Groundsel), Amsinckia ssp
(Fiddleneck), and Crotalaria ssp
(Rattlebox)
The ingested PA toxin is carried to the liver via the portal circulation and metabolized by hepatic microsomal enzymes into the toxic pyrrole derivatives
These derivatives are highly reactive and can cross-link double stranded DNA which inhibits nuclear acids, cellular replication and protein synthesis Pyrrole
As a result the hepatocytes are unable to divide (or continue cellular replication) and they become enlarged and form megalocytes Pyrrole derivatives toxicosis
When megalocytes die, they are replaced by connective tissue and fibrosis instead of new hepatocytes,Eventually the liver shrinks, becomes cirrhotic and failure is imminent
Hepatocytes surrounding the portal triads are typically affected first, but with massive consumption extensive centrilobar hepatocellular necrosis occurs
Although fibrosis around portal triads may lead to portal hypertension, horses rarely develop ascites and diarrhea which are common clinical signs in ruminant PA toxicity
PA toxicity becomes a venoocclusive disease when bridging portal fibrosis appears, which ultimately disrupts blood supply to the liver, making regeneration impossible
Additional pathologic findings of PA toxicosis include cardiac muscle necrosis,colitis, widespread hemorrhages and adrenal cortical hypertrophy
Crotolaria ssp contain the toxic agent monocrotaline, which is pneumotoxic and can cause hydrothorax, pulmonary edema, epithelialization and pulmonary arteritis
PAs are rapidly excreted from the body through urine, milk and the placenta
Megalocytic hepatopathy from PA intoxication can be presumptively diagnosed based on clinical signs, laboratory evidence of liver disease and historical documentation of exposure to PA-containing plants
Because periportal disease occurs in PA toxicosis, GGT and ALP are persistently elevated, although SDH and AST may be normal late in the disease course
Bilirubin is typically increased and elevated bile acids are commonly observed,The branched chain to aromatic amino acid chain ratio is decreased (meaning greater amounts of circulating aromatics are present)
Definitive diagnosis is made through liver biopsy and the confirmation of the presence of megalocytosis, biliary hyperplasia and periportal fibrosis are pathogneumonic for PA toxicity
There is no antidote for PA toxicity
In most cases, despite supportive therapy, death occurs within 10 days of onset of clinical signs of liver failure PA toxicosis
Serum bile acids > 50μmol/L suggests a grave prognosis and when extensive fibrosis and megalocytosis are present hepatic regeneration is not possible and treatment is not warranted
Treatment with branched chain amino acids may decrease clinical signs of PA induced hepatic encephalopathy but will not prevent death
Since the ingestion of PA-containing plants is pasture-associated, typically more than one horse may be affected
As the case, most attention and financial input should be placed upon asymptomatic horses that may also have ingested PAs
Most PA plants are identified within the pasture or by analysis of feed
Progression of PA disease or successful therapy may be monitored with serial blood sampling for hepatic enzyme assessment and serial biopsy interpretation
GGT is the most reliable indicator for subclinical cases of PA toxicity
Horses with mild clinical signs and reversible histologic lesions (ie no fibrosis) have been reported to survive if they maintained an appetite and were not exposed to any further PA-contaminated feed
Fields of oat and alfalfa hay are typically contaminated with PA-containing plants and often-times sheep are allowed to graze down these pastures because of their decreased susceptibility to PAs
CHRONIC ACTIVE HEPATITIS in HORSES,(CAH) is an idiopathic, chronic, progressive hepatopathy in horses
In most cases it represents a sustained inflammatory process in the liver CAH
It is characterized by biliary hyperplasia with concomitant periportal or biliary inflammation and associated hepatocellular damage on histologic examination CAH
Clinical signs of CAH are insidious in onset and compatible with progressive liver failure including depression, exercise intolerance, weight loss, anorexia, colic, icterus, and fever
Signs are variable and may be intermittent CAH
Coronary band exfoliative dermatitis has been reported CAH
Differential diagnoses CAH include PA toxicity, bile stones (choleliths), abdominal abscessation, and other chronic wasting diseases
Although a similar syndrome of CAH exists in humans (which has been linked to autoimmune disease, chronic hepatitis B virus infection, non viral hepatitis, Wilson’s disease and drug allergy), the exact cause of CAH in horses is unknown
