Hepatic disease Flashcards
Name 3 causes of copper accumulation in the liver
- Increased copper intake
- Primary defects in copper metabolism
- Impaired biliary excretion of copper
How does the histopathology of a patient with an inherited copper storage disorder differ from the histopathology of a patient with copper accumulation due to cholestasis?
- Primary/inherited storage disorder - centrilobular copper accumulation
- Secondary to cholestasis - periportal copper accumulation
What gene mutation found in Bedlington Terriers results in copper storage disorder?
COMMD1
What cat breeds have a predisposition for copper storage disorder?
Siamese and European shorthair
What dog and cat breeds have been shown to develop hepatic amyloidosis?
Abyssinian, Oriental, Siamese cats
Shar-pei dogs
In cats, copper colored irises (that are inappropriate for the breed) have been linked to what disease?
Portosystemic shunts
Microvascular dysplasia has been renamed what?
Congenital portal vein hypoplasia
What breed develops a progressive vacuolar hepatopathy? What are they potentially predisposed to?
Scottish Terriers
Hepatocellular carcinoma
- Icterus typically cannot be detected until the serum bilirubin is above what?
- Icteric plasma can be detected when the serum bilirubin is above what?
- Icterus: above 3 (maybe even 5)
- Icteric serum: above 0.5-1
What is the serum half life of ALT in dogs? In cats?
Dogs: 48-60 hours
Cats: 6 hours
Where do ALT and AST reside within the hepatocytes?
Mostly within the soluble fraction of the cytosol. Some AST in the mitochondria
How is ALP attached to hepatocyte membranes? What causes its release?
Attached by glucosyl phosphatidylinositol linkages. Release is facilitated by the presence of bile acids, which exert a detergent-like effect on the membrane anchor
In dogs, what is the sensitivity and specificity of ALP for hepatobiliary disease? In cats?
Dogs: 80% sensitivity, 51% specificity
Cats: 50% sensitivity, 93% specificity
What are the 3 major ALP isoenzymes in the dog?
bone-induced (B-ALP), corticosteroid-induced (C-ALP), and liver induced (L-ALP)
What is the half life of ALP in dog? In the cat?
Dogs: 70 hours
Cats: 6 hours
In cats with hepatic lipidosis, what is the pattern of liver enzyme elevation? In cats with necroinflammatory hepatobiliary diseases?
Hepatic lipidosis: ALP»_space;> GGT
Necroinflammatory disease: ALP < GGT
What percent of hepatic function must be lost for hypoglycemia to result?
75%
Why does liver disease cause low BUN?
Decreased hepatic function leads to decreased conversion of ammonia to urea = decreased BUN
What percent of hepatic function must be lost for hypoalbuminemia to result?
70%
Hyperalbuminemia has been reported with what disease?
Hepatocellular carcinoma
Why does sepsis result in hyperbilirubinemia?
Cytokines inhibit the expression of hepatocyte transporters necessary for bilirubin transport
Hyperbilirubinemia is present in what percent of cats with hepatic lipidosis?
95%
Patients with extra hepatic bile duct obstruction may remain icteric for several weeks after the obstruction is removed. Why?
Conjugated bilirubin in the plasma binds irreversibly to albumin (called delta bilirubin) - half life is about 2 weeks
Paired pre- and post-prandial bile acids have what sensitivity and specificity in diagnosing PSS?
99% sensitive, 95-100% specific in both dogs and cats
Why might pre-prandial bile acids be higher than post-prandial bile acids?
Interdigestive gallbladder contraction, variations in gastric emptying/transit time, variations in response to CCK. Not of clinical significance
What may cause falsely elevated post-prandial bile acids?
Lipemia
What are the vitamin K dependent clotting factors? Decreased activation of vitamin K dependent factors leads to prolongation in what?
- II, VII, IX, X, proteins C and S
- Prolonged PT
How can hepatobiliary disease lead to vitamin K deficiency?
Malabsorption of fat due to cholestasis can lead to malabsorption of fat soluble vitamins
What is the most common coagulation abnormality in cats with hepatobiliary disease?
Prolonged PT
Name 3 clotting inhibitory proteins produced by the liver
Antithrombin III, protein C, protein S
What is hypersplenism? What is it caused by?
Portal hypertension can lead to splanchnic pooling of blood. This results in prolonged capturing of platelets at their degradation site in the spleen, resulting in thrombocytopenia - called hypersplenism
How to proteins C and S act as anti-coagulants?
Bind together and degrade factors Va and VIIIa
What is the protein C activity in dogs with PSS? In dogs with microvascular dysplasia?
Protein C activity is of <70% is found in 88% of patients with PSS but only 5% of patients with MVD. Can be used to discriminate between them
CT scan is _____ times more likely to correctly identify a congenital PSS than AUS
5.5x
FNA of focal liver lesions has the highest sensitivity for detecting which diseases?
Vacuolar change (sensitivity 58%)
Neoplasia (sensitivity 52%)
What is the positive predictive value for detecting round cell tumors on hepatic FNA? For hepatocellular carcinoma?
Round cell: PPV 75%
Hepatocellular carcinoma: PPV 100%
What is the diagnostic accuracy of Tru-Cut biopsies compared to surgical biopsy?
Discordance in 50% of samples for both dogs and cats - worse with hepatobiliary diseases, better (80% accurate) for neoplasia
How many laparoscopic or surgical liver biopsies should be obtained?
Per consensus statement: at least 5 from at least 2 liver lobes: 3 for histopathology, 1 for culture, and 1 for copper
What essential antioxidant is stored in hepatocytes and has been shown to be depleted/reduced concentrations in a wide variety of hepatic diseases?
Glutathione
What is glutathione made of?
A tripeptide synthesized from L-glutamate, L-cysteine, and glycine
What is the function of S-adenosyl methionine (SAMe)? What is the rational for using it in hepatic disease?
Essential for the synthesis of glutathione via the transsulferation pathway. Administering it during hepatic disease may help prevent the depletion of hepatic glutathione and therefore prevent oxidative damage
What is N-acetylcysteine (NAC) and what is the rational for using it in hepatic disease?
