JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

November 2023

U-M05

 

SIGNALMENT (JPC Accession # 1483487): Southdown ewe

 

HISTORY: Tissue from a Southdown ewe that had been kept out of the sunlight for three years because of a photosensitivity that developed shortly after weaning.

 

HISTOPATHOLOGIC DESCRIPTION: Kidney: Diffusely, there is marked cortical and medullary interstitial fibrosis which widely separates, surrounds, and replaces approximately 50% of the tubules. Multifocally, remaining tubules are either shrunken and atrophic or dilated up to 150 µm in diameter (tubular ectasia), lined by attenuated epithelium, and contain a variable amount of brightly eosinophilic, homogenous protein (tubular proteinosis) and occasionally, sloughed epithelial cells. Diffusely, tubular epithelial cells exhibit one or more of the following changes: Hypertrophy with indistinct cell borders and microvacuolated cytoplasm (degeneration); shrunken with bright eosinophilic cytoplasm and a pyknotic to absent nucleus (necrosis); or a high nuclear to cytoplasmic ratio with amphophilic cytoplasm and a vesiculate nucleus with rare mitotic figures (regeneration). Multifocally, tubular epithelial cells occasionally contain granular to globular yellow-brown pigment (bilirubin). Multifocally, there are moderate numbers of lymphocytes, plasma cells, occasional macrophages, and reactive fibroblasts which infiltrate the interstitium. Multifocally, glomeruli are surrounded by dense fibrous connective tissue (periglomerular fibrosis) and Bowman’s space is often lined by cuboidal, hyperplastic, and hypertrophied epithelial cells, which rarely are adhered to Bowman’s capsule (synechia). Multifocally in less than 25% of glomeruli there is either global or segmental increase in mesangial cell density. Mesangial cells are mildly hypertrophied, and there is moderate thickening of the basement membrane of Bowman’s capsule. 

 

MORPHOLOGIC DIAGNOSIS: Kidney: Fibrosis, interstitial, diffuse, marked, with tubular ectasia, degeneration, necrosis, loss, regeneration, and pigmentation, and interstitial lymphoplasmacytic nephritis, Southdown, ovine.

 

ETIOLOGIC DIAGNOSIS: Inherited hyperbilirubinemic nephropathy

 

CONDITION: Gilbert (pronounced “zheel-BAIR”) syndrome; congenital hyperbilirubinemia

 

GENERAL DISCUSSION:

• Congenital photosensitivity (mutations) in Southdown sheep was first reported in New Zealand (1942) and later in California
• Inherited as an autosomal recessive gene; classified as a sublethal trait that results in impaired hepatic uptake of unconjugated bilirubin (conjugated bilirubin in Corriedale sheep)
• Affected sheep die early from photosensitization unless they are protected from sunlight (housed indoors) or fed a chlorophyll-free diet
• Disease is characterized by concomitant photodermatitis and hyperbilirubinemia
• Affected sheep have few liver lesions but ultimately die of progressive fibrosing interstitial nephritis (the cause of which is poorly defined) and renal failure by 3 to 5 years of age

 

PATHOGENESIS:

• Attributed to defective ATP-dependent transport system for organic anions, including bilirubin diglucuronide à Cannot excrete bilirubin into bile efficiently 
• Pathogenesis of progressive renal lesions is not clear; the following are important features in the development of renal failure:
  • Medullary fibrosis and loss of capillaries in close contact with the thin limb of the loop of Henle > interferes with the countercurrent mechanism of water resorption
  • Proximal tubules become lined by less specialized low cuboidal epithelial cells lacking a brush border > impaired solute resorption
  • Cortical fibrosis > impaired glomerular function/sclerosis
• Photosensitization: Congenital phylloerythrin (phytoporphyrin) transport defect
  • Intestinal microbes convert chlorophyll to phylloerythrin > phylloerythrin is absorbed in the intestines > hepatic elimination of phylloerythrin is impaired > accumulation of phylloerythrin in skin > exposure to ultraviolet (UV) or visible light > phylloerythrin absorbs light energy > phylloerythrin releases energy which interacts with adjacent tissue > formation of reactive oxygen species > oxidative injury > edema and erythema of the skin > exudative and dermal necrosis

 

 

TYPICAL CLINICAL FINDINGS:

• Severe, persistent photosensitization beginning at 5 to 7 weeks of age which coincides with change to chlorophyll-containing diet
• Polyuric renal failure in sheltered sheep
• Clinical pathology: Unconjugated hyperbilirubinemia and isosthenuria, but animals do not become icteric

 

TYPICAL GROSS FINDINGS:

• Skin: Severe dermatitis of primarily unpigmented areas; progressive “green discoloration" of skin with increasing age; green teeth (most reliable finding)
• Kidney: In young animals, the cortex is mottled red and gray and stained with bilirubin; in animals 3 to 5 years old, the kidneys are firm and fibrotic with radiating gray streaks in the cortex
• +/- dark/discolored liver, lymphadenitis, pulmonary edema, pleural effusion and testicular atrophy

