Case Presentation: A 40-year-old female with history of non-ischemic cardiomyopathy (EF 25-30%), obesity and depression presented with one week of right upper quadrant abdominal pain associated with nausea and vomiting on May 4. Weight on March 26 was 246lb.Workup showed total bilirubin 7.7, alkaline phosphatase 413, ALT 263, AST 194, albumin 3.4, INR 1.3.CT abdomen pelvis showed faint diffuse heterogenous enhancement predominantly involving the right hepatic lobe. Sacubitril/valsartan (Entresto) and Ethacrynic acid were started two months and one month prior to symptom onset. Liver enzymes started to raise 3 weeks after initiation of Ethacrynic acid. TTE showed EF 15-20%.MRCP showed cholelithiasis. Work up was negative for primary biliary cirrhosis, autoimmune hepatitis, iron overload, viral hepatitis, and alpha-1 antitrypsin deficiency. Total bilirubin peaked to 29.7,AST to 202 and ALT to 297, four days after stopping Entresto and Ethacrynic acid, with predominant cholestatic pattern. Liver biopsy showed cholestasis with feathery degeneration consistent with drug induced liver injury. There was no evidence of congestive hepatopathy ( Hepatic venous pressure gradient 2 mm Hg) when hepatic manometry pressures were checked. Her weight was 222-225lb while in the hospital. Her systolic blood pressure was in 90s without any room for diuresis. She was started on Ursodiol and discharged with a total bilirubin of 19.4, AST 54 and ALT 93 with close outpatient follow up with discontinuation of ethacrynic acid and sacubitril/valsartan. She was started on Bumetanide in the outpatient setting, for volume overload and she lost 20 pounds and weighed 204lb. Bilirubin trended down to 13.7 on July 3. She was readmitted 2 months after recent discharge with a weight of 215lb, with cardiogenic shock requiring heart transplant on August 20. Total bilirubin is 1.1 on Nov 12.
Discussion: Any kind of liver injury prompts us to do work up for viral, ischemic, congestive, obstructive and autoimmune pathology. We need to check if patient has taken any OTC supplements, herbal products and all the prescribed medications a patient is on. There is one case report highlighting Entresto as the cause of liver injury. Predominance of AST and ALT elevation was seen with Entresto with peak was less than 1000IU/ml. It took 40 days for normalization of AST and ALT after stopping the medication. Bilirubin was not elevated. There is only one case report from 1967 which showed correlation between Ethacrynic acid and liver injury, when the medication was discontinued and reintroduced due to lack of other diuretics. Jaundice was noticed 2 weeks after starting the medication, increased for a week after stopping the medication and cleared in 2 weeks. Bilirubin peaked at 8mg/dl, AST and ALT peaked at 300 IU/L. Autopsy report showed chronic venous congestion but there was no stagnation of bile.We all need to know how long it takes for a medication effect to resolve. In our case, bilirubin started to get worse even after stopping the medication and it took months before bilirubin started coming down. Diuresis was also continued at the same time.Stopping goal directed medical therapy worsens the heart failure. This patient was lucky to get a heart transplant which may not be possible for every patient.
Conclusions: When multiple factors are at play at different periods of time, with limited data to refer to, it is difficult to pinpoint one etiology as the diagnosis. We think there is an interplay of medications and CHF at different points of time causing liver injury.