A formulation of L-cysteine that helps replenish hepatic intra-cellular cysteine and glutathione concentrations , thereby protecting against oxidative injury
What is the mechanism of action of silymarin?
- Anti-oxidant: scavenges free radicals and reduces lipid peroxidation
- Anti-inflammatory: reduces production of inflammatory cytokines
- Inhibits hepatic fibrosis
The bioavailability of silymarin is improved when it is combined with what substance, which acts as a solubilizing agent?
Phosphatidylcholine
What does Denamarin contain?
SAMe, silymarin, and phosphatidylcholine
What is the most biologically active form of vitamin E?
Alpha-tocopherol
What is the main role of vitamin E?
Anti-oxidant: protects phospholipids from oxidative injury by scavenging free radicals
What is ursodeoxycholic acid and what are its beneficial properties?
Hydrophilic bile acid
- Displaces more toxic hydrophobic bile acids from the circulating pool
- Choleretic effect, which increases excretion of endogenous toxins
- Inhibits hepatocyte apoptosis
- Suppresses IL-2 production (anti-inflammatory)
What drug may be used for copper chelation if D penicillamine is not tolerated?
Trientine
How does zinc decrease the absorption of dietary copper?
Zinc induced synthesis of metallothionein in enterocytes. Metallothionein binds copper, preventing it from entering circulation. When the enterocytes die and are shed in the feces, the copper goes too
Plasma concentrations of zinc should be measured while supplementing it. What concentration is effective for reducing copper? What concentration is toxic?
- Around 200mcg/dL is effective
- Over 800-1000mcg/dL causes hemolysis
Why don’t we need to supplement most patients with copper storage hepatopathy with zinc for long term maintenance?
Commercial hepatic diets are already supplemented with it
What anti-emetic drug is metabolized by the liver’s cytochrome P450 enzymes and should be dose reduced in patients with hepatic failure?
Maropitant
Where are hepatic lesions primarily located in cats? In dogs?
Cats: biliary system is predominately affected
Dogs: hepatic parenchyma is predominately affected
What are the four classifications of cholangitis?
- Neutrophilic (usu. cats)
- Lymphocytic (usu. cats)
- Destructive cholangitis (usu. dogs)
- Chronic cholangitis associated with liver flukes (usu. cats)
What are the consistent histologic findings that accompany cholangitis?
Portal inflammation, fibrosis, bile duct proliferation
What is currently the most common infectious cause of acute hepatitis in dogs? What serovars are implicated?
Leptospirosis - Leptospira interrogans or kirschneri
What organism is commonly cultured from the bile of dogs and cats with biliary disease and acute hepatitis?
Clostridium spp.
What drugs can cause acute hepatitis through idiosyncratic drug reactions?
Carprofen, TMS
What form of copper is likely hepatotoxic?
Cupric form - Cu2+
How does copper result in hepatotoxicosis?
Copper is a component in the redox cycling that generates oxidative radicals that deplete hepatic antioxidant defenses and damage cellular components
How does a mutation in COMMD1 lead to copper storage disease?
Leads to a defect in the ability to excrete copper from hepatocytes into the bile canaliculi
What is the inheritance pattern of the COMMD1 mutation in Bedlingtons?
Autosomal recessive
What is a rare presentation of copper storage hepatopathy that results from massive release of copper into circulation?
Acute hemolytic crisis
What is the proposed pathogenesis of neutrophilic cholangitis in cats?
Ascending bacterial infection
What are the histopathologic features of neutrophilic cholangitis? When is it called cholangiohepatitis?
- Neutrophils are noted within the bile duct lumen, closely associated with the bile duct, or between biliary epithelial cells
- Becomes cholangiohepatitis when the inflammation extends beyond the limiting plate and into the hepatic parenchyma
What percent of cats with neutrophilic cholangitis have hyperbilirubinemia? Elevated liver enzymes?
- Hyperbilirubinemia present in 2/3 of cats
- Elevated AST in 98%, ALT in 50-57%
- Elevated ALT in 14-48%
Vagotonic shock can occur after performing what procedure?
Core needle biopsy, particularly with a semi-automatic or automatic Tru-Cut device
What is the most consistent biochemical abnormality with lymphocytic cholangitis in cats?
Hyperglobulinemia
What liver fluke infects cats and leads to chronic cholangitis?
Platynosomum
What is the intermediate/paratenic host of Platynosomum?
Lizards! Called lizard poisoning haha
Clinical signs of Platynosomum infection occur due to what processes?
Bile duct obstruction by the flukes or hepatic failure from damage by the flukes
What is the treatment for Platynosomum?
Praziquantel
Describe the normal anatomy of the portal venous system
Venous blood draining from the spleen, pancreas, stomach and intestines enters the portal vein. The portal vein then perfuses the liver through a sinusoidal network and drains through the hepatic veins to the caudal vena cava
What large shunting vessels exists in the developing fetus that bypasses hepatic circulation?
Ductus venosus
What stimulates the ductus venosus to close in newborn animals? When should it close by?
Closure is initiated by blood pressure changes after umbilical venous flow ceases. Thromboxane and other adrenergic stimuli may help with closure. Should close by 3-10 days of age
Why does a PSS result in poor hepatic development?
Tropic factors, such as insulin and glucagon, are bypassing the liver and are not available to stimulate hepatic growth
What percent of congenital PSS are extrahepatic? What is the most common form?
- 66-75% are extra hepatic
- A single portocaval shunt is the most common
What percent of congenital PSS are intrahepatic?
25-33%
Describe the pathogenesis of acquired portosystemic shunts
Chronic portal hypertension leads to opening of fetal, vestigial blood vessels that are typically tortuous, extra hepatic vessels located near the kidneys
Describe primary portal vein hypoplasia (PVH) with portal hypertension (also called non cirrhotic portal hypertension)
A congenital disease consisting of portal hypertension despite a patent portal vein (no PSS) and a non cirrhotic liver. Thought to be due to severe, diffuse intrahepatic vascular malformations
Describe portal vein hypoplasia (PVH) without portal hypertension (formerly MVD)
- Microscopic malformation of the hepatic vasculature - characterized by small intrahepatic portal vessels, portal endothelial hyperplasia, random juvenile intralobular blood vessels and central venous hypertrophy.