In addition to the possibility of an immune-mediated or hypersensitivity reaction, equine CAH may be a manifestation of chronic cholangitis
Many horses with CAH have evidence of suppurative inflammation involving the biliary system, in addition to periportal inflammation and hepatocellular necrosis
In some cases, coliform organisms have been isolated from the liver, supporting ascending infection from the GI tract through the common bile duct into the liver
Diagnosis in horses includes mild elevations in SDH and AST, but GGT and ALP are persistently elevated with CAH
Bile acids and bilirubin are typically increased and BSP half-life is prolonged CAH
Immunodiagnostics including determination of the antinuclear antibody (ANA) titer and anti-immunoglobulin immunofluorescent staining of skin lesions (coronary band dermatitis) may help confirm diagnosis of immune-mediated disease process in CAH
Liver biopsy should be performed even with the evidence of clinical signs and serum biochemical profile support of liver disease and the sample should be submitted for both histopathologic examination and bacterial isolation with culture and sensitivity CAH
The definitive diagnosis of CAH depends upon the presence of characteristic histopathologic findings: progressive periportal hepatocellular necrosis with varying stages of bridging necrosis
Mononuclear cells are the predominate inflammatory infiltrate, but neutrophils predominate if cholangiohepatitis is present CAH
Treatment of CAH involves initial supportive therapy for hepatic failure based on the degree/severity of clinical signs
Maintenance of proper appetite and nutritional are important CAH
Specific therapy for CAH depends on the histopathologic findings
In patients where an autoimmune process or hypersensitivity is suspected (ie presence of abundant plasma cells as with lymphocytic-plasmacytic hepatic infiltrates), corticosteroid therapy may be beneficial in CAH
In humans with auto-immune CAH, steroids improve attitude and appetite, reduce inflammation and hinder fibrosis
However, in horses, short-term CAH improvement is observed but survival time remains the same and long-term prognosis remains poor steriods
If the liver biopsy reveals cholangitis long term antimicrobial therapy is warranted (4-6 weeks)
Antibiotic choice should be made based on culture and sensitivity results, with preference for use of an antibiotic which is concentrated or excreted in bile
Corticosteroids in this case should be used with caution in CAH involving infection
Liver biopsy and response to therapy are the best prognostic indicators
Patients with early/less severe histologic lesions have a fair prognosis with corticosteroid treatment, but the prognosis remains poor for horses with functional hepatic failure and extensive fibrosis
The presence of cirrhosis warrants a grave prognosis in CAH
CHOLELITHIASIS / CHOLANGIOHEPATITIS in HORSES,Although biliary tract disease in horses is rare it may result from both intrahepatic and extrahepatic causes
Intrahepatic biliary tract diseaseis causes include cholangitis, cholelithiasis (bile stones or calculi within the bile ducts), chloledocholelithiasis (stone within the common bile duct) and presence of a foreign body
Extrahepatic biliary tract disease causes include abscess formation, inflammatory disease near the common bile duct and neoplasia
Chloledocholelithiasis is the most common cause of biliary obstruction in horses
Bile stones form from precipitates or aggregates of biliary components, which are normally soluble
Most choleliths have a mixed composition of bilirubin, bile pigments, cholesterol and carboxylic acid, calcium phosphate and sodium taurodeoxycholate
Other mechanisms of biliary disease involved in the pathogenesis include parasites (ascarids), ascending biliary infection or inflammation, biliary stasis, changes in bile composition, and foreign body presence
There have been pathogenic bacteria cultured from biliary tracts in horses with choleliths
Salmonella ssp, E
coli, Aeromonas ssp, Citrobacter ssp, Group D Streptococcus ssp, and Clostridium perfringens bacteria cultured from biliary tracts in horses with choleliths
It is unclear what role the bacteria have in stone formation, were they the cause or the likely result
Clinical signs of cholelithiasis in horses include a classic triad of signs: colic (intermittent but recurrent), fever, and jaundice
Clinical HE (hyperammonemia), photosensitization and weight loss are additional common clinical signs in horses w/ cholelithiasis
Abnormal serum biochemical parameters include elevated GGT, ALP, AST, and SDH in horses w/ cholelithiasis
Total bilirubin is elevated from both indirect and direct portions
When greater than 30pct of the total bilirubin is direct or conjugated cholelithiasis should be suspected in horses
Obstruction of bile flow also causes elevated bile acids
