Valproic Acid Induced Fulminant Hepatic Failure

Charlene LePane, DO(1), Daniel Kett, MD(2), Richard Phillips, MD(3) , Arie Regev, MD(4)

The Department of Internal Medicine and Gastroenterology3 at Mt. Sinai Medical Center1 and the Divisions of Pulmonary and Critical Care Medicine2 and Hepatology4 at the Leonard Miller School of Medicine at the University of Miami

Miami, Florida

Introduction:

Fulminant hepatic failure is defined by the rapid development of severe acute liver injury accompanied by impaired synthetic function and encephalopathy in an individual with either a previously normal liver or well compensated liver disease. Proposed definitions of the time course for fulminant hepatic failure include the development of encephalopathy within eight weeks of the onset of symptoms in a patient with a previously healthy liver (<1>), or the appearance of encephalopathy within two weeks of developing jaundice, in a patient with or without previous underlying liver dysfunction (<2>). Fulminant hepatic failure can result from a wide variety of causes, of which idiosyncratic drug reactions appear to be associated with a high mortality. This case reports an idiosyncratic reaction to valproic acid in a young woman with a previously healthy liver.

Case Report:

A 19-year-old woman with a one year history of depression was transferred to the intensive care unit at our institution with a four day history of nausea, vomiting and abdominal pain. During the year preceding her admission, the patient had been treated with a selective serotonin reuptake inhibitor (SSRI). Due to sub-optimal control of her depression on SSRI therapy, she was started on valproic acid approximately than two weeks prior to presentation. At a clinic visit the patient was found to have markedly elevated liver transaminases and she was transferred to a local hospital. Upon admission, she was found to be at stage I of encephalopathy with laboratory evidence of severe hepatic injury. The patient was then transferred to our institution for further work-up and treatment.

On admission to our medical center the patient appeared ill, confused and restless. Her vital signs included a blood pressure was 132/80 mm Hg, pulse of 100 beats per minute, respiratory rate of 24 breaths per minute and an oral temperature was 38.4 C. The sclera were mildly icteric and her mucous membranes were dry. Her lungs were clear and heart sounds were normal. The abdomen exam was large, however non-distended. Rebound tenderness and guarding were exhibited. The liver and spleen could not be palpated. Her lower extremities demonstrated no edema, and asterixis was not appreciated. Several tattoos were noted on her upper and lower extremities. Laboratory values are presented in Table 1.

Table 1

Variable	Admission Labs	Day 1	Day 1 Evening	Day 2	Day 3	Day 4	Day 5	Day 6	Day 14
White Cell Count (Per mm3)	16.5	8.9		6.8	9.6	13	12.8		7.8
Haemglobin (g/dL)	10.4	10.6		9.0	8.4	9.2	9.0		10.2
Platelet Count (Per mm3)	153	156		179	186	246	242		355
Prothrombin time (sec)	50.7	26.9	21.7	20.7	19.9	15.5	14.3		12.5
Prothrombin time (INR)	5.4	2.69	2.05	1.93	1.84	1.35	1.23		1.05
Aspartate aminotransferase (U/I)	>2600 unquantifiable	3254	1122	394	185	74	63		54
Alanine aminotransferase (U/I)	>2600 unquantifiable	4461	2688	1494	959	582	442		118
Alkaline phosphotase (U/I)	86	108	102	76	68	68	85		99
Total bilirubin (mg/dL)	2.4	2.4	2.5	2.6	2.4	2.5	2.7		0.7
Direct bilirubin (mg/dL)	1.5
Albumin (g/dL)	2.8	2.4	3.0	3.2	3.5	3.6	3.1		4.8
Lactate dehydrogenase (IU/L)	2700	8054
Serum Creatinine (mg/dL)	2.2	1.2	1.1	1.0	1.0	0.9	1.0		0.9
Ammonia (umol/L)		66						18

The admission haematologic and biochemical laboratory values represent those collected at the previous hospital before transfer. An abdominal CT and US both demonstrated an enlarged liver and free intra-peritoneal fluid. Additionally, the serum and urine toxicology screens were negative. Her valproic acid level was subtherapeutic. Upon arrival to our medical center, additional viral serology and autoimmune markers were requested. The patient received Vitamin K, albumin, midadrine, octreotide, levocarnitine, and lactulose enemas. Review of past medical records at our institution, approximately three years prior to this hospitalization, revealed she previously had a negative mono spot, hepatitis C antibody and rapid plasma reagin.