- These lesions allow for abnormal communication between the portal and systemic circulation at a microvascular level
What percent of dogs with PVH also has a macrovascular PSS?
58%
Describe hepatic arteriovenous malformations
Multiple high pressure arterial and low pressure venous communications - usually a branch of the hepatic artery communicates with the portal vein via multiple aberrant shunting vessels. Leads to portal hypertension due to the high pressure arterial blood entering the portal venous system
Extrahepatic PSS is hereditary in what breed, which has a odds ratio for PSS 36 times higher than all other breeds combined?
Yorkshire terrier
In the Maltese, what is the inheritance pattern for both PSS and PVH?
Recessive, partially penetrant mode of inheritance
Left divisional intrahepatic PSS are heritable in what breed?
Irish Wolfhounds
Does GI hemorrhage occur more frequently with intrahepatic or extrahepatic PSS?
Intrahepatic
What other congenital defect is common with PSS?
Cryptorchidism - 30% of male cats, 50% of male dogs
PVH with portal hypertension is more common in what dog breed?
Doberman Pinschers (27% of cases)
What changes to GFR are noted in 81% of dogs with PSS?
Increased GFR and renal volume
What dog breed can have elevated bile acids without disease condition?
Normal Maltese dogs
What inborn error in ammonia metabolism can lead to hyperammonemia and hepatic encephalopathy in cats?
Deficiency in the ornithine transcarbamylase enzyme
Transcolonic scintigraphy utilizes what radioisotope to identify PSS?
Technetium pertechnetate
Describe how transcolonic scintigraphy is performed
A bolus of the radioisotope is infused into the colon and the pet is imaged with a gamma camera. In a normal dog, the isotope should go through the caudal mesenteric vein to the portal vein, liver, and then the heart. In a dog with PSS, it goes to the heart directly.
Why are milk and vegetable proteins less likely to precipitate HE than animal proteins?
Lower concentrations of aromatic amino acids (tryptophan, phenylalanine) and higher concentrations of branched chain amino acids (leucine, isoleucine, valine)
If a diuretic is used for ascites, why is spironolactone a better choice than furosemide for dogs with portal hypertension?
Furosemide can worsen hypokalemia, which can precipitate HE
What is the prognosis for dogs with PSS treated medically?
- ~50% are euthanized within 10 months of diagnosis (average age 20 months)
- 33% survive long term (MST 4.7 years of age)
- Typically worse prognosis with intrahepatic PSS - worse HE
What are prognostic factors for dogs with PSS treated medically?
- Age of onset of clinical signs (older survive longer)
- Low BUN = worse prognosis
- No correlation with other blood work changes
What is the goal of surgical PSS correction?
To attenuate the shunting vessel and increase portal blood pressure in order to encourage portal vein development without causing excessive portal hypertension
In steroid hepatopathies, where does vacuolar change start in histopathology?
In the centrilobular regions
What are the most consistent hormonal changes observed in Scottish Terriers with glycogen-like vacuolar hepatopathy?
Increases in progesterone and androstenedione post-ACTH stim test. Variable changes in cortisol on ACTH or LDDST
What is the term for fat accumulation within hepatocytes?
Steatosis
Microvascular steatosis describes multiple vacuoles that are smaller than the cell nucleus. This is commonly seen in what canine disease?
Diabetes mellitus
Name 4 causes of hepatic steatosis
Hepatocyte injury (aflatoxin, vitamin A intoxication), congenital PSS, feline hepatic lipidosis, diabetes mellitus
What is the definition of feline hepatic lipidosis?
Diffuse involvement of >50% of hepatocytes with cytoplasmic lipid-containing vacuoles, leading to acute liver failure
What is the difference between primary vs secondary hepatic lipidosis?
Primary: occurs in overweight cats that have been fasted or anorexic for a prolonged period of time but have no underlying disease. Typically must lose 25-40% of body weight for lipidosis to develop
Secondary: occurs in association with another disease process (cholangitis, pancreatitis, IBD, DM, hyperthyroidism, etc)
What 3 predisposing factors contribute to the development of hepatic lipidosis?
Obesity, stress, and anorexia
Describe the pathogenesis of feline hepatic lipidosis
- Fasting combined with stress leads to increased peripheral lipolysis => increased circulating triglycerides and fatty acids
- The liver is unable to remove triglycerides fast enough, possibly due to decreased protein intake and decreased apoprotein production
- Triglycerides accumulate in the liver (from 1% in normal cat to 43%)
How does hepatic lipidosis lead to acute liver failure and cholestasis?
- Marked steatosis interferes with hepatocyte function/metabolism
- Cholestasis results from compression of the small intrahepatic cholangioles
What are the characteristic biochemical changes with primary hepatic lipidosis?
Marked hyperbilirubinemia, elevated ALP and ALT with a normal GGT
What is the single most important factor affecting prognosis in cats with hepatic lipidosis?
Early, intensive feeding
Without assisted feeding, what is the mortality rate of hepatic lipidosis? With assisted feeding?
Without feeding tubes: 90% mortality
With feeding tubes: 14-40%
What should the nutrient composition of a diet for cats with hepatic lipidosis be?
High protein - most effective at reducing hepatic lipid
There is strong evidence that cats with hepatic lipidosis have systemic and hepatic oxidative injury. Therefore, what medications are recommended?
SAMe, vitamin E
Cats with hepatic lipidosis often have prolonged clotting times that normalize with what medication?
Vitamin K injection
What is hemochromatosis? What are potential underlying causes
Iron overload in the liver, caused by:
1. Increased absorption in the intestines (must be VERY high in the diet)
2. Abnormal iron excretion
3. Increased hepatic iron storage due to red cell hemolysis
Rare in dogs/cats
Where does iron accumulate in the liver?
Periportal - leads to fibrosis and hepatic lesions
Hemochromatosis has been reported in dogs with what enzyme deficiency?