A neutrophilic leukocytosis and elevated fibrinogen and globulins are common cholelithiasis
Diagnosis of cholelithiasis combines abnormal hepatic enzymes with transabdominal ultrasound examination
Hepatomegaly and bile duct dilation from biliary obstruction may be visualized cholelithiasis
The echogencity of the liver parenchyma is increased (comparable to that of the spleen) and bile ducts are tortuous cholelithiasis
In cholelithiasis Stones are often visualized and may or may not cast an acoustic shadow
Differential diagnoses of cholelithiasis include other causes of liver failure and intermittent colic with or without fever (verminous arteritis, mesenteric abscesses, enterolithiasis, abdominal neoplasia and urolithiasis)
Histologic evaluation from biopsy specimen in cholelithiasis commonly reveals periportal fibrosis, with bile duct stasis and hyperplasia and suppurative cholangitis being less common
Treatments are few and prognosis is guarded for cholelithiasis in horses
Relief of biliary flow obstruction and management of hepatitis and associated complications of liver failure should be addressed cholelithiasis
Unfortunately, choledolithotomy and choledolithotripsy have been described in horses, but with only limited successes in treating cholelithiasis
Antimicrobial therapy is warranted, especially in the event of surgical manipulation, as the potential for bacteremia is likely cholelithiasis
In humans, drugs like chenodeoxycholate or ursodeoxycholic acid, Actigall® are used to dissolve cholesterol stones, but have not reportedly been used in large animals
HEPATIC LIPIDOSIS in HORSES,Also known as syndromes of HYPERLIPIDEMIA / HYPERLIPEMIA / TRIGLYCERIDEMIA
These three syndromes of hyperlipidemia, hyperlipemia and hypertriglyceridemia are similar and characterized by the classic clinical signs of anorexia, depression and lethargy
A hyperlipidemic patient has mild to moderately elevated serum triglycerides (TGs) <500mg/dl (reference range 11-71mg/dl) with no evidence of lipemic serum or hepatic dysfunction
Hyperlipemic patients have moderately elevated TGs (>500mg/dl) with milky serum and fatty infiltrates observed within the liver
These are the classic fatty liver ponies, donkeys and miniature horses historically known for this disease (similar to fatty cow syndrome and hepatic lipidosis in cats) hyperlipidemic horses
Another group of equine patients is now recognized as hypertriglyceridemic‖ These horses have moderately to severely elevated serum TG’s (>500mg/dl), no evidence of lipemia (no milky serum) and no evidence of fatty liver
It is these horses that are more and more commonly being recognized in equine intensive care units today hypertriglyceridemicll
Risk factors for development of excess circulating TGs include Miniature Horses/ponies/donkeys,Females,ObeseAnimals,Endotoxemia,Enterocolitis,Azotemia,Pregnancy (late gestation),Lactation,Stress,ANYTHING WHICH PREDISPOSES THE ANIMAL TO A NEGATIVE ENERGY BALANCE
In times of decreased appetite and caloric intake, or if energy demands are increased such as with late pregnancy, the glycogen stores from the liver are quickly used up and the major source of energy is then shifted to fatty acid oxidation
This is where obese horses become victims of hyperlipemia because they have such exorbitant amounts of fat that may be used for fatty acid oxidation
The mobilization of fat is triggered with onset of stress or the inability to maintain energy homeostasis and with such great sources of readily available lipid for use, rapid fat mobilization occurs
In addition to anorexia or increased energy demands, when underlying disease is present, such as with enterocolitis, endotoxemia, azotemia, infection, parasitism, neoplasia or other stress such as transport or weaning the onset of fatty acid oxidation is also triggered
This phenomenon has typically been recognized in ponies, miniature horses and donkeys onset of fatty acid oxidation
Clinicians are beginning to understand this metabolic derangement occurs in our critically ill population of horses as well onset of lipid metabolism
A review of fatty acid (FA)lipid metabolism is warranted, as it is important to understand how dietary fats are converted from the intestinal tract and ultimately packaged in the liver
There are both exogenous and endogenous sources of fat supplied to the liver for processing
Exogenous fat sources are acquired with dietary intake
Most very small (<10 carbon atoms) short chain fatty acids, which are non-water soluble, are incorporated into phospholipids or TG’s by the intestinal epithelium and sent to the liver by the portal blood
The metabolism of larger FA’s is slightly different than most very small <10 carbon atoms
Larger lipid molecules are broken down within the small intestinal lumen by bile acids, which actually surround the FA’s