On the first day of hospitalization the patient remained encephalopathic. Ammonia was measured to be mildly elevated at 66 mmol/L (normal 17-63). Her coagulopathy improved with her as the prothrombin time decreased from 50.7 seconds to 26.9 seconds, and the INR from 5.4 to 2.69. Aspartate aminotransferase and alanine aminotransferase were quantified as critically high (3254, 4461 u/L respectively) and platelets were stable at 156,000 per mm3. Her acute renal failure improved with serum creatinine decreasing from 2.2 mg/dL to 1.2 mg/dL. Her abdominal pain remained unchanged.

Throughout the subsequent hospital days she gradually improved. By the fifth hospital day her neurological exam was normal, abdominal pain was almost completely resolved and she was tolerating a diet without complications. Octreotide, midadrine, albumin, lactulose and levocarnitine were discontinued. She developed a S. haemolyticus urinary tract infection and was started on appropriate antibiotic coverage. Viral serology and autoimmune markers became available. Ferritin (4069), iron (53), 24-hour copper collection (16, normal 2-30) and ceruplasmin (18, normal 18-53) levels were normal therefore, hemochromatosis and Wilson’s disease were less likely the cause of hepatic failure. Viral markers for hepatitis A, B, and C were all negative. Cytomegalovirus IgG and herpes simplex virus IgG were both positive however IgM for both of these viruses were negative therefore confirming a viral syndrome was not the contributing factor either. Of interest, her immunoglobulin quantitative ratio was normal thus confirming a normal immune response. Finally, anti smooth muscle antibody (13.9, normal <20), liver kidney microsome antibody, AMA and ANA were all negative furthermore supporting our initial suspicion that this patient’s acute-onset hepatic failure was likely due to an idiosyncratic reaction to valproic acid.

By day 14 of hospitalization her encephalopathy, coagulopathy and renal failure had completely resolved. She denied any abdominal discomfort, had normal bowel habits, and was cleared for discharge. She returned home with follow up with her primary care physician and psychologist.

Discussion:

Valproic acid (VPA) is a branched-chain carboxylic acid indicated for seizures, acute mania and as prophylaxis for bipolar disorder. It is nearly completely absorbed from the gastrointestinal tract and is metabolized extensively by the liver via glucuronic acid conjugation and beta and omega oxidation to produce multiple metabolites. CYP (p450) mediated omega oxidation, which is normally responsible for a small component of VPA metabolism, may generate toxic metabolites that have been implicated in the idiosyncratic hepatic, metabolic, and neurologic adverse effects of VPA (<3>, <4>).

VPA combines with carnitine and results in carnitine depletion during long-term or high dose VPA therapy (<5>). Hypocarnitinemia results both in impaired mitochondrial fatty acid oxidation for energy production and impaired VPA metabolism. Microvesicular steatosis is a subsequent histological finding. Although the patterns of liver injury secondary to certain medications may vary, VPA is particularly known to cause microvesicular steatosis, in which small fat droplets are present within the hepatocytes and do not displace the nucleus. VPA-induced hyperammonemia and hepatotoxicity maybe mediated in part by carnitine deficiency, carnitine supplementation may prevent the attenuate of these adverse effects.

According to the law of Hyman Zimmerman (<10>) drug-induced hepatocellular jaundice is a serious lesion where the mortality ranges from 10-50%. The true incidence of drug-related hepatotoxicity is difficult to determine, however the estimated reported incidence is between 1 in 10,000 and 1 in 100,000 patients (<8>). Drug-induced hepatic injury is the most frequent reason cited for the withdrawal from the market of an approved drug, and it also accounts for more than 50 percent of the cases of acute liver failure in the United States today. More than 75 percent of cases of idiosyncratic drug reactions result in liver transplantation or death (<9>).