Pyruvate kinase deficiency leading to hemolytic anemia and many transfusions
What is amyloid?
A complex protein that can exist in 2 forms: the normal, soluble form or an abnormal aggregated form of beta-pleated sheets. The aggregated form causes disease
What is serum amyloid A?
An acute phase protein produced in large amounts by hepatocytes during inflammatory disease
Why do some patients develop amyloidosis due to an increase in serum amyloid A after an inflammatory event?
Unclear - likely genetic and environmental factors contribute to why some animals develop amyloidosis and others do not
What cat breeds produce a very limited range of serum amyloid A proteins compared to DSH and are more prone to amyloidosis?
Abyssinians and Siamese
In Abyssinians, how does amyloidosis typically present?
Amyloid seems to have tropism for the kidneys. Present with CKD due to renal medullary (rather than glomerular) involvement. Can have liver involvement, but it typically does not result in clinical signs
In Siamese, how does amyloidosis present?
Amyloid seems to have tropism for the liver. Present for acute intra-abdominal bleeding from the fracture of a very friable liver, leading to anemia and hypotension. Can also present with jaundice and hepatomegaly
How is amyloidosis in cats diagnosed and treated?
Renal or hepatic biopsy
Treat any underlying inflammatory conditions, supportive care. Colchicine is toxic in cats
In dogs, how does amyloidosis from serum amyloid A present?
Typically as a protein losing nephropathy from glomerular disease
Hepatic involvement from amyloidosis has been reported in one dog breed. Which breed?
Shar Peis - primary hepatic involvement reported in 4 dogs. Can also suffer spontaneous hepatic rupture
Describe cytotoxic hepatotoxicosis
The parent compound or a locally produced metabolite lead to direct hepatocyte necrosis and elevations in ALT
Describe cholestatic hepatotoxicosis
Compounds inhibit or downregulate transporter pumps in the sinusoidal or canalicular membranes, thus interfering with bile salt efflux and hepatocyte function. Leads to elevations in ALP
Describe dose dependent or intrinsic hepatotoxicosis
- Increasing toxicity occurs with increasing dosages. Virtually all animals would be affected at high enough doses.
- Relatively predictable
- Therapeutic drug monitoring may be useful, requires a dose reduction but not necessarily drug discontinuation
Name 4 mechanisms of dose dependent hepatotoxicosis and give examples of toxins that cause these mechanisms
- Oxidative stress (acetaminophen, azathioprine, azoles)
- P450 induction (phenobarbital)
- Mitochondrial dysfunction (tetracyclines, amiodarone)
- Transporter dysfunction (endotoxin)
Describe idiosyncratic hepatotoxicosis
- Reactions develop only in a small percentage of the population and are difficult to predict
- Often caused by reactive metabolites that are variably produced among individuals
- Require discontinuation of the drug and any related drugs
Name 2 mechanisms of idiosyncratic hepatotoxicosis and give examples of toxins that cause these mechanisms
- Oxidative stress (methimazole, diazepam?)
- Lead to haptens that trigger a humoral or T cell mediated immune response (potentiated sulfas, zonisamide?)
Acetaminophen can be safely used at lower doses in dogs, but is a dose dependent hepatotoxin at high doses. What histopathologic changes does it cause in the liver?
Acute centrilobular hepatic necrosis
In cats, acetaminophen is toxic even at low doses. Why?
Cats do not express the enzyme that glucuronidates acetaminophen and may lack the transporter that exports it
What are signs of acetaminophen toxicosis in cats?
Methemoglobinemia and cyanosis predominate over direct liver toxicosis
Acetaminophen is bioactivated to a reactive metabolite called NAPQ1. How is this metabolite detoxified?
Through glutathione conjugation
How can acetaminophen toxicity be treated?
With the glutathione precursor, N-acetylcysteine or with SAMe
Hepatotoxicosis from phenobarbital is dependent on what?
Cumulative dose - most dogs develop signs after being on it for at least one year and duration of administration correlates to how severe histopath findings are
What are the typical histopathologic findings in phenobarbital hepatotoxicosis?
Bridging portal fibrosis, bile duct hyperplasia, nodular regeneration
How is phenobarbital thought to cause hepatotoxicosis in dogs? Why aren’t cats affected?
- Induction of cytochrome P450 enzymes may lead to increased bioactivation and hepatotoxicity of other drugs, dietary components or environmental toxins
- Induction of cytochrome P450 does not occur in cats - no hepatotoxicosis
What parameters should be monitored every 6 months in dogs on phenobarbital?
- Serum phenobarbital levels: avoid >40 mcg/mL
- Chemistry: New hyperbilirubinemia, hypoalbuminemia, or ALT > ALP is worrisome
- Bile acids
How does ketoconazole result in hepatotoxicity?
An oxidative metabolite causes glutathione depletion and covalently binds to liver proteins
Which of the azoles may be less hepatotoxic?
Fluconazole
If a new elevation in ALT is noted while on azole drugs, what should be done?
Dose reduction, preceded by a rest period depending on severity
Azathioprine leads to increases in ALT +/- ALP in what percent of dogs? When does it typically occur
- 20%
- Occurs 14 days after starting the drug (sooner than cytopenias - 50 days)
What is the mechanism by which azathioprine causes hepatotoxicity?
Oxidative metabolites are created by xanthine oxidase
What breed seems to be at higher risk of azathioprine toxicosis?
German Shepherds
What chemotherapeutic agent can cause a 5 fold increase in ALT in 29% of dogs and clinical signs of hepatotoxicosis in 6% of dogs?
Lomustine (CCNU)
CCNU toxicity is more common in what breed and age of dog?
Boxers and dogs <5 years of age
In a randomized, placebo controlled study, what drugs were effective in reducing the incidence and severity of CCNU hepatotoxicosis?
SAMe combined with silymarin (Denamarin) - should be considered for all dogs on CCNU
In a retrospective study of ~400 dogs receiving doxycycline, what percent developed ELE?
36-39% (up to 23x ALT and 16x ALP)
- Study DID NOT rule out other causes of ELE though
What is the most common antimicrobial associated with idiosyncratic drug reactions?
