Etiology

• Caused primarily through thiamine deficiency.
• Thiamine and more specifically thiamine pyrophosphate (TPP), one of 4 thiamine metabolites is key for brain glucose metabolism, production of acetylcholine and other neurotransmitters.
• Thiamine is not stored by ruminants, all requirements are dietary.
• See Cerebrocortical necrosis pathophysiology.

• Low intakes.
  • Calves as pre-ruminants cannot obtain thiamine through fermentation and rely wholly on dietary intake.
• Impaired microbial thiamine synthesis.
  • Adult ruminants obtain thiamine requirements through microbial fermentation Microbial fermentation, so any disease process that affects fermentation. ie Acidosis Ruminal acidosis, will reduce available thiamine.
• Increased bacterial thiaminase production.
  • Thiaminase destroys thiamine.  There are 2 types:
    • Thiaminase 1 is specifically a catalyst that helps to generate thiamine analogues that inhibit thiamine dependant reactions, these require a co-factor. Co-factors include certain plants, Brassica, Horsetail and Nardoo ferns, medications such as Levamisole and Benzimidazoles, and other products of fermentation.
  • Thiaminase 2 splits thiamine by catalysing the hydrolysis process and works more effectively under acidic conditions, ie change in rumen pH in acidotic cattle.
• Inadequate absorption of thiamine.
  • Chronic liver disease (more so in humans, ie alcoholics with liver cirrhosis) would expect to see other clinical signs with chronic liver disease prior to PEM in ruminants.
• Sulphur toxicity induced PEM.
  • TPP is degraded by Sulphite, a toxic metabolite of sulphur. The rate of this destruction is affected by level of sulphur, pH and temperature.
  • Common sources of Sulphur: from oral ingestion; feeds/forage, contaminated water courses, mineral supplements (especially gypsum), brassica plants Brassica toxicity, molasses and urine acidifiers.
• Amprolium.
  • A coccidiostat used in poultry has been associated with PEM, due to inhibiting the conversion of thiamine to TPP and inhibiting brain glucose metabolism.
  • Inhibition of TPP phosphorylation from free base Thiamine (requires, thiamine, ATP, Magnesium and Thiamine pyrophosphokinase (TPPK)) and then absorption of TPP. Any shortage of these four factors will reduce TPP available.

Predisposing factors

Specific

• Commonly seen in feedlot fast growing youngstock, rumen acidosis predisposes bacterial thiaminases to increase.
• Animals on high concentrate diets treated with high volumes of anthelmintic, antibiotics or amprolium.
• Sulphur rich diets, maximum dry matter intake advised by NRC (2001) is 0.4% for forage systems and 0.3% for feedlot cattle.
• High intakes of water that is high in sulphate, ie North America can be up to 2000ppm and high summer temperatures can increase fluid intake.
• Occasionally seen in poor quality milk replacer diets Milk replacers.

Pathophysiology

• Characterized by cerebral necrosis – caused by pressure necrosis due to edema.
  • Disruption of the cellular ATP pump (expels sodium ions in exchange for potassium ions).
  • If dysregulated sodium accumulates in the cell and causes cell swelling.
  • The skull is an enclosed bony structure, cell swelling causes neurons to be compressed and undergo pressure necrosis.
  • The grey matter is most commonly affected.
• Neuronal ATP is generated through glycolysis, (via pentosephosphate pathway) Transketolase is a rate limiting step as its co-factor is TTP, a thiamine metabolite. Thiamine deficiency will slow this whole process.

Timecourse

• Depends on causal factor.
• Sudden and acute if ingested toxic plants, toxic levels of sulphur or sudden ruminal acidosis occurrence.
• Two to three weeks after change of diet to development of subclinical ruminal acidosis.
• 15-30 days if exposed to high dietary sulphur.
• Low intakes in calves, longer term chronic onset, may see other ill thrift signs first.