Hepatobiliary Diseases in Pets - New Diagnostic Approach - 2024 PDF

 By Prof/ SABRY MOUSA Professor in Department of clinical veterinary medical sciences ,Faculty of Veterinary Medicine, Jordan University of science and technology 2024  Cont...

 By Prof/ SABRY MOUSA Professor in Department of clinical veterinary medical sciences ,Faculty of Veterinary Medicine, Jordan University of science and technology 2024  Content I- Introduction Anatomical consideration, blood flow , bile flow Physiological function of the liver II- Diagnostic approach( strategies) Historical information (Age ,breed predisposition -Classification of liver diseases) Clinical presentation Gastrointestinal signs PU/PD Hepatocencephalopathy Coagulopathies Acholic feces Abdominal distension Jaundice III- Clinical pathology  Hematology (CBC)  Liver involvement (Liver enzymes and bilirubin)  Liver functions (More specific : Bile acid – Ammonia- Bilirubin) (Non-specific : TP – Albumin – cholesterol –Urea- Glucose – globulin)  Most recent biomarkers (CRP – Vit D – Kallestin – Serum miRNA-)122  Urinalysis Fecal analysis IV- Diagnostic imaging  Survey x-ray  Ultrasonography  CT , MRI , Sciengraphy  Endoscopy (Survey Laparoscopy – Advanced ERCP) V- Liver biopsy  Indications  Techniques  Fine needle aspiration (FNA)  Tru-cut needle ( blind /US-guided / laparoscopic)  Laparoscopic / laparotomy biopsy ( wedge biopsy)  Cytology  Histopathology  Anatomical considerations  The Liver Anatomy The liver, that lies across the stomach and duodenum and derived from the embryonic gut.3 The liver is the largest gland in the body and is located in the cranial abdomen between 3rd and 4th ribs in dogs and cats.12 Its gross anatomical divisions comprise the right, left, caudate and quadrate lobes with their own blood supply and biliary drainage The portahepatis transmits the hepatic artery, portal vein and right and left hepatic ducts (the portal triad), together with lymphatic and autonomic nerves..13 The anatomy of the liver differs between dogs and cats. Dogs have two separate ducts a pancreatic duct and a bile duct. In cats, however, the bile duct joins the pancreatic duct; this may allow the reflux and mixing of gastric secretion with both pancreatic secretions and bile.14 The internal structure of the liver is made small hexagonal functional units known as lobules. Each lobule consists of a central vein surrounded by hepatic portal veins and hepatic arteries. These blood vessels are connected by many capillary-like tubes called sinusoids which extends from the portal veins and arteries to meet the central vein like spokes on a wheel. Each sinusoid passes through liver tissue containing two main cell types including Kupffer cells and hepatoctes‫مهف‬  Blood supply of liver Liver receives nutrients and oxygen from two large blood vessels (hepatic artery and portal vein).Protection These blood vessels subdivided into small capillaries(hepatic sinusoids), blood flow via sinusoids and empties into central vein of each lobule. Central vein coalesce into hepatic vein which leave liver and drain into posterior vena cave which open at right side of heart.  Biliary flow Bile produced by liver collected in bile canalculi which in between adjacent hepatocyte then merge to form bile duct in hepatic lobules. Intra hepatic duct drain into right and left hepatic duct which exist liver and merge to form common hepatic duct. Common hepatic duct joins with cystic duct from gall bladder to form common bile duct which drain into duodenum. Bile either drain directly duodenum via common bile duct or temporary store in gall bladder via cystic duct.  Liver physiological functions The liver is responsible for metabolizing carbohydrates, lipids, and proteins into biologically useful materials.()15,17 The liver is storage organs of many essential nutrients, vitamins and minerals obtained from blood passing through the hepatic portal system The liver is responsible for the production of several vital proteins components of prothrombin, fibrinogen and albumins. The liver functions as an organ of the immune system through the function of the Kupffer cells that line the sinusoids Act as accessory digestive gland: as it produce and excrete bile which essential for emulsification of fats and help in absorption of vit k from diet as fat dependent absorption Angiotensinogen(hormone raising blood pressure when activated by renin enzyme which released by kidney when it sense low blood pressure. Breakdown and excretion of waste products (ammonia to urea which excreted in urine, drug metabolism). The liver disease diagnosed by:  using history and physical examination  liver function tests and medical imaging techniques.  