Potentiated sulfonamides. Of course it is.
When does hepatotoxicosis secondary to sulfonamides occur?
5-30 days after starting treatment (mean 12 days)
What are clinical signs associated with idiosyncratic drug reactions to potentiated sulfas?
Fever (55%), neutropenia, thrombocytopenia, hemolytic anemia, polyarthropathy, proteinuria, KCS, skin lesions, uveitis
What breed of dog is overrepresented among cases of potentiated sulfa toxicity?
Dobermans - typically develop arthropathy and glomerulonephritis rather than hepatotoxicosis though
Sulfonamide antimicrobials are oxidized to form what?
Nitroso metabolites that covalently bind to proteins and act as happens
- Idiosyncratic drug reactions are convincingly immune mediated in humans
When does idiosyncratic hepatotoxicosis from carprofen occur?
5-30 days after starting the drug (median 19 days)
What liver enzyme is always elevated in carprofen induced hepatotoxicosis?
ALT - clinical signs with a normal ALT rules out carprofen toxicosis
What percent of cats develop hepatopathy and jaundice within one month of starting methimazole?
1-2%
How does methimazole cause hepatotoxicosis?
An oxidative metabolite causes glutathione depletion and centrilobular hepatic necrosis
What are other potential clinical signs of methimazole toxicosis?
Blood dyscrasia, facial excoriation
Diazepam can cause a fatal, idiosyncratic hepatotoxicosis in what species?
Cats
What produces aflatoxins and where are they found?
Produced by Aspergillus spp., found in moldy corn, peanuts, or soy (contaminated pet food, bird seeds)
Decreases in what biochemical parameters may be more sensitive for detection of aflatoxin hepatotoxicosis than ELE or bilirubin early in the course of disease?
Serum protein C, antithrombin, and cholesterol
What is the most prominent histopathologic finding with aflatoxin hepatotoxicosis?
Diffuse hepatocyte lipid vacuolation
Massive hepatic necrosis is not seen
What percent of dogs with aflatoxin hepatotoxicosis survive?
1/3 - with intensive treatment for liver failure
What is the mechanism of action for Amanita mushroom toxicosis?
- Contain amatoxins, which inhibit RNA polymerases, leading to decreased mRNA generation, arrested protein synthesis, and necrosis. Also stimulate massive insulin release
- Primarily affects metabolically active cells - intestinal crypt cells, hepatocytes, renal tubules
What are the clinical signs of Amanita toxicosis and when do they occur?
- 6-24 hours after ingestion: vomiting, bloody diarrhea, abdominal pain
- 24-48 hours: severe hypoglycemia
- 36-84 hours: massive hepatic necrosis and renal tubular necrosis
What drug prevented fatalities from Amanita mushrooms when given at 5 and 24 hours after ingestion?
Silybin
Blue green algae are not algae haha. What are they?
Photosynthetic cyanobacteria
What cyanotoxins are produced by blue green algae and what is their mechanism of action?
Microcystin and nodularin
- Inhibit serine/threonine protein phosphates in the liver, leading to disruption of cytoskeletal proteins
How rapidly do dogs develop clinical signs and hepatic failure after eating blue green algae?
Within hours
What part of the Sago palm is most toxic?
The seeds, but roots and leaves can still cause clinical signs
What is “zone 1” in liver anatomy? What are these cells susceptible to?
- Contains hepatocytes closest to the arterial or portal inflow
- Susceptible to injury from directly acting toxicants
What is “zone 2” in liver anatomy?
- Contains the transitional midzone hepatocytes
What is “zone 3” in liver anatomy? What are these cells susceptible to?
- Contains the periacinar hepatocytes, closest to the hepatic veinules
- Susceptible to hypoxic injury (furthest from the oxygen supply)
- Also susceptible to injury caused by toxic metabolites of the cytochrome P450 system (active in this area)
What toxin impairs hepatic synthesis of ALT, and therefore ALT may be normal despite acute hepatic necrosis?
Microcystins from blue green algae
How does hypokalemia increase the risk/precipitate HE?
Hypokalemia stimulates renal proximal tubule ammoniagenesis
How does metabolic alkalosis increase the risk/precipitate HE?
Facilitates the diffusion of ammonia into the CNS
What percent of dogs develop clinical signs from idiosyncratic hepatotoxicosis from zonisamide and when does it occur? What percent develop chronic ELE?
Acute: 0.52%, 13-16 days after starting treatment
Chronic: subclinical ELE in <10%
What were the most common clinical signs in cats with congenital PSS?
Abnormal behavior (82%), ptyalism (73%), stunted growth (47%), ataxia (41%), copper colored irises (38%)
In cats with congenital PSS surgically corrected using a thin film band, what percent had complications? How many died?
32% complication rate
- 23.5% seizures
- 11.7% (4 cats) euthanized due to refractory seizures post-op
What percent of cats with a congenital PSS present with microcytosis?
76%
What percent of dogs with congenital PSS have ammonium urate urolithiasis? What are the risk factors for it?
- 35%
- Male dogs, older dogs, and dogs previously treated with medical management more likely to have stones
How are PSS named?
The name of a shunt is derived from the name of the portal vessels from which it originates and the name of the first systemic vein to which it joins
Regarding surgical outcome for dogs with congenital extrahepatic PSS, what technique was superior to placement of a thin film band in a meta-analysis?
Ameroid constrictor
What blood test can be used to evaluate extrahepatic PSS closure post-operatively?
Injection of lidocaine and measurement of its metabolite monoethylglycylxylidide (MEGX) - more metabolism = shunt closure
What technique can be used to surgically correct intrahepatic PSS in cats?
Percutaneous transvenous coil embolization
What amino acid abnormalities are found in dogs with congenital PSS? What occurs post-operatively?
- Increased aromatic amino acids, lower levels of branched chain amino acids
- Does not improve with medical management, despite neurologic improvement
- Ratio of these amino acids improves, but does not normalized with surgery
In dogs with portal hypertension and acquired shunting from chronic hepatitis, what changes were noted in the RAAS system?
