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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Acute Fatty Liver with Lactic Acidosis and Hepatic Dysfunction

Last Update: May 4, 2019.

Description. Acute fatty liver with lactic acidosis and hepatic dysfunction is a dramatic and distinctive clinical syndrome associated with medications that affect mitochondrial function. The hallmark of the syndrome is hepatic microvesicular steatosis (small droplet fat) accompanied by lactic acidosis and clinical and laboratory features of hepatic failure, such as stupor, coma, encephalopathy, hyperammonemia, hypoglycemia and coagulopathy.

Latency to Onset. The onset of hepatic steatosis and lactic acidosis varies with the causative agent and pathophysiology of mitochondrial failure. Drugs that directly inhibit mitochondrial function or protein synthesis directly cause this syndrome within 7 to 28 days, as is typical with aspirin in Reye syndrome and intravenous tetracycline particularly when given to pregnant women. For agents that inhibit mitochondrial DNA synthesis and cause mitochondrial failure as a result of lack of replacement of mitochondria, such as the nucleoside analogues, this syndrome arises after 2 to 3 months of continuous therapy.

Symptoms. Initial symptoms are nonspecific and vague and include nausea, poor appetite, weight loss and abdominal discomfort. These prodromal symptoms precede evidence of hepatic injury by 1 to 4 weeks. With onset of lactic acidosis, shortness of breath and weakness arise followed by stupor and coma. Jaundice occurs late and is usually mild. Once lactic acidosis is present, this syndrome is life threatening.

Serum Enzyme Elevations. Serum aminotransferase levels are usually minimally elevated even with the onset of hepatic failure. Decrease in serum albumin, prolongation of prothrombin time, appearance of hyperammonemia, hypoglycemia and lactic acidosis often precede the appearance of jaundice, which tends to be late and mild-to-moderate in severity (bilirubin <10 mg/dL). The mitochondrial dysfunction often affects multiple organs and myopathy, neuropathy, pancreatitis and optic neuritis can be prominent (and, in some instances, overshadow the liver injury).

Drugs. Typical agents that cause hepatic steatosis and lactic acidosis include intravenous tetracycline, aspirin (in Reye syndrome), linezolid, and the d-nucleoside analogues, fialuridine, didanosine, stavudine and zidovudine.

Differential Diagnosis. The syndrome of microvesicular fatty liver with lactic acidosis and hepatic dysfunction is usually due to medications, but can occur spontaneously in patients with rare inherited forms of mitochondrial dysfunction (urea-cycle disorders). Lactic acidosis is also typical of ischemia and multiorgan failure and can be present in cases of acute liver failure.

Criteria for Definition. Elements important in diagnosis of acute fatty liver with lactic acidosis and hepatic dysfunction due to medications include:

1.

Rise in serum lactate (confirmed on two samples)

2.

Hepatic steatosis shown by liver biopsy or by imaging techniques

3.

Rise in serum aminotransferase or alkaline phosphatase or bilirubin levels above 2 times the ULN

4.

Decrease in serum albumin, or prolongation of prothrombin time or rise in serum ammonia levels.

The major differential diagnosis of the hepatic steatosis is alcoholic or nonalcoholic fatty liver disease and steatosis induced by sudden weight gain or corticosteroids. The differential diagnosis of lactic acidosis includes ischemia, shock and multiorgan failure. The overall clinical presentation, however, is quite distinct between these conditions and acute fatty liver with lactic acidosis and hepatic failure.

Representative Cases

Case 1. Liver injury, hyperlactatemia and pancreatitis induced by stavudine.