However, for identification of specific hepatopathies definitive diagnosis of liver disease the histopathological examination is required to set recommended treatment. 9,10 The hepatic diseases are managed by:  Reducing predisposing factors  providing intravenous fluid to rehydrate  Administering gastro-intestinal protectants to prevent ulcerations, avoiding the use of sedatives  supplementation of low protein diets and Zinc for regulation of protein and nitrogen metabolism,  cholecystectomy  Antibiotics are also used for management of hepatic diseases.10,11  Diagnosis of Hepatobiliary diseases in Dogs and cats Diagnosis of liver disease Diagnosis  of liver diseases cannot be straightforward because the symptoms of the organ may be ambiguous or may easily interfere with the symptoms of other diseases.  However, liver disease can be diagnosed by using history and clinical symptoms, liver function tests, medical imaging and tissue analysis or biopsy.()2  Diagnosis of Liver Disease Diagnostic evaluation (Strategy) of the hepatobiliary system has several aims.  To determine if hepatobiliary disease is present  To assess liver function  To definitively diagnose hepatobiliary disease  To monitor response to treatment [.]4  History and clinical examination  The liver has a tremendous (approximately 80 %) reserve capacity and a remarkable potential to regenerate.  Symptoms occur only when progressive disease exhausts hepatic reserves. Diseases often remain subclinical for lengthy periods of time; symptoms may be relatively mild and nonspecific because the liver reserve prevents overt abnormalities.  Symptoms such as lethargy, vomiting, or mild polyuria and polydipsia (PU/PD) may alert the clinician that a liver disorder could be developing [3,.]5  Predispositions and patient history (breed, age, sex)  Acute hepatitis (AH) and chronic hepatitis (CH) typically affected middle- to older aged dogs and female dogs were more frequently affected than males (Poldervaart et al, 2009).  Chronic hepatitis and cirrhosis usually affects dogs with age above five years old (Dill-Mackey, 1995; Fuentealba et al, 1997).  American and English Cocker Spaniels, West Highland White Terriers, Doberman Pinschers, Labrador Retrievers, Bedlington Terriers and many other breeds are associated with hepatitis.  Hepatitis may develop at any age, but not before2 years of age (Meyer and Rothuizen, 2013).  Age of dogs diagnosed with lymphoma ranged from 6 - 9 years with some variation according to type of lymphoma and breed(Pastor et al, 2009).  Golden Retrievers, Boxers, Bullmastiffs, Bernese Mountain Dogs, Bulldogs and Rottweiler recognized to have high incidence of lymphoma, but German Shepherds, poodles, Bichon Frise dogs, German shorthaired pointers, West Highl and white terriers are with a lower relative risk of lymphoma(Edwards et al, 2003; Modiano et al, 2005).  Golden Retrievers, Bulldogs and Bullmastiffs breeds reported to have lymphoma at a younger age due to these dog breeds have a naturally shorter lifespan(Modiano et al, 2007).  Choleliths incidence may be higher in small-breed dogs and more common in middle-aged to older dogs (Center, 2009; Kumar & Srikala, 2015).  The Liver Diseases Ethiopathophysiology Infectious hepatitis  Viral hepatitis: Infectious canine hepatitis (canine adenovirus type-1). feline leukemia and feline infectious peritonitis can results in feline viral hepatitis, as the viruses destroy liver tissues.  Parasites diseases: Toxoplasma gondi and Leishmania infantum in cats and dogs cause chronic hepatitis.Infection with liver fluke Platynosomum concinnum can cause acute and chronic cholangitis. :Bacterial diseases Leptospirosis is caused by Leptospira Interrogans Serovars Icterohemorrhagic and canicola. Mycotic infection: candidiasis is caused by Candidia albicans, histoplasmosis by Histoplasma capsulatom; aspergilosis by Aspergilus fumigates. 