Increased plasma renin and aldosterone compared to dogs with congenital PSS or healthy dogs
Why would RAAS activation occur with portal hypertension?
Compensatory response to systemic and splanchnic arterial vasodilation
Dogs and cats with what congenital anatomic abnormality were more likely to have ductal plate malformations?
Peritoneopericardial diaphragmatic hernias (PPDH) or central diaphragmatic hernias
What serum lipoproteins are abnormal in cats with hepatic lipidosis?
- Increased LDL and lower HDL in cats with hepatic lipidosis
- No difference in serum cholesterol or triglycerides
Hepatocutaneous syndrome may have a heritable component in what breed?
Shih Tzus - in a retrospective study of 18 dogs, common ancestry was identified in 12
If a liver biopsy specimen contains at least a certain number of triads, the histopathologic interpretation is unlikely to vary, no matter what the sampling method. How many triads are needed?
At least 3-12
What percent of dogs and cats undergoing liver lobectomy require a blood transfusion?
17% of dogs and 40% of cats
In a study comparing 3mm and 5mm laparoscopic cup biopsies, how many more portal triads were obtained with the 5mm samples?
21 vs 14 triads
In a study comparing 3mm and 5mm laparoscopic cup biopsies, what was the diagnostic accuracy of the two methods compared to a wedge biopsy?
Percent agreement with histopathology from the wedge biopsy was the same (67 and 69%). So despite a smaller sample size, the 3mm was just as accurate
What percent of cats develop major (<6% change in PCV) or minor bleeding after percutaneous ultrasound guided liver biopsy?
Minor bleeding in 43%, major bleeding in 57%. 16% required intervention
In cats undergoing percutaneous ultrasound guided liver biopsy, major bleeding was associated with which diagnosis?
Hepatic lipidosis
In a retrospective study of 253 patients undergoing ultrasound guided cholecystocentesis, what percent developed bile peritonitis?
0.7%
In dogs undergoing percutaneous ultrasound guided liver biopsy, what percent developed major hemorrhage?
42%, but only 2% required intervention (mean change in PCV 7%)
Sedation with dexmedetomidine is associated with what change in the gallbladder?
Thickening of the GB wall (>2mm) in 24% of dogs. Occurred 20-40 minutes after sedation.
Gallbladder wall thickening has been associated with what cardiac disease in dogs and cats?
Pericardial effusion
Describe the most common hepatic tumors in dogs vs cats
Dogs:
- Metastatic tumors and malignant tumors more common
- Of primary tumors, hepatocellular carcinoma most common (>50%)
Cats:
- Primary tumors and benign tumors more common
- Bile duct adenomas most common primary tumors
More than 80% of dogs with hepatocellular carcinoma are over what age?
> 10 yrs
What breed may be predisposed to hepatocellular carcinoma?
Miniature Schnauzers
What is the metastatic rate for canine hepatocellular carcinoma and how does it vary with morphology?
For massive, solitary HCC (53-83% of cases), metastasis is rare: 0-37%
For nodular or diffuse HCC, metastasis is common: 93-100%
What is the most common malignant hepatic tumors in cats?
Bile duct carcinoma aka cholangiocarcinoma
What dog breed may be predisposed to bile duct carcinoma?
Labradors
In cats with bile duct carcinoma, what percent had intraperitoneal metastasis and carcinomatosis?
67-80%
What is the definition of chronic hepatitis?
- Presence of lymphocytic, plasmacytic, and/or granulomatous inflammation
- Hepatocyte death +/- fibrosis and regeneration
Where does inflammation typically originate in chronic hepatitis?
Portal regions, can then spill over into the hepatic lobule
What is cirrhosis?
End stage chronic hepatitis characterized by substantial architecture distortion, fibrosis, and sinusoidal portal hypertension
What is lobular dissecting hepatitis?
Form of chronic hepatitis characterized by lobular inflammation with fine fibrosis dissecting around single hepatocytes or groups of hepatocytes, hepatocyte necrosis, and marked ductular reaction
Mild to moderate inflammation with NO hepatocyte necrosis/apoptosis, no fibrosis, and no architectural remodeling should raise concern for what disease process?
A non-specific reactive hepatopathy - look for causes of extrahepatic inflammation in the splanchnic system
In cases of non-specific reactive hepatopathy, what clinicopathologic changes are seen?
- ALT/ALP less than 3x the upper reference limit
- Normal function testing
Name 4 vector borne infectious diseases that have been linked to chronic hepatitis
- Leptospirosis: usually causes acute hepatitis, but some evidence for chronic pyogranulomatous hepatitis
- Ehrlichia canis
- Babesiosis: nonsuppurative hepatitis
- Leishmaniasis: granulomatous inflammation
Name 4 drugs that can result in chronic hepatitis
Phenobarbital, primidone, phenytoin, lomustine
What is the most common toxic injury resulting in chronic hepatitis?
Copper
What breeds are predisposed to copper induced chronic hepatitis?
Bedlington terrier, Labrador Retriever, Dalmatian, Doberman, West Highland White Terrier
Increased ALT activity and histopath changes begin when hepatic copper concentrations exceed what level?
- Usually >1000 ug/g dw
- Always >1500 ug/d dw
- Individual thresholds vary, likely due to environment, genetic factors
What histopathologic changes may influence copper quantification?
Regenerative nodules and fibrotic tissues have decreased copper accumulation
How does alpha-1 antitrypsin deficiency lead to chronic hepatitis? What breeds has it been identified in?
- Results in hepatocyte retention of abnormally folded proteins => CH
- Cocker Spaniels
How does erythropoietic protoporphyria result in chronic hepatitis? What breed has it been reported in?
- Leads to abnormal accumulation of porphyrins within hepatocytes
- Reported in a colony of GSDs
What criteria raise concerns for an immune mediated chronic hepatitis?
Lymphocytic infiltrates, abnormal expression of MHC class II proteins, positive serum autoantibodies, familial history of disease, female predisposition, response to immunosuppression
How does the signalment and clinical presentation of dogs with lobular dissecting hepatitis differ from other causes of chronic hepatitis?
