DMN 2: Lesson 99 Circulatory disorders and hepatic infiltrations

What are some circulatory disorders?

Passive congestion

Congenital portosystemic shunt

Congenital portal vein hypoplasia

Portal hypertension with acquired vascular shunts

Telangiectasis

Passive congestion

Characterized by reduced hepatic outflow due to cardiac dysfunction

Caused by right-sided heart failure which produces elevated pressure in the caudal vena cava that extends to the hepatic vein and its tributaries

High pressure in the hepatic vein leads to centrilobular congestion of sinusoids

What are 2 common causes of right-sided heart failure resulting in hepatic congestion?

Valvular endocardiosis of the tricuspid valve in old dogs 

Canine heart worm 

Pathogenesis of passive congestion leading to liver disease 

congestion —> hypoxia —>  centrilobular degeneration —> atrophy and loss of hepatocytes 

What does chronic hypoxic injury lead to?

Steatosis (fatty degeneration)

What does passive congestion lead to?

Enhanced lobular pattern (nutmeg liver)

What does the liver look like grossly from passive congestion?

Lobes of the liver are enlarged with rounded edges

What does the cut liver surface look like from passive congestion?

Enhanced lobular pattern - nutmeg liver 

What is congenital portosystemic shunt (PSS)?

Abnormal vascular structure that allows portal blood to bypass the liver and drain directly into systemic circulation

How are animals affected by PSS?

Stunted

1. Frequently develop signs of hepatic encephalopathy due to hyperammonemia

   1. Ataxia

   2. Seizures

   3. Blindness

   4. Head pressing

Gross features and histology of congenital PSS

Grossly the liver is small (micro hepatica) 

Single anomalous vessel connecting portal circulation with systemic circulation

Histologically there is lobular atrophy, portal miniaturization with small or absent portal veins, and reduplication of arterioles 

What are the 2 types of congenital PSS?

Intrahepatic shunts 

Extrahepatic shunts 

Intrahepatic PSS

Commonly formed due to failure of closure of the ductus venosus (fetal vessel)

Most common in large breed dogs

Extrahepatic PSS

Portal vein to caudal vena cava anastomosis

Portal vein to azygous vein anastomosis

Most common in small breed dogs and cats

How may congenital PSS affect ammonia metabolism? 

Dogs with PSS have abnormal ammonia metabolism —> can result in ammonium biurate crystalluria 

Congenital portal vein hypoplasia (hepatic microvascular dysplasia)

Congenital vascular anomaly of dogs and occasionally cats

Suspected inheritance in small breed dogs such as:

Yorkies

Maltese

Cairn terriers

Tibetan spaniels

Shih-tzus

Javanese

What is congenital portal vein hypoplasia and how does it effect the animal?

Characterized by abnormally small portal veins 

Results in diminished hepatic perfusion and portal hypertension 

Affected animals typically have micro hepatica and ascites 

How to tell apart PSS and congenital portal vein hypoplasia

Indistinguishable

Radiology is recommended

What are some causes of portal hypertension?

Thrombosis or other types of occlusion within the portal vein or hepatic outflow

What are some causes of intrahepatic portal hypertension?

Fibrosis

Nodular regeneration

Lobular remodeling

Veno-occlusive disease

Microvascular dysplasia

Sinusoidal amyloidosis

What can persistent portal hypertension lead to?

Ascites and development of acquired portosystemic shunts 

What are some hepatocellular infiltrations?

Amyloid

Copper

Iron

Bile pigments

Lysosomal storage diseases

Glycogen

Lipids

What are the main mechanisms of abnormal intracellular accumulations?

Inadequate removal and degradation

Excessive production of an endogenous substance

Deposition of an abnormal exogenous material

What are the 4 pathways in abnormal cellular infiltrations?

1. Defect in metabolism (ie lipidosis)

2. Defect in protein folding or transport (amyloidosis)

3. Lack of an enzyme resulting in failure to degrade a substrate due to inherited enzyme deficiencies (resulting in storage diseases)

4. Ingestion/inhalation of indigestible materials (ie accumulation of carbon after inhalation)

What is amyloidosis? 

Extracellular deposition of abnormal proteinaceous substance in tissues —> protein misfolding disorder 

Consists of 2 forms of proteins

What are the 2 types of proteins in amyloidosis?

Amyloid light chain protein

Amyloid associated protein

What is an amyloid light chain protein?

Derived from abnormal plasma cells secreting of light chain fragments into circulation

What is an amyloid associated protein?