[Modified from: Bleeker-Rovers C, Kadir S, van Leusen R, Richter C. Hepatic steatosis and lactic acidosis caused by stavudine in an HIV-infected patient. Neth J Med 2000; 57: 190-3. PubMed Citation]

A 45 year old man with HIV infection developed nausea, vomiting and abdominal pain 3 months after starting stavudine (400 mg twice daily). He had been on didanosine (400 mg daily) and prednisone (5 mg daily) for more than 2 years and had previously received zidovudine. On physical examination, he was jaundiced and had right upper quadrant abdominal tenderness. Serum bilirubin was 14 mg/dL, alkaline phosphatase 400 U/L and ALT 300 U/L. Serum amylase levels were mildly elevated. Ultrasound showed changes compatible with fatty liver; percutaneous liver biopsy revealed macrovesicular steatosis and cholestatic hepatitis. Both didanosine and stavudine were stopped. The patient improved, and all tests were normal 3 weeks later. After recovery, stavudine was restarted in the same dose and, within a week, serum lactate levels increased from normal to 9.1 mmol/L, but serum aminotransferase levels did not change. Stavudine was stopped again and the patient remained well off of all antiretroviral therapy and had normal serum enzymes over the next year.

Key Points

Medication:Stavudine (40 mg twice daily)
Pattern:Cholestatic (R=1.9)
Severity:3+ (jaundice, hospitalization)
Latency:3 months
Recovery:3 weeks
Other medications:Prednisone 5 mg daily, didanosine 400 mg daily

Comment

Stavudine was considered to be the most likely cause of the liver injury and hyperlactatemia, although didanosine may have contributed or increased the risk. He had received didanosine without problems for the previous two years, the liver injury arising only with the addition of stavudine. This syndrome appears to be rapidly reversible with withdrawal of nucleoside analogue therapy in the early stages of hyperlactatemia and liver injury.

Case 2. Fatal lactic acidosis and hepatic steatosis after stavudine therapy.

[Modified from: Cornejo-Juáz P, Sierra-Madero J, Volkow-Fernáez P. Metabolic acidosis and hepatic steatosis in two HIV-infected patients of stavudine (d4T) treatment. Arch Med Res 2003; 34: 64-9. PubMed Citation]

A 45 year old woman with HIV infection developed worsening peripheral neuropathy followed by jaundice and severe abdominal pain, 5 months after changing her antiretroviral regimen from zidovudine and didanosine to nevirapine, stavudine, lamivudine and hydroxyurea. On admission, physical examination showed dehydration, jaundice and abdominal tenderness with tachypnea and tachycardia. Serum bilirubin was 14.3 mg/dL, ALT 45 U/L, alkaline phosphatase 835 U/L, amylase 968 U/L, lactate 14.3 mmol/ L and arterial pH 7.26. Tests for hepatitis B and C were negative. Abdominal ultrasound showed pancreatic edema and echogenicity of the liver suggestive of steatosis. Despite intensive medical support, she developed intractable lactic acidosis and multiorgan failure, dying within 48 hours of admission.

Key Points

Medication:Stavudine (400 mg twice daily)
Pattern:Cholestatic (R<1)
Severity:5+ (fatal)
Latency:5 months
Recovery:None
Other medications:Nevirapine, lamivudine, hydroxyurea; previously zidovudine, didanosine

Comment

Five months after stavudine was added to a chronic antiretroviral regimen, this patient developed severe liver injury and lactic acidosis that was rapidly fatal. Symptoms of neuropathy had been present for several weeks and diagnosis was delayed until severe lactic acidosis was present. The mitochondrial injury from nucleoside analogues can affect liver, pancreas, muscle and peripheral nerves singly or in combination.

Case 3. Liver failure from intravenous tetracycline.

[Modified from: Robinson MJ, Rywlin AM. Tetracycline-associated fatty liver in the male. Report of an autopsied case. Am J Dig Dis 1970; 15: 857-62. PubMed Citation]

A 72 year old man treated for cystitis and diverticulitis with 10 days of iv tetracycline developed lactic acidosis and multiorgan failure. The patient had no previous history of liver disease or risk factors for hepatitis. When initially admitted to the hospital, he had fever, abdominal pain, leukocytosis and an abnormal urinalysis, but liver tests were normal (Table). He was treated with hydration and iv tetracycline in doses of 3 grams daily. His fever improved slowly but by day 4, liver tests were mildly abnormal and they had worsened by day 8. Colistin was added on day 6, and chloramphenicol was substituted for tetracycline on day 10. The following day, he developed progressive restlessness, stupor and respiratory failure. He had renal failure and severe acidosis and he died within hours of attempting resuscitation and dialysis. Autopsy showed an enlarged fatty liver with minimal inflammation and no obvious hepatocellular necrosis. Fat was also identified in renal tubular cells. There was marked ascites and hemorrhagic pancreatitis.