- Younger: 2 years vs 7 years
- More likely to have ascites: 80% vs 33%
What percent of dogs with chronic hepatitis have ELE with no clinical signs?
20%
What clinicopathologic change is the earliest indication of chronic hepatitis?
Elevated ALT - persistent (>2 month), unexplained ALT elevations should raise concern for CH
What microRNA may be increased with minimal liver injury in the absence of elevated ALT (may be used to detect early CH)?
miR-122
Hyperbilirubinemia is reported in what percent of dogs with CH?
50% - poor prognostic indicator
How does the sensitivity and specificity of serum ammonia compared to bile acids for detecting cirrhosis and APSS?
Similar sensitivity
Ammonia is more specific - not affected by cholestasis
What does the liver look like on ultrasound with CH?
- Size is variable, smaller with advanced disease
- Usually hyperechoic due to fibrosis or glycogen-type vacuolation
- Can develop small hypoechoic nodules later in disease
- Low sensitivity, no changes are pathognomonic
Portal vein thrombosis should be suspected when what clinical signs and clinicopathologic abnormality are present?
Ascites, abdominal pain, thrombocytopenia
In humans, risk of bleeding after liver biopsy is associated with what coagulation parameters?
- PT and aPTT >1.5x upper limit
- Platelet count <50,000
- Anemia PCV < 30%
- Fibrinogen <100 mg/dL
What number of portal triads should be obtained for hepatic biopsy per the consensus statement?
12-15
Vital signs and PCV should be monitored how often after liver biopsy per the consensus?
Every 2 hours until 6 hours post-biopsy
What stains are useful to identify hepatic fibrosis?
Sirius red, Masson’s trichrome
What stains are useful to identify copper?
Rhodanine or rubeanic acid
What is the gold standard for quantitative copper assessment?
Atomic absorption spectroscopy
Copper restricted diets (<0.12mg/100kcal) are recommended for all dogs with a copper concentration greater than what?
> 600 ug/g dw
How rapidly with D penicillamine normalize hepatic copper concentrations?
Depends on initial copper concentration:
- Up to 1500 ug/g normalize by 6 months
- 2000-3000 ug/g normalize by 9 months
D pencilliamine may cause what change to the liver that resolves with drug discontinuation?
Mild to moderate vacuolar hepatopathy and mild ALP elevations
Co-treatment with D-penicillamine and what supplement are strictly contraindicated?
Zinc - negate each other
What diseases is ursodiol indicated for?
CH with cholestasis, inflammation involving the bile ductules, and bile-borne bacterial infections
What is the prognosis for dogs with CH with or without cirrhosis? With lobular dissecting hepatitis?
Without cirrhosis: 561 +/- 281 days
With cirrhosis: 23 days
LDH: 48 days
What clinicopathologic factors have the strongest association with poor prognosis in chronic hepatitis?
Hyperbilirubinemia, prolonged PT/aPTT, hypoalbuminemia
What is the diuretic of choice for managing ascites?
Spironolactone
What is the ductal plate? What are congenital ductal plate abnormalities?
- Ductal plate: a double layer of embryonic epithelium surrounding the portal veins - prescursor of the interlobular and intralobular bile ducts
- Developmental abnormalities of the portal triad
How does congenital hepatic fibrosis develop?
Maturation arrest of small interlobular bile ducts from the ductal plate leads to fibrosis
How does Caroli disease develop?
Maturation arrest of the medium intrahepatic bile ducts from the ductal plate
In dogs with idiopathic chronic hepatitis, treatment with cyclosporine monotherapy lead to biochemical remission (ALT <1.1x upper limit) in what percent of dogs? How long did it take?
79% (no control group) in 2.5 months
What other heavy metal was increased in dogs with high hepatic copper (>400)?
Lead
What biochemical abnormality was more common in dogs with high hepatic lead levels?
Microcytosis
No correlation with inflammatory or fibrosis scores
Resting serum bile acids are highest in dogs with what liver diseases?
Cirrhosis (98 umol/L) and congenital circulatory anomalies (80)
What is the sensitivity of resting serum bile acids for congenital PSS? Post-prandial bile acids?
Resting: 87.5%
Post-prandial: 91%
What serum miRNAs are correlated with grade of hepatitis and stage of fibrosis?
miR-122 and miR-29a
Anti-histone antibodies were elevated in what breed with chronic hepatopathy compared to healthy dogs?
Dobermans
What vasoconstrictive molecule is 3.7 times higher in dogs with chronic hepatitis than in healthy dogs?
Endothelin-1
What cell cycle inhibitor and marker of cellular senescence was higher in liver biopsies from dogs with chronic hepatitis than normal dogs? How did it correlate with prognosis?
- p21 - median positive hepatocytes 90% vs <15% in controls
- Dogs with immunopositivity > 91.8% had shorter survival time
What new drug has shown promise for decreasing hepatic copper concentrations in dogs?
Ammonium tetrathiomolybdate
What copper transporter gene may be associated with copper hepatitis in Dobermans and has been identified in 3 cats?
ATP7B
What are the 3 types of hepatic encephalopathy?
- Type A: due to acute liver disease
- Type B: due to PSS with no intrinsic liver disease
- Type C: due to cirrhosis, portal hypertension or APSS
What two processes generate ammonia in the GI tract?
- Urease producing bacteria break down nitrogenous products (like urea) to ammonia
- Glutamine is broken down by glutaminase into glutamate and ammonia by enterocytes (glutamine <=> glutamate + ammonia)
What two pathways does the liver use to break down ammonia?
- Ammonia is converted to urea by periportal hepatocytes through the urea cycle
- Glutamine is synthesized by perivenous hepatocytes
What is the role of the kidneys in ammonia metabolism?
Contain BOTH glutaminase and glutamine synthetase - so can both metabolism or synthesize glutamine
What tissue acts as an “ammonia sink” because it contains the most glutamine synthetase in the body?
Skeletal muscle - loss of skeletal muscle is a predisposing factor for HE
What cell in the brain contains glutamine synthetase? What cell contains glutaminase?