Secreted by liver in response to cytokines

What is hepatic amyloidosis?

Occurs in many species

Commonly a result of secondary (reactive) amyloidosis due to prolonged systemic inflammation (amyloid AA)

What species and breeds has inherited or familial amyloidosis been reported in?

Shar-pei dogs, abyssinian and siamese cats

How does amyloidosis affect the liver?

Grossly, livers are enlarged with rounded edges, friable, and pale

severe cases can lead to hepatic failure

Severely affected livers are friable and susceptible to fracture and hemorrhage

Histological amyloidosis

Amyloid deposition within the space of dissent, portal tracts, and within and around blood vessels 

Deposition starts in space of disse and extends into the sinusoids 

When severe, this can result in pressure atrophy and necrosis of hepatocytes 

What is the special stain used for amyloid?

Congo red

What does accumulation of copper lead to?

Production of reactive oxygen species 

What does production of oxygen species cause?

Oxidative injury to mitochondria and cellular membranes and subsequent centrilobular necrosis

Where have disorders of copper metabolism been commonly described?

In dogs, specifically bedlington terriers and Labrador retrievers

Causes canine copper-associated hepatopathy

Canine copper-associated hepatopathy

Common cause of chronic hepatitis in dogs

Pathogenesis is poorly understood - diet? genetics- bedlington terriers (mutation in commd1 gene in this breed)

Pathogenesis of canine copper-associated hepatopathy 

Copper accumulates in centrilobular regions and within kupffer cells —> leads to ongoing oxidative injury with hepatocellular necrosis, chronic inflammation, fibrosis, nodular remodeling, and eventual end-state liver 

Hepatocellular copper accumulation in sheep

Copper storage is poorly regulated in sheep

Sheep are more susceptible to copper toxicosis

Low dietary molybdenum and sulfur in sheep exacerbates copper toxicosis

Rapid release of copper into blood can precede chronic copper accumulation in the liver resulting in hemolysis

Copper release may be triggered by stress or illness

Copper accumulation, red intracytoplasmic granules

How to diagnose hepatocellular copper accumulation 

Diagnosis requires biopsy 

Rhodanine special stain is used to identify and quantify granules of copper 

What is another name for iron storage disease?

Hemochromatosis

What is iron storage disease?

Abnormally increased amount of iron storage within the liver

Inherited condition reported in people, mynah birds, toucans, salers cattle, and horses

Excessive intake of dietary iron in pet birds may also lead to hemochromatosis

Bile pigment hepatocellular accumulation 

Bile accumulates in the liver during cholestatic disease

Contributes to hepatocellular injury 

Lysosomal storage disease

Large group of rare inherited metabolic disorders that result from defects in lysosomal function

Missing enzymes are inherited as autosomal recessive disorders

What does lysosomal storage disease lead to?

Leads to accumulation of substances within lysosomes which results in cytoplasmic swelling and vacuolization of hepatocytes, macrophages, neurons, and other cell types

Affected animals are usually young

Types of canine degenerative vacuolar hepatopathy

Glycogen-type VH

Lipid-type VH

Glycogen-type VH

Associated with stress, Cushing’s, genetic storage disease (inherited), glucocorticoid administration

Lipid-type VH

Associated with hypoxia, certain toxins, or with metabolic/endocrine disease such as hypothyroidism and diabetes mellitus

Severe cases of VH

Can result in progressive liver injury leading to end-stage liver (cirrhosis) 

How to resolve VH?

Requires identification and treatment of the underlying disease

Liver biopsy is often pursued in these patients because of unexplained increase in serum ALP and mildly elevated ALT

Why would ALP be elevated in VH?

due to severe swelling of hepatocytes which can lead to blockage of bile canaliculi and intrahepatic cholestasis

Hepatocellular glycogen accumulation

Liver is enlarged, pale, with enhanced lobules

Diagnosis require liver biopsy

Treatment requires identification of underlying cause

How do steroids affect hepatocellular accumulation?

Glycogen accumulation

Feline hepatic lipidosis

Occurs in obese cats after a period of anorexia —> cats frequently develop hepatic failure, icterus, and hepatic encephalopathy 

Bovine fatty liver disease

Common in dairy cows in late gestation or peak lactation, especially after any period of inappetence or anorexia

Hepatic lipidosis of ponies, mini horses, and donkeys

Occurs in overweight pregnant or lactating mares after a period of stress or anorexia