Key Points

Medication:Tetracycline (3 grams iv daily for 10 days)
Pattern:Hepatocellular
Severity:5+ (death from hepatic failure and lactic acidosis)
Latency:4 days
Recovery:Fatal
Other medications:Colistin and chloramphenicol (after onset of liver injury)

Laboratory Values

Days After StartingDays After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
03280.3Started iv tetracycline
4190102.4BUN 39 mg/dL
853011.52.2Colistin added im every 12 hours
10Tetracycline stopped; chloramphenicol started
1111550156.8BUN 105; CO2 11 mEq/L
Increasing stupor and respiratory failure, hemodialysis and resuscitative measures failed
Normal Values<40<13<1.2

Comment

Acute fatty liver caused by tetracycline was initially thought to occur only in pregnant women during the last trimester, but was subsequently reported to occur at other times during pregnancy, after delivery, in nonpregnant women, in men and even in children. The syndrome typically occurs after 3 to 10 days of relatively high doses of im or iv tetracycline. The case above is typical in demonstrating that the precipitous onset of symptoms is a late phenomenon and has a grim prognosis; symptoms are preceded by several days of worsening liver injury, although laboratory tests may be only mildly or moderately abnormal. Acute fatty liver is accompanied by minimal hepatic inflammation and liver cell necrosis and is a syndrome of mark mitochondrial failure, early appearance of hepatic synthetic dysfunction and lack of ATP to drive normal metabolism. The injury is not confined to the liver and renal failure and pancreatitis are common. As in this case, the immediate cause of death is typically multiorgan failure due to lactic acidosis or pancreatitis.

Case 4. Reye syndrome in a child with juvenile rheumatoid arthritis.

[Modified from: Norman MG, Lowden JA, Hill DE, Bannayne RM. Encephalopathy and fatty degeneration of the viscera in childhood: II. Report of a case with isolation of influenza B virus. Canad Med Assoc J 1968; 99: 522-6. PubMed Citation]

A 9 year old girl with juvenile rheumatoid arthritis on salicylates developed nausea, vomiting and drowsiness and was admitted to hospital for suspected salicylate intoxication. However, blood salicylate levels were within the therapeutic range (17.5/mg/dL) and she developed progressive restlessness, confusion and ultimately coma. She had acidosis and hypoglycemia and was treated with intravenous fluids. Serum AST levels were normal on admission, but rose to 696 U/L which led to an emergency liver biopsy that showed microvesicular fatty change with no inflammation, fibrosis or architectural distortion. The liver was devoid of glycogen. Despite supportive care and artificial ventilation, she developed progressive coma, cerebral edema and died 72 hours after admission which was 5 days after initial symptoms of vomiting. Autopsy showed cerebral edema and steatosis in the liver with both macro- and microvesicular fat. Although there was no antecedent history of upper respiratory illness, she had complained of headaches for 2 weeks before onset and influenza B virus was isolated from the liver biopsy and from multiple tissues at autopsy.

Key Points

Medication:Aspirin (salicylate levels maintained at 20 to 25 mg/dL)
Pattern:Hepatocellular (acute fatty liver) (R=33)
Severity:5+ (death)
Latency:2 months from initiation of aspirin use, 1 day after onset of vomiting
Recovery:None
Other medications:Vitamins, throat lozenges and proprietary laxative

Laboratory Values

Days After StoppingAST (U/L)Alk P* (KAU/L)Arterial pHGlucose (mg/dL)Other
07.25Serum salicylate levels 17.5 mg/dL
135276.8025IV fluids initiated, bilirubin 1.2 mg/dL
2696127.51155Ventilatory support, liver biopsy
34757.43>200
44Death from cerebral edema
Normal<35<207.4070-115
*

King Armstrong units.