Glutamine synthetase = astrocytes
Glutaminase = Neurons
What change does hyperammonemia induce in astrocytes?
Astrocytes become swollen and their morphology changes (to an Alzheimer type II astrocyte) - may be due to increased osmotic pull from increased glutamine in the cells, other mechanisms may occur too
What neurotoxin accumulates in the blood due to decreased biliary excretion and synergies with ammonia to cause HE?
Manganese
Which form of ammonia is lipid soluble and able to be absorbed from the GI tract?
NH3 (NH4+ is not lipid soluble)
How does hypokalemia precipitate HE?
Movement of intracellular potassium to the extracellular space leads to intracellular acidosis, which traps ammonium ions in the cell
In a study of cats with renal azotemia, what percent of cats had hyperammonemia?
22% - average creat 5.9, ammonia 95
All AKI or AoCKD
What percent of the liver’s blood supply is delivered via the portal system?
75-80%
Describe the hepatic sinusoids
Blood from the portal vein and hepatic artery enter at the portal triad and mix together in the hepatic sinusoids. The sinusoidal endothelial cells have large fenestrations and lack a basement membrane = leaky capillary bed that delivers blood to the hepatocytes
What is Ohm’s law and how can it be applied to hepatic blood flow?
P (pressure) = Q (blood flow) x R (resistance)
Portal vein pressure = portal blood flow x intrahepatic venous resistance
How is portal vein pressure directly measured? What is the normal pressure in dogs/cats?
- Catheterization of the portal vein and insertion of a manometer or pressure transducer
- Normal = 6-8.5 mmHg, depending on anesthesia protocol
What is free hepatic vein pressure (FHVP), wedged hepatic vein pressure (WHVP), and hepatic venous pressure gradient (HVPG)?
- FHVP = a balloon catheter is inserted into the jugular or femoral vein and advanced into the hepatic vein to measure pressure (roughly equal to caudal vena cava pressure)
- WHVP = the balloon is inflated to occlude the hepatic vein (roughly equal to sinusoidal pressure)
- HVPG = WHVP - FHVP
In humans, how is successful treatment of portal hypertension defined?
> 20% decrease in HVPG or a reduction to <12 mmHg
Name 3 clinical consequences of portal hypertension
Development of multiple acquired portosystemic shunts, ascites, hepatic encephalopathy
If portal blood flow increases, what happens in the sinusoids to maintain a normal portal venous pressure?
Increased blood flow stimulates sinusoidal endothelial cells to release nitric oxide => dilation of the intrahepatic vessels to accommodate a large blood volume without a change in pressure
What is prehepatic portal hypertension and what is it caused by?
- Increased resistance in the extrahepatic portal vein
- Caused by mural/intraluminal obstruction (congenital atresia, fibrosis, thrombosis, neoplasia) or extraluminal compression. Hepatic AV fistulas can also cause it (arterial blood gets into the portal system)
What is intrahepatic portal hypertension? What are the 3 subdivisions?
- Increased resistance in the microscopic portal vein tributaries, sinusoids, or small hepatic veins
- Further classified into pre sinusoidal, sinusoidal, or postsinusoidal PH
Why does pre sinusoidal intrahepatic portal hypertension occur?
- Increased resistance in the terminal intrahepatic portal vein tributaries
- Caused by noncirrhotic portal hypertension, primary hypoplasia of the portal vein, idiopathic or congenital hepatic fibrosis, Caroli’s disease, Heterobilharzia
What causes sinusoidal portal hypertension?
- Fibrotic hepatopathies: sinusoidal endothelial cells lose their fenestrae and acquire a collagenous basement membrane => increased resistance
- Nodular hyperplasia can rarely distort the sinusoids enough to cause PH as well
What causes post sinusoidal intrahepatic PH?
Veno-occlusive disease - caused by damage to the sinusoidal endothelium and hepatocytes in the centrilobular region => obliteration of the small terminal hepatic veins by fibrosis
What is posthepatic portal hypertension and what is it caused by?
- Associated with obstruction of the larger hepatic veins, posthepatic caudal vena cava, or right atrium
- Right heart failure, pericardial disease, pulmonary hypertension, Budd-Chiari syndrome
What is Budd-Chiari syndrome?
- Obstruction of hepatic venous outflow in the larger extrahepatic veins or caudal vena cava
- Usually due to neoplasia, thrombosis, congential fibrois webs
How do hepatic stellate cells contribute to PH?
During injury, HSC differentiate into contractile, fibrogenic myofibroblasts
- Produced large amounts of ECM
- Secrete inflammatory cytokines and vasoconstrictive substances (endothelia 1)
What occurs in the splanchnic vasculature during PH?
Progressive vasodilation due to an excess of vasodilatory substances (nitric oxide) secreted in response to sheer stress - opposite of the intrahepatic vasculature
How does vasodilation in the splanchnic system worsen PH?
Increases portal blood flow, which worsens PH
Vasodilation of the splanchnic system results in pooling of blood in the abdomen and a decrease in effective systemic blood volume. How does the body compensate?
- Increased cardiac output (inotropic and chronotropic compensation)
- Activation of RAAS => volume expansion => worsening PH and ascites
What form of portal hypertension does not lead to the formation of MAPPS?
Posthepatic PH
How long do MAPPS take to form?
5-14 weeks of sustained PH
What is hepatorenal syndrome and what causes it?
- Reversible renal failure
- Splanchnic vasodilation leads to release of angiotensin, ADH, and norepinephrine => profound renal vasoconstriction => renal failure
How does the protein content of the ascitic fluid reflect the anatomic location of PH?
Prehepatic and pre sinusoidal PH = low protein content
Posthepatic, sinusoidal, post-sinusoidal = high protein content (>2.5)
What diet is appropriate for a dog with ascites?
Low sodium: <0.05g/100kcal
What percent of ascites fluid can be safely removed?
20-50%
Larger volumes can cause circulatory collapse or decreased renal function
What form of PH is NOT common in cats? Why?
Intrahepatic PH - cats typically develop inflammatory biliary diseases, which lead to periductal fibrosis. This would not affect the blood vessels until a very late stage (usually die before then)
