Chronic Liver Failure and Progressive Neurologic Decline due to Mitochondrial Depletion

Abstract

Purpose: A 43-year-old African American female presented to the GI Clinic for follow-up of chronic liver disease after a prolonged hospitalization for neurologic complaints of vision disturbance, transient left-sided facial droop, left-sided weakness, and dysphagia. She experienced cognitive deficits, which improved over time. Past medical history includes chronic liver disease with a biopsy in 2002 consistent with small duct sclerosing cholangitis, history of esophageal varices with banding, hepatic and metabolic encephalopathy, achalasia status post multiple Botox injections and Heller Myotomy, chronic pelvic pain, depression. She does not smoke or drink. She has had multiple abdominal surgeries. Family history is outlined in the pedigree as shown in Figure 1. The patient uses a wheelchair and speaks slowly and softly, though coherently. She has external ophthalmoplegia with marked strabismus, as demonstrated in Figure 2. Abdomen reveals multiple healed surgical scars and is diffusely tender to palpation, no ascites. Neurological exam reveals generalized weakness. Pertinent labs include WBC 2.3, Hgb 8.7, Plt 68, T bili 1.6, INR 1.3. Creatinine 0.7. MELD 11. A liver biopsy from 2002 shows features of chronic cholestasis with portal fibrosis, ductal proliferation, periductal fibrosis and loss of some bile ducts. MRCP reveals poor visualization of the intrahepatic ductal system and a 9 mm CBD without filling defect. MRI of the brain reveals Manganese deposition in the basal ganglia, abnormal signal intensity in the splenium of the corpus callosum and minimal gliotic or small vessel chronic ischemic changes involving the cerebral white matter. Genetic studies for mitochondrial disorders detected a heterozygous novel variant in the DNA polymerase gamma 1 gene (POLG1), c.1837C>T (p. H613Y). There were a total of 7 heterozygous DNA polymorphisms identified, including the novel variant, H613Y, in exon 9 of this gene. Family member studies of our patient's sister (her deceased affected nephew's mother) for this variant was negative. Further testing for mitochondrial depletion on repeat liver biopsy were declined by the patient, and no other family members would consent to genetic analysis. This case represents a complicated mixture of chronic liver disease, neurologic manifestations, and a complex family history of liver disease. Genetic testing in this patient's case is abnormal, but not diagnostic. However, the conglomeration of findings including hepatic encephalopathy, liver failure, chronic progressive external ophthalmoplegia, and abnormal neurologic features suggestive of metabolic stroke with an abnormal MRI, are strongly suggestive of a mitochondrial syndrome.