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Progressive renal lesions:
  • 3 months: Thin radial bands of myxomatous tissue in the medullary rays and atrophy of adjacent collecting ducts
  • 1 year: Collagen replaces myxomatous tissue
  • 2 to 5 years: Progressive interstitial fibrosis with cortical thinning, protein casts, hyaline droplet formation and tubular ectasia; aggregates of lymphocytes and plasma cells within fibrous bands; bile pigment in macrophages and proximal tubular epithelial cells

 

DIFFERENTIAL DIAGNOSIS:

• Causes of photosensitization:
  • Type I: Primary photosensitization (ingestion of preformed photodynamic substances)
    • Helianthrone pigments include the red fluorescent pigments
      • Hypericin pigment in St. John’s Wort (Hypericum perforatum)
      • Fagopyrin pigment in Buckwheat (Fagopyrum esculentum)
    • Furocoumarin pigment (psoralens) found in a variety of plants à Also induces corneal edema and keratoconjunctivitis (unlike the helianthrones)
      • Spring parsley (Cymopterus watsonii)
      • Bishop’s weed (Ammi majus)
      • Dutchman’s breeches (Thamnosma texana)
    • Drugs: Phenothiazine (less common)
  • Type II: Photosensitization due to defective pigment synthesis (abnormal porphyrin metabolism resulting in endogenous pigment accumulation)
    • Bovine congenital hematopoietic porphyria: Deficiency of uroporphyrinogen III cosynthetase (red-brown teeth and bone)
    • Bovine erythropoietic protoporphyria: Deficiency of ferrochelatase, recessive in Limousin cattle
    • Also reported in pigs and cats 
  • Type III: Hepatogenous photosensitization (accumulation of phylloerythrin, a product of chlorophyll, in cases of cholestasis, nonspecific hepatocellular injury in herbivores, or congenital hyperbilirubinemia)
    • Most common type of the four in domestic animals
      • Most common toxic plants are Lantana camara (lantana) and Tribulis terrestris (“Geeldikkop”); sporidesmin (mycotoxin produced by Pithomyces chartarum); Panicum spp.
      • Congenital hyperbilirubinemia (Southdown and Corriedale sheep) 
      • Type IV: Idiopathic
        • Ingestion of certain plants, such as alfalfa (Medicago sativa)

 

• Causes of hyperbilirubinemia:
  • Hemolytic: Piroplasmosis, anaplasmosis, leptospirosis, EIA (retrovirus)
  • Toxic: Lupines, vetches, chronic copper poisoning, leptospirosis (causes both toxic and hemolytic icterus)
  • Obstructive: Blockage of biliary canaliculi by swollen injured hepatocytes, obstruction of ducts (by flukes, tapeworms, or ascarids), compression by biliary cirrhosis, swelling of bile duct walls in cholangitis, gallstones, pressure on the ductal system (neoplasia, granulomas, abscesses), pressure on the duodenal papillae by duodenitis

 

• Conjugated hyperbilirubinemia:
  • Occurs with primary liver disease or extrahepatic biliary obstruction; both conjugated and unconjugated bilirubin are elevated

 

• Unconjugated hyperbilirubinemia:
  • Overproduction of bilirubin: Intravascular or extravascular hemolysis; ineffective erythropoiesis
  • Impaired hepatic uptake of bilirubin: Drugs such as Novobiocin and cholecystographic compounds

 

COMPARATIVE PATHOLOGY:

• Gunn rats and squirrel monkey (Saimiri sciureus) are animal models for impaired bilirubin conjugation that is associated with absent or reduced activity of the hepatic enzyme UGT, causing nonhemolytic unconjugated hyperbilirubinemia
• EHBR and TR- rats and Corriedale sheep: Exhibit hepatic excretion abnormalities (conjugated hyperbilirubinemia) and are animal models for Dubin-Johnson syndrome

 

References:

1. Cianciolo RE, Mohr FC. Urinary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier Inc; 2016:429.

2. Cullen JM, Stalker MJ. Liver and biliary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier Inc; 2016:271, 293-294.

3. Cuppage FE, Shimamura T, McGavin MD. Nephron obstruction in mutant Southdown sheep. Vet Pathol. 1979;16(4):483-485.

4. Gill RM, Kakar S. Liver and gallbladder. In: Kumar V, Abbas AK, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 10th ed. Philadelphia, PA: Elsevier, Inc.; 2021:853-854.

5. Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:578-580.

6. McGavin MD, Cornelius CE, Gronwall RR. Lesions in Southdown sheep with hereditary hyperilirubinemia. Vet Pathol. 1972;9(2):142-151.

7. Miller MA, Lyle LT, Zachary JF. Mechanisms and Morphology of Cellular Injury, Adaptation and Death. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier Mosby; 2022:54.

8. Stockham SL, Scott MA. Fundamentals of Veterinary Clinical Pathology. 2nd ed. Ames, IA: Blackwell; 2008:171-174.

9. Van Wettere AJ, Brown DL. Hepatobiliary System and Exocrine Pancreas. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier Mosby; 2022:498-499.

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