31  Non-Infectious  Wilson's disease:  inherited disease of copper metabolism. When the hepatic storage capacity of Cu is exceeded, parenchymal inflammation, hepatocyte damage and subsequent chronic hepatitis and cirrhosis.32 and followed by cell death with Cu release into the plasma causing hemolysis.  Reactive Hepatitis  inflammatory disorder of the liver induced by an extra hepatic process. As gastrointestinal, respiratory diseases, heart failure, diseases of the urinary and reproductive system. inflammatory mediators activate kupffer cells in the liver parenchyma induces reactive hepatitis results excessive damage of liver cells Drugs and toxins Drug-induced hepatotoxicity is a significant cause of acute liver failure, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure the organ.()19 Ex :Anticonvulsants drugs (phenobarbital) , Antifungal (ketoconazole) , analgesics(paracetamol in cat ) , pesticides, herbicides, cleaning agents and plant toxins Endocrine Disorder Diabetes mellitus, hyperadrenocorticism )Cushing’s disease), and hyperthyroidism can all cause impaired liver function because of their effects on the organ.(38) Excessive liver metabolism causes the liver overload and the liver become hepatomegaly.()18 Autoimmunity Hepatitis  In artificial insemination by husband (AIH), the liver cells are no longer recognized as ‘belonging’ to organisms are there attacked by the immune system resulting in chronic inflammation of the liver.()35  The aetiology of AIH remains unknown  female dogs and cats are more susceptible.()36 Classification of hepatobiliary Diseases Acute hepatitis  Acute hepatitis is morphologically characterized by combination of inflammation hepatocellular apoptosis and necrosis and in some instances, regeneration.  This can result in sudden death of the animal even within 48-hours after the start of the disease. ()28 Chronic hepatitis  long-term pathological process of continuous destruction of liver parenchyma and its gradual substitution with fibrous tissue, which ultimately results in liver cirrhosis associated with a fatal outcome.() 42  it is considered irreversible, and usually it is idiopathic in origin.  It is a regularly diagnosed condition in dogs, is less frequently encountered in cats but more frequently in dogs.()43  Biliary Tract Abnormalities Dogs and Cats -1Cholangitis complex  Cholangitis (cholangiohepatitis) is inflammation of the biliary system and liver.  It is the most common primary hepatic disorder in felines..()11,47 -2Cholelithiasis  formation of stones in the gallbladder.()48  Occur due to imbalances influxes between bile salts and cholesterol and gall- bladder motility, bile stasis and biliary inflammation. 3- Pneumobilia  The presence of gas in the biliary system  It is a common finding in dogs and cats that have recently undergone biliary surgery or endoscopic biliary procedure, infection by gas forming bacteria (emphysematous cholangitis).()50 -4Choledocholithiasis:  It is condition when a gallstone lodged within any duct of the bile system. (common bile duct, the cystic duct and the common hepatic duct.)  Gallstones usually form in the gallbladder.()51 5- Cholecystitis  Cholecystitis means painful inflammation of the gallbladder most cases are caused by gallstones.  Gallbladder walls become inflamed and stretched (distended) lead to compli- cations.(.)52 -6Hepatic Neoplsia  occur in the liver either as a primary disease or due to metastases from tumors of the spleen, pancrease, and gastrointestinal tract  The categories of hepatic tumors in cats and dogs are hepatocellular, bile duct and mesenchymal.()18  In dogs, malignant tumors are more common  Benign cystic bile duct adenoma is more frequent in cats. Clinical manifestations of liver diseases  Clinical Signs in Cats and Dogs with hepatobiliary diseases (Nelson, et al (2014) General, Nonspecific - muscular hypotonia - Anorexia - Jaundice - Depression - Bilirubinuria - Lethargy - acholic feces - Weight loss - Metabolic encephalopathy Coagulopathies - Small body stature * Dr. Sabry Moussa * - Poor or unkempt hair coat - Nausea - vomiting - Diarrhea - Dehydration - Polydipsia - polyuria More Specific but Not Pathognomonic - Abdominal enlargement organomegaly - effusion N.B Individual animals will show some but not all of these signs and many animals with hepatobiliary disease will show no clinical signs at all. 33 Mostly Encountered Clinical Symptoms of Liver