Lipases released from the pancreas into the common bile duct coat the bile acid and cleave it into 2 FFA’s (now freefatty acids)and one monoglyceride
Bile acids will continue down the SI lumen and eventually be reabsorbed by the ileum (enterohepatic recirculation of bile acids)
The 2 FFA’s and monoglyceride will then combine into water soluble MICELLEs for absorption into the enterocyte
The micelles enter the unstirred layer which is the quiet layer of fluid within the small intestinal tract adjacent to the brush border (villus tips of the small intestinal enterocytes)
It is the unstirred layer that makes absorption by the enterocytes more favorable
The micelles, with their hydrophilic tails encircling the hydrophobic center, are absorbed across the apical membrane of the enterocyte via FA-binding proteins and simple diffusion
Within the enterocyte, the micelle is transported to the smooth endoplasmic reticulum, where it is re-esterified into triglycerides with phospholipids, cholesterol and proteins
The rough ER then packages the re-esterified micelles into chylomicrons, which are also water soluble, and expels them from the enterocyte into the lateral space, or the space between two adjacent enterocytes
The lateral space is used for absorption of large molecules which are too large for absorption through the basement membrane or capillaries
The chylomicrons are picked up by the lymphatic circulation, carried to the thoracic duct and finally dumped into the vena cava and ultimately carried to the liver for processing
Endogenous sources of fat include triglycerides which are mobilized from adipose tissue during times between meals under the control of hormonal modulators
Glucagon, norepinephrine, and epinephrine bind to the G protein-coupled receptor on the adipocyte, which activates adenylate cyclase to produce cyclic AMP
cAMP consequently activates protein kinase A, which phosphorylates (and activates) hormone-sensitive lipase
Hormone sensitive lipase is the enzyme responsible for the lipolysis of FA’s from peripheral adipocytes
The triglycerides, liberated from the fat cells by hormone sensitive lipase are broken in to 3 parts: FFA’s, NEFA’s and glycerol,these products are bound to albumin and released into the bloodstream and carried to the liver for further processing
Once in the liver, the fate of the lipid depends upon the energy requirements of the animal or person and the amount of fat and glucose absorbed from the daily diet
Since there is limited storage space in the liver for glycogen extra glucose is made into FA’s, as an alternate means of glucose removal This is why candy bars give us fat pads
Regardless of the source or the form in which the lipids arrive, the liver is responsible for transforming them into usable products
Lipid products include oxidation to acetyl CoA and used in the TCA cycle to make ATP for energy,esterification into TG’s for storage in the liver,used for gluconeogenesis (the creation of glucose out of non-carbohydrate sources)or made into ketone bodies
Finally, the FFA’s can be used to make TG’s that are released into the sinusoidal blood as very low density lipoproteins, known as VLDL’s
VLDL’s are composed of an esterified TG, wrapped in phospholipids with cholesterol and protein, similar to but smaller than chylomicrons, and are transported easily through the bloodstream to adipose tissue
The enzyme lipoprotein lipase (LPL) is found on the endothelial surface of adipocytes,and when activated will bind the VLDL and catalyze the hydrolysis of the FA from the TG core,promoting storage of fat within the fat cell
The activity of LPL in the adipocyte is the rate-limiting step in clearing the VLDL’s from the blood and its activity is stimulated by insulin
Contrary to some thought that the liver is dysfunctional in ponies/horses with hyperlipemia, the liver actually performs quite well by synthesizing the excess fat that arrives from peripheral lipolysis into VLDL’s
Additionally, in ponies and horses with hyperlipemia, the enzyme LPL on the surface of the adipocyte endothelium, is actually upregulated, but is overwhelmed from the shear amount of VLDL’s being dumped into circulation from the liver
So, it appears that it is the OVERPRODUCTION of VLDL from the liver, and not the failure of the LPL and removal of VLDL from the blood, which is ultimately responsible for hyperlipemia in ponies, miniature horse and donkeys
Horses are much less likely to suffer ketoacidosis, unlike cows and cats, because of the hepatic efficiency at synthesizing TG’s and VLDL’s and exporting them back to the bloodstream
In the event the liver’s ability to process TG’s and secrete VLDL’s is overwhelmed hepatic lipidosis ensues