There have been several proposed definitions of liver injury. Chalasani et al (<11>) defined ranges of hepatotoxicity as mild to moderate hepatotoxicity is defined by liver transaminases up to ten times the normal limit. Severe hepatotoxicity is defined by total bilirubin greater than 3 regardless of transaminases or transaminases greater than ten times the normal limit. Regardless of the degree of liver injury, an extensive investigation is mandatory. Autoimmune disease should be suspected if liver injury occurs in conjunction with antinuclear antibodies, smooth-muscle antibodies or increased globulin levels. Metabolic and genetic disorders must also be of consideration. Hemochromatosis may be the diagnosis if the patient demonstrates elevations in ferritin, serum iron level, and total iron-binding capacity. Wilson’s disease may be suspected if a young person presents with Keiser-Fleisher rings, an increased 24-hour urine copper collection and low serum ceruplasmin level. Alpha1-antitrypsin levels should also be evaluated.

Possibly the most important susceptibility factor for hepatotoxicity is genetic variability (<6>). Genetic polymorphisms have a strong influence on drug-metabolism and may increase risk (<7>). It is possible that drug-related injuries may be avoided by means of screening modalities that can identify abnormal gene polymorphisms or nucleic acid expression profiles in a patient before initiation of a drug. A revolution in our ability to prevent future events of drug-induced hepatotoxicity is promising with the increasing interest in pharmacogenomics.

Conclusion:

Fulminant hepatic failure is a devastating condition whereby previously healthy individuals become gravely ill in a very short period of time. The time course our patient presented in is most consistent with valproic acid as the precipitant of her fulminant hepatic failure. Other potential etiologies considered were eliminated after an extensive investigation was conducted. VPA has been demonstrated to cause an idiosyncratic reaction resulting in fulminant hepatic failure. This case is unique in that it identifies a patient who was subjected to pharmacological intervention that has not been illustrated to benefit nor treat depression. According to our review of the literature, there have been no cases reported of hepatotoxicity in the setting of valproic acid treatment of depression. Regardless of the indication for usage, we strongly recommend that liver enzymes should be monitored closely when initiating VPA therapy.

References:

1 Trey, C, Davidson, LS. The management of fulminant hepatic failure. In: Progress in Liver Disease, Popper, H, Shaffner, F (Eds), Grune and Stratton, New York 1970 p.282.

2 Bernauau, J, Reuff, B, Benhamou, JP. Fulminant and subfulminant liver failure: Definitions and causes. Semin Liver Dis 1986; 6:97.

3 Chadwick, DW. Concentration-effect relationships of valproic acid. Clin Pharmacokinet 1985; 10:155.

4 Gugler, R, von Unruh, GE. Clinical pharmacokinetics of valproic acid. Clin Pharmacokinet 1980; 5:67.

5 Ishikura, H, Matsuo, N, et al. Valproic acid overdose and L-carnitine therapy. J Anal Toxicol 1996; 20:55.

6 Larrey D, Pageaux GP. Genetic predisposition to drug-induced hepatotoxicity. J Hepatolo 1997;26:Suppl 2:12-21.

7 Evans WE, McLeod HL. Pharmacogenomics — drug disposition, drug targets, and side effects. N Engl J Med 2003; 348:538-549.

8 Larrey D. Epidemiology and individual susceptibility to adverse drug reactions affecting the liver. Semin Liver Dis 2002;22:145-155.

9 Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002;137:947-954.

10 Zimmerman H. September 1999 2nd Edition Hepatotoxicity. Lippincott Williams & Wilkins.

11 Chalasani N, Aljadhey H, Kesterson J, Murray MD, Hall SD. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology 2004; 126:1287-1292

Please send all correspondence to:

Daniel H. Kett, M.D.

Associate Professor of Clinical Medicine

Leonard Miller School of Medicine

Director, Medical Intensive Care Unit

Jackson Memorial Hospital, C455A

1611 NW 12th Avenue

Miami, FL 33136

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