A Gastrointestinal Start…..

1. A Gastrointestinal Start….. Case Presentation Jessica Schroeder Principal Biochemist Royal Cornwall Hospital

2. Presentation to ICU April 2004 • 34y old lady admitted on 29/4 • Sudden onset abdomen pain. • Nausea and vomiting • On examination • Writhing in pain • Soft abdomen

3. Blood tests on admission • U+Es - N • LFTs - N • CRP - 15 • Amylase - 110 • Ca 2+ - 3.67(2.20 – 2.55) • Phosphate -2.78(0.87 – 1.46) • HB - 19.6 (HCT - 0.593) • WCC - 42.1 (neutrophilia) • Plat - 533 • INR - 1.3

4. ICU admission blood gases • Severely acidotic • pH 6.99 (7.35 – 7.45) • pCO2 4.54 kPa (4.27 – 6.40) • pO2 13.8 kPa (11.1 – 14.4) • HCO3 8.4 mmol/L • Lactate 15 mmol/L

5. CT Abdomen • Markedly dilated colon and rectum • Bowel wall enhancement and thickening • Acute colitis

6. Treatment • Ventilated • Sedated with propofol • IV hydration • IV pamidronate • IV antibiotics • Haemofiltration

7. PROGRESS • Copious diarrhoea and vomiting • Lactic acidosis • ?due to sepsis • Raised calcium • Due to severe dehydration. • PTH measured when corrected calcium 2.67 mmol/L was 15.5 (10-69 pg/mL) • Vitamin D 9.9 (4 – 40ug/L) • Calcium normalized with rehydration + pamidronate

8. Progress • Abdominal X-ray / clinically • improvement in bowel distension • Sigmoidoscopy • “ischaemic bowel” • Diagnosis • toxic megacolon

9. Surgery - Day 2 • Total colectomy • End ileostomy • Histology • “consistent with acute colitis of either infective or inflammatory origin”

10. Following surgery • Extremely unwell • Severe persistent acidosis • Arterial lactate(normal range, 0.6 – 1.8 mmol/l) • on admission - 15 mmol/l • day 8 - 3.4 mmol/l • Multi-organ failure • Persistent encephalopathy and severe muscle weakness

11. Day 8 – neurology opinion • Ventilated on ITU • Slow progress • Generalised weakness and wasting

12. CT scan - brain • Calcification • in basal ganglia • periventricular • extending into the cerebellum • No evidence of a stroke

13. Review of past medical history • Normal birth and no significant childhood illnesses. • 1990 – diagnosed with ‘Irritable bowel’. • Eczema • Nov 1999 – Post partum galactorrhoea, irregular menstruation and post natal depression. No visual problems or headache. • Prolactin – 800 - 950 mU/l

14. Review of past medical history • MRI scan • Abnormal ?pituitary microadenoma • ‘Evidence cerebral atrophy and abnormal signals from basal ganglia’ • Galactorrhoea resolved following treatment with bromocriptine • 2000 • Marginal hearing loss – not requiring hearing aid.

15. Clinical Diagnosis • In view of past history and poor response to this episode of colitis • ?Mitochondrial disorder • Probably MELAS • Mitochondrial Encephalomyopathy • Lactic Acidosis • and Stroke like episodes

16. Mitochondrial disorders – genetics • Mitochondrial DNA is a 16,469 bp double stranded molecule located in mitochondria. • Mt DNA encodes for 13 polypeptides essential for the generation of energy. • Mitochondrial disorders can arise from either mitochondrial or nuclear DNA defects • Inherited or sporadic • With very rare exceptions mtDNA is maternally inherited

17. Mitochondrial DNA • Pathogenic mtDNA can exist along with normal mtDNA (heteroplasmy). • Heteroplasmy varies in individual cells, tissues and organ system. • The mtDNA mutation load needed for clinical expression is 70- 90%. • Manifests at lower load in tissues that are dependent on high oxidative metabolism.

18. MELAS • Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke like episodes • Maternally inherited • Onset generally in childhood • 80% have A to G mutation at bp-3243 • Rare to find more than one fully expressed MELAS in same family • Maternal relatives often oligo or asymptomatic

19. MELAS • Present with a variety of clinical manifestations (usually present 4-15 yrs) • Migraine-type headache and vomiting • Hearing loss, blindness • Occasional seizures, stroke-like episodes • Dementia or mental retardation • Short stature

20. MELAS • Cardiomyopathy • Type 2 diabetes • Muscle weakness and exercise intolerance • Acute onset of GI manifestations • ischemic colitis and intestinal obstruction

21. Key features leading to diagnosis of MELAS • Persistent lactic acidosis in absence of sepsis • History • Irritable bowel • Neurosensory deafness • Abnormal MRI • Persistent encephalopathy and severe muscle weakness • Blood sample: To Prof Turnbull • mitochondrial DNA A to G mutation at bp 3243 • Muscle biopsy • Heteroplasmic for MELAS A to G Mutation at 3243

22. Arterial lactate mmol/l Deterioration CRP 240 METHYL PRED “More awake” CRP 15 “Much Improved”

23. MELAS – discussion with ‘experts’ • Presentation with acute GI symptoms is well documented • 1o pathology ischaemia due to abnormality of oxygen carriage by mitochondria • Unusual for no ischaemia on CT • Agreed trial of iv steroids • Prognosis for improvement from the acute episode can be good

24. Further evidence of MELAS • Further history • walked on tip-toes as a child aged 7(as does her son) • calf muscles always small • general lethargy for a few years

25. Family History • Grandmother • being investigated for degenerative brain condition “parkinsons” • Mother • has had symptoms, but unkeen to discuss • for referral to neurologist • Two sons • one walks on tip-toes • No siblings • Mother has sisters and nieces (asymptomatic)

26. Summary and progress report • 34y old lady presented with sudden onset abdominal pain • Removal of colon and formation of ileostomy • 55 days on ICU • Combination of slow progress and ‘piecing’together her clinical history led to diagnosis of MELAS • Discharge - significant neurological problems • Cognitive problems and concentration difficulties • Generalized weakness • ?Reversal ileostomy • Ongoing follow up neurologists, surgeons and rehab

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