Diseases  Hepatic encephalopathy clinical signs * Lethargy * Depression * Behavioral changes * Head pressing * Circling * Dr. Sabry Moussa * * Pacing * Central blindness * Seizures (uncommon) * Coma (uncommon) * Hypersalivation (especially cats) 35 * Dr. Sabry Moussa * A, female miniature poodle with congenital portosystemic shunt. The plasma ammonia concentration was 454 µg/dl. B, male mixed-breed dog with chronic hepatic failure and acquired portosystemic shunting. The plasma ammonia concentration was 390 µg/dl. (Nelson , et al ()2014 36  Portal hypertension and ascites  Chronic liver disease increases resistance blood flow to the liver and results portal hypertension and the back flow of blood, lymphatic fluid  From increased pressure in portal system there is leakage of blood from capillaries and causes abnormal fluid accumulation in abdomen cavity is ascites from low albumen production in the liver, organ failure like liver and heart.(28,55)  Jaundice (Ictrus)  One of the most common symptoms of liver disease is jaundice  yellowish tinge to the skin, in the eyes gums and ears.  The liver is responsible for excreting bilirubin, When the liver isn’t functioning this bilirubin builds up in the blood and leads to the yellowish appearance.  The causes of jaundice are classified as prehepatic, hepatic, or post- hepatic in origin. Pre-hepatic jaundice occurs when red blood cell breakdown or hemolysis, produces bilirubin faster than the liver can metabolize it.  Hepatic jaundice results from primary and diseases within the liver that interfere with the liver cells' ability to metabolize bilirubin or excrete it normally into the biliary tract.  Post-hepatic jaundice can result from obstruction to the flow of bilirubin-containing bile within the bile duct or from injury that causes leakage from the gallbladder or bile duct. (20,46)  3years, Female Golden retriever suffering from (Tick infestation + anterior uveitis) – (Acute hepatitis) years, male Golden retriever 3 years, male Golden retriever 4 suffering from (Hg gastroenteritis of suffering from (Anorexia + ) fresh blood) – (Acute hepatitis )jaundice) – (Acute hepatitis  years, male German 4 shepherd suffering from years, male Great dane 6 (Recurrent Epistaxis, suffering from (Chronic hematochezia) – vomiting + ascitis + blue eye) – )(Chronic Hepatitis  years, female German6.shepherd suffering from (Mam Tumor - metastatic to liver) – )(Masses years, male German 7 ½ shepherd suffering from (Acute greenish vomiting + Pallor of m.m Saddle cellulitis) – + )(Acute hepatitis  Abdominal Effusion  Abdominal effusion is much more common in dogs than in cats with liver disease. On the basis of cell and protein content, abdominal fluids are classified by standard criteria as: Transudates modified transudates (moderate to low cellularity with moderate to low protein concentration) Exudates (high cellularity and protein concentration) Chyle blood * Dr. Sabry Moussa * 46  Abdominal Effusion  Ascites is reserved for fluid of low to moderate protein content and low to moderate cell count (transudate or modified transudate)  it is usually related to disorders of hepatic or cardiovascular origin or severe protein-losing enteropathy or nephropathy.  The general pathogeneses:  Excessive formation by increased venous hydrostatic pressure  Decreased intravascular oncotic pressure  Altered vascular permeability and insufficient resorption * Dr. Sabry Moussa * 47 7years, male Husky years, male 1.1 suffering from Golden suffering from (Gastrsoieeznutrritis+ (Emaciation, chronic )es )vomiting, sc hg years, male choc golden 4 suffering from (Demodex Excess use of + )antiparasitic drugs years, Female 1 ½ Griffon suffering from (Hematoemesis + )Ascitis years, male 8 Griffon suffering from ,(Pulmonary edema + Chronic V miting )jaundice Algorithm for initial evaluation of the cat or dog with abdominal distention  Polyuria and polydipsia  Increased thirst and volume of urination seen primarily in dogs and rarely in cats ,The underlying mechanisms are poorly understood but several factors are suspected to * Dr. Sabry Moussa * contribute to polydipsia (PD) and polyuria (PU:)  Changes in the function of portal vein osmoreceptors that stimulate thirst early after drinking, before a change in systemic osmolality  Loss of the renal medullary concentrating gradient for urea 52  Laboratory Diagnosis of hepatobiliary Diseases in dogs and cats  Hematology  Patients with hepatobiliary disease can be anemic as a result of blood loss, dysmorphias and anemia.  