Tyrosinemia & Amino Acid Defects

📚 Table of Contents

• Overview
• Hereditary Tyrosinemia Type I
• Other Forms of Tyrosinemia

1️ Overview

• Multisystem disease affecting liver, kidney, and nervous system
• Defect in fumarylacetoacetate hydrolase (FAH)
• Last step in tyrosine degradation
• Expressed in hepatocytes, renal tubules, lymphocytes, erythrocytes, fibroblasts, chorionic villi
• Other causes of elevated tyrosine:
  • Transient tyrosinemia of the newborn
  • Severe hepatocellular dysfunction
  • Congenital enzyme deficiencies
  • Hyperthyroidism
  • Vitamin C deficiency

2️ Hereditary Tyrosinemia Type I (Hepatorenal)

Epidemiology & Pathogenesis

• Autosomal recessive
• Defect in FAH → accumulation of fumarylacetoacetate, maleylacetoacetate, succinylacetoacetone (SA)
• Incidence:
  • General: 1 in 20,000–100,000
  • Scandinavia: 1 in 8,000
  • Quebec (Saguenay–Lac Saint-Jean): 1 in 1,846
• Maleylacetoacetate → Fanconi syndrome
• Reactive intermediates → DNA damage → ↑ HCC risk
• SA inhibits porphobilinogen synthesis from δ-ALA
• Newborn screening: succinylacetone on dried blood spot
• Serum tyrosine may yield false positives

Clinical Features

Acute

• Acute liver failure: vomiting, diarrhea, hepatosplenomegaly, edema, ascites
• Severe hepatic dysfunction: coagulopathy (unresponsive to vitamin K), hypoglycemia, hypoalbuminemia
• Coagulation profile:
  • ↓ Factors II, VII, IX, X
  • Normal Factor VIII
  • Low-normal Factor V
• Suspect in any infant with abnormal coagulation

Chronic

• Growth failure
• Fanconi syndrome: phosphaturia, renal rickets
• Neurological crises: pain, paresthesias, posturing, flaccid paralysis, respiratory failure
• Often triggered by infection
• Causes of death: liver failure, bleeding, neurological crises
• HCC in <25% of patients
  • Surveillance: ultrasound/CT, α-fetoprotein

Diagnosis

• ↑ Urine succinylacetone (most diagnostic)
• ↑ Urine δ-ALA (less specific)
• Coagulopathy with normal Factors V and VIII
• Hypoalbuminemia, hypoglycemia, mild ↑ bilirubin/transaminases
• Hemolytic anemia
• Fanconi syndrome: phosphaturia, glucosuria, proteinuria, aminoaciduria
• Liver biopsy:
  • Acute: cholestasis, hemosiderin, pseudo-acini, giant cells, necrosis
  • Chronic: cirrhosis, bile duct proliferation, regenerative nodules

Management & Treatment

• Vitamin K does not correct coagulopathy
• Dietary restriction of phenylalanine and tyrosine
  • Formulas: Tyrex®, Tyros®
• Nitisinone® (NTBC)
• Nitisinone is a potent inhibitor of 4-Hydroxyphenylpyruvate Dioxygenase (4HpPD) which catalyzes the conversion of 4-hydroxyphenylpyruvate to homogentisate in the tyrosine catabolism pathway. It is used to treat Hereditary Tyrosinemia Type I (HT1) because HT1 is caused by deficiency of fumarylacetoacetase, the last enzyme in tyrosine degradation. Inhibiting 4HpPD prevents formation of toxic downstream metabolites like fumarylacetoacetate and succinylacetone. By blocking 4HpPD, Nitisinone halts tyrosine breakdown early, reducing liver and kidney damage in HT1 patients
  • >95% respond with improvement
  • Monitor liver function, urine SA
  • Ophthalmologic exams (corneal crystals)
  • Early NTBC may ↓ HCC risk
• α-fetoprotein every 6–12 months
• Liver ± kidney transplant for non-responders
  • 1-year survival >90%
  • Renal issues may persist

3️ Other Forms of Tyrosinemia