Livertox

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Description.  The course of illness resembles acute viral hepatitis with insidious onset, a hepatocellular pattern of injury and jaundice.  Symptoms (if present) include fatigue, anorexia, nausea and right upper quadrant tenderness.  Illness typically lasts 2 to 4 weeks and ultimately resolves, but severe instances can result in acute liver failure and death.

 

Latency to Onset.  The time to onset of acute hepatitis is typically 2 to 24 weeks; unlikely after 52 weeks or before 4 days.

 

Symptoms.  Typically an insidious onset of fatigue and nausea, followed by anorexia, abdominal discomfort (liver pain) and then dark urine and jaundice.  There may be low grade fever and transient, indefinite rash during the incubation period.  Itching is typically absent early in the course, but may arise if jaundice is prolonged.

 

Serum Enzyme Elevations.  Peak ALT rising to 800 U/L (~20 times ULN) with accompanying alkaline phosphatase <3 times ULN (<345 U/L).  “Probable” cases can have ALT rising to above 400 U/L (~10 times ULN), with alkaline phosphatase <2 times ULN (<230 U/L), particularly later during the course.  Serum enzyme may rise for another 5 to 10 days after the medication is stopped and then decrease promptly, typically by 50% within 30 days.

 

Drugs.  Typical agents that cause an acute viral hepatitis like illness include isoniazid, pyrazinamide, disulfiram, fenofibrate, ephedra, greater celandine, green tea, and other herbals.

 

Differential Diagnosis.  Diagnosis should focus on acute hepatitis A, B, C and E and reactivation of hepatitis B.  Acute biliary obstruction can resemble acute hepatitis during the first days after onset.  Finally, ischemic hepatitis may superficially resemble acute hepatitis, but the rapid onset and rapid recovery are distinctive.

 

Criteria for