Comment

A well described case of Reye syndrome arising in a child on chronic salicylate therapy for juvenile rheumatoid arthritis. This case was described before epidemiological data linked Reye syndrome with influenza B and aspirin and is strikingly prescient. The initial symptoms were probably due to lactic acidosis, and AST levels rose shortly thereafter. In cases with recovery, aminotransferase levels fall as rapidly as they had risen. Initially, liver tissue shows microvesicular fat and absence of glycogen as the liver cell uses glycolysis to compensate for the lack of ATP produced by mitochondria. When this mechanism fails, lactic acid levels rise and hepatocytes release enzymes triggered by apoptosis from mitochondrial and cell functional failure. These processes occur rapidly, even before aminotransferase and bilirubin levels rise (the latter being a product of hepatocellular failure).

Case 5. Acute fatty liver and lactic acidosis from fialuridine.

[NIH Clinical Center]

In March 1993, a 43 year old man with chronic hepatitis B and glomerulonephritis was the initial patient enrolled in a clinical research protocol using fialuridine [FIAU], a newly developed oral nucleoside analogue with proven activity against hepatitis B virus (HBV) in vitro and in vivo. Serum levels of HBV DNA decreased rapidly on therapy (using a direct hybridization assay with a lower limit of detection of ~1 million copies/mL) and aminotransferase levels improved (Table). After 8 weeks of therapy, however, he complained of numbness and tingling in his fingers. Physical examination and nerve conduction tests were normal. When symptoms did not improve, fialuridine was stopped. He improved symptomatically but liver test and HBV DNA results returned towards pretreatment values. One week later (2 weeks after stopping fialuridine), he had the rapid onset of severe shortness and breath and weakness and was admitted with lactic acidosis, dehydration and shock. Serum aminotransferase levels were minimally increased, but he was jaundiced (bilirubin 5.8 mg/dL) and had features of hepatic failure with prothrombin time of 15.4 seconds, albumin 2.8 g/dL, ammonia 77 mmoL, and lactate levels of 18.8 mg/dL (normal <2.5). Hydration and treatment with sodium bicarbonate improved the acidosis, but lactate levels remained high. He developed worsening coagulopathy, ascites and hepatic encephalopathy and was transferred to a liver transplant center. There he was treated with an experimental hepatic assist device but lactate levels continued to rise. He underwent emergency liver transplantation 102 days after starting and 25 days after stopping fialuridine, but suffered primary graft nonfunction and died two days later with hemodynamic collapse and severe lactic acidosis (lactate levels 60.6 mg/dL). The explanted liver showed diffuse microvesicular and focal macrovesicular fat, severe cholestasis and ballooning hepatocellular degeneration.

Key Points

Medication:Fialuridine (15 mg daily: 0.25 mg/kg)
Pattern:Hepatocellular
Severity:5+ (death from hepatic failure and lactic acidosis)
Latency:3 months
Recovery:Fatal
Other medications:None

Laboratory Values

Time After StartingTime After StoppingALT (U/L)HBV DNA (M copies)Bilirubin (mg/dL)Other
013630.00.6Started on fialuridine
1 week220<1.00.4
4 weeks109<1.00.6
8 weeks86<1.00.4
11 weeks0Fialuridine stopped because of symptoms of neuropathy
12 weeks6 days1525.00.6
13 weeks17 days2113.05.8Lactic acidosis and shock
14 weeks21 days1203.017.4Transfer to Transplant Center
15 weeks25 days6220.0Emergency liver transplantation
Death from hemodynamic collapse with lactic acidosis
Normal Values<40<1.2
*

M=million copies by DNA hybridization.