Microangiopathy is more common in dogs than in cats can occur as a result of hepatic neoplasia or DIC, and may lead to the formation of schistocytes [.]57,58  Mild to moderate thrombocytopenia may occur in patients with severe liver disease. This may be the result of a decreased production of thrombopoietin by the liver , Disseminated intravascular coagulopathy,  infectious diseases affecting the liver, such as leptospirosis may result in thrombocytopenia [.]58  Liver Function Test Based on Liver Enzymes  Elevated liver enzymes may indicate inflammation or damage to liver cells.  Inflamed or injured liver cells leak higher amounts liver enzymes into the blood stream, which can result in elevated liver enzymes on blood tests.  The elevated liver enzymes most commonly found are Alanine transaminase (ALT), Aspartate transami- nase (AST), Alkaline phosphatase (ALP), Gamma-glutamyltrans- peptidase (GGT).63 Nelson, C. et al (2014): Small Animal Internal Medicine , sixth EDITION Nelson, C. et al (2014): Small Animal Internal Medicine , sixth EDITION  Serum biochemical constituents findings in selected hepatobiliary diseases Negasee KA ()2021 Duncan & Prasse’s veterinary laboratory medicine : clinical pathology / [edited by] Kenneth S. Latimer. – 5th ed (.)2011  KALLISTATIN  Kallistatin is a protein that in animals is produced by the SERPINA4 gene which is serine proteinase inhibitor also called tissue kallikrein inhibitor.  It binds tightly to tissue kallikrein but weakly to other serine proteinases such as chymotrypsin and elastase [.]66  It is a new and reliable biomarker for the diagnosis of liver cirrhosis. serum kallistatin levels in patients with LC were significantly lower than those in healthy controls, demonstrating a close correlation between the reduction in serum kallistatin levels and severity of early hepatic disease. Serum kallistatin levels could therefore provide an additional biomarker for the detection of LC and progressive loss of liver function along in response to the therapy  VITAMIN D  The accumulative data showed that the clinical manifestations and prognosis of chronic liver diseases are associated with serum vitamin D levels.  The insufficiency or deficiency of vitamin D is common in various kinds of chronic liver diseases including viral hepatitis B and C.  Serum 25-hydroxyvitamin D and vitamin D receptors are possibly interrelated with the incidence, treatment and prognosis  Although the exact role and mechanisms of vitamin D have not been fully elucidated in chronic liver diseases, it is potentially beneficial in the treatment of chronic liver diseases. [44, 73, 74,.]75  Novel serum hepatic biomarker "Hepatocyte-derived microRNA- 122"(miRNA-.)122  microRNAs are cluster of small noncoding RNAs molecules consisting of 24–18nucleotides (Ambros,.)2004  miRNAs are involved in normal physiological processes as well as involved in the pathogenesis of many diseases including inflammatory diseases, tumours, autoimmune diseases, metabolic diseases and viral infections (Wang et al,.)2016  miRNA-122 is found almost exclusively in hepatocytes (Liver specific biomarker) represent 70% of the total liver miRNA population (Lagos- Quintana et al, 2002; Krützfeldt et al, 2005;Castoldi et al,.)2011  miRNA-122 is an important regulator of cholesterol metabolism , lipid metabolism ,iron homeostasis and very important for reducing hepatic inflammation and tumor suppressing(Hsu et al, 2012 and Tsai et al,.)2012  miRNA-122 is more sensitive than ALT due to an earlier and/or higher increase of it during hepatic injury compared to ALT in humans and mice studies (Wang et al, 2009; Zhang et al, 2010; Starkey Lewis et al, 2011 and Thulin et al,.)2014  Elevation of serum miRNA-122 levels were prominent in dogs with acute hepatitis (AH) or chronic hepatitis (CH), biliary diseases And neoplastic diseases like hepatocellular carcinomas (HCC) and hepatic lymphoma (HL) less prominent in dogs with reactive hepatopathy (RH) or steroid induced hepatopathy (SIH) (Verzijl et al,.)2014  Urinalysis  Urine specific gravity decreased in patients with hepatic insufficiency or portosystemic shunts (PSSs.)  Bilirubinuria (