The fatty infiltrates of the hepatocytes disrupt normal hepatocellular function, which may result in hepatic rupture and/or hepatic failure
In the critical patient, there are hormonal factors that act to potentiate the mobilization of fat, the production of VLDL’s, and the inability to uptake VLDL from the circulation to place them back into the adipocyte
Some of the biggest players that act to potentiate the mobilization of fat are Insulin,glucocorticoids,catecholamines,ACTH,ADH,P4,TH,GH and even LPS (endotoxin)
Insulin naturally prevents hypertriglyceridemia by inhibiting hormone sensitive lipase, the enzyme necessary for peripheral lipolysis
In the presence of insulin, such as following a meal less adipose tissue is mobilized for FA release to the liver
Insulin also stimulates gluconeogenesis in the liver following a meal and activates adipocyte endothelial LPL, which will remove VLDL’s from circulation
In sickness and disease, ponies may suffer insulin resistance to a greater degree than that of horses
Insulin resistance promotes peripheral lipolysis and encourages hyperlipemia
Critically ill equine patients have been shown to have increased levels of both circulating catecholamines and cortisol
In ponies, NE linearly stimulates the release of FFA from adipoise tissue this effect has not been shown to occur in horses
The presence of LPS, in association with endotoxemia, has also been proven to encourage the development of hyperlipemia
At low doses, LPS increases hepatic synthesis of FA’s and promotes peripheral lipolysis, and at higher doses, LPS interferes with LPL, thereby decreasing the clearance of VLDL from circulation
These mechanisms are governed by the production of inflammatory cytokines,TNF,IL1,IL6,which are upregulated and produced from macrophages and monocytes in the presence of LPS
Azotemia appears to potentiate elevated serum TG’s
A significant association between increased serum creatinine and elevated serum TG’s is known but the physiologic mechanism remains unclear
It is clear, however, that individuals with hypercreatininemia have an inhibitory stimulus of lipoprotein lipase at the peripheral adipocyte capillary endothelium, thereby increasing the amount of serum TG’s that remain in the bloodstream
Diagnosis of hyperlipemia should be considered in any obese pony or donkey with clinical signs of anorexia, depression and lethargy
In horses, hypertriglyceridemia is suspect with decreased attitude and appetite in the face of critical illness
Confirmation of elevated TGs should be present (TGs > 85mg/dl) and with hyperlipemia, the serum should be opalescent (creamy / milky)
Elevations of VLDLs and nonesterified FAs may also be recognized,If the liver is affected, abnormal enzyme results include increased SDH,GGT,bile acids, bilirubin, and ammonia elevated TGs
End-stage liver failure results in decreased glucose, BUN, and albumin
Ultrasonographic evaluation of the liver is helpful for monitoring echogenicity and size margins of the liver
With fatty infiltrates the liver swells, and may result in hepatic fracture and death in the most severe cases
The presence of elevated TGs leads to a vicious cycle of inappetance and further elevations in TGs,Horses typically suffer anorexia, depression, lethargy and diarrhea
Horses with endotoxemia and enterocolitis should be treated accordingly, mares that are pregnant may require abortion and lactating mares should have foals weaned to ultimately correct the negative energy balance
In addition to correction of the underlying disease process, provision of alternate energy sources is critical and both parenteral and enteral nutritional plans are likely in the initial phases of treatment
Typically, as the TG level decreases appetite slowly returns
Most clinicians begin therapy w/ 5pct dextrose CRI (2ml/kg/h)as a mode of partial parenteral nutrition and alternate energy source which additionally stimulates insulin release
Enteral feeding is likely to afford the most efficient resolution of triglyceridemia
Enteral feeding of only 10pct of daily energy requirements is often successful in stimulating appetite and forced feeding is often necessary
Small, frequent feedings are encouraged through nasogastric tube if necessary
Administration of insulin may also be necessary to counteract hyperglycemia from dextrose CRI and may be administered intramuscularly twice daily
Insulin decreases the activity of hormone sensitive lipase and stimulates tissue LPL in the periphery
Administration of heparin should be used cautiously it potentiates LPL and may inhibit hormone sensitive lipase but it also alters coagulation and subsequent hemorrhage has been reported
Prognosis is guarded with survival rates 66pct in critically ill horses, but hyperlipemia in ponies carries a much higher fatality rate (100pct in one study)
Created by: alljacks