Comment

Fialuridine [FIAU] was the first orally available nucleoside analogue developed as therapy for chronic hepatitis B, but was abandoned when it was found to cause fatal liver injury during a phase 2 trial being conducted at the National Institutes of Health. In preclinical studies, fialuridine showed no evidence of hepatotoxicity in several animal species. In small phase 1 trials in humans with chronic hepatitis B, 10 to 28 day courses of fialuridine were well tolerated and resulted in marked declines in HBV DNA levels and sustained remissions of disease in a proportion of patients. Administration of the medication beyond 8 weeks, however, led to a severe and inexorably progressive acute fatty liver with lactic acidosis and liver failure. Of the 17 patients enrolled in the study, 5 died of lactic acidosis, hepatic failure and pancreatitis, 2 recovered after emergency liver transplantation, and the remaining 10 survived (most had received fialuridine for less than two months). The case above was the initial patient enrolled whose acute presentation led to the immediate termination of the trial. The premonitory symptoms of numbness and tingling were due to peripheral neuropathy which was also caused by mitochondrial failure. Unlike stavudine, didanosine and intravenous tetracycline, fialuridine caused an irreversible lactic acidosis and hepatic failure and patients developed the progressive syndrome weeks and even months after stopping therapy. Two patients underwent successful liver transplantation despite severe lactic acidosis (which was partially controlled by continuous infusions of 20% glucose). Both patients survived transplantation without recurrence of hepatitis B and died 15 and 16 years later with normal liver function, the causes of death being colon cancer and melanoma.

Histologic Images

Photomicrographs by

David E. Kleiner, MD, PhD

Laboratory of Pathology

National Cancer Institute

(See high resolution images)

Microvesicular steatosis due to fialuridine toxicity: The hepatocytes are swollen and pale. At this magnification the individual vacuoles cannot be seen. There are no confluent areas of necrosis and very little inflammation.

Microvesicular Steatosis due to Fialuridine Toxicity

Histologic Features to Note:

The hepatocytes are swollen and pale. At this magnification the individual vacuoles cannot be seen. There are no confluent areas of necrosis and very little inflammation.

(See high resolution image)

Microvesicular steatosis due to fialuridine toxicity: Under high magnification, some of the hepatocytes clearly have a foamy appearance due to the numerous tiny vacuoles filling the cytoplasm. In some cells, the vacuoles are so tiny that the cytoplasm has a pale granular appearance.

Microvesicular Steatosis due to Fialuridine Toxicity

Histologic Features to Note:

Under high magnification, some of the hepatocytes clearly have a foamy appearance due to the numerous tiny vacuoles filling the cytoplasm. In some cells, the vacuoles are so tiny that the cytoplasm has a pale granular appearance.

(See high resolution image)

Microvesicular steatosis due to fialuridine toxicity: A digitally enlarged micrograph demonstrating the fine vacuolation seen in microvesicular steatosis.

Microvesicular Steatosis due to Fialuridine Toxicity

Histologic Features to Note:

A digitally enlarged micrograph demonstrating the fine vacuolation seen in microvesicular steatosis.

(See high resolution image)

Microvesicular steatosis due to fialuridine toxicity: In addition to microvesicular steatosis, hepatocellular and canalicular cholestasis was seen (arrows). Depending on the amount of bile pigment present, the color of bile may vary from dark green‐brown to pink or red, as in this example.

Microvesicular Steatosis due to Fialuridine Toxicity

Histologic Features to Note:

In addition to microvesicular steatosis, hepatocellular and canalicular cholestasis was seen (arrows). Depending on the amount of bile pigment present, the color of bile may vary from dark green‐brown to pink or red, as in this example.

(See high resolution image)

Microvesicular steatosis due to fialuridine toxicity: In another case of fialuridine toxicity, the steatosis was mixed, with scattered cells showing large fat vacuoles characteristic of macrovesicular steatosis.

Microvesicular Steatosis due to Fialuridine Toxicity

Histologic Features to Note:

In another case of fialuridine toxicity, the steatosis was mixed, with scattered cells showing large fat vacuoles characteristic of macrovesicular steatosis.

(See high resolution image)

Microvesicular steatosis due to fialuridine toxicity: In this digitally magnified photo, the cell in the center has both a single large vacuole and numerous tiny vacuoles. Other cells in this case showed pure microvesicular steatosis.

Microvesicular Steatosis due to Fialuridine Toxicity

Histologic Features to Note:

In this digitally magnified photo, the cell in the center has both a single large vacuole and numerous tiny vacuoles. Other cells in this case showed pure microvesicular steatosis.

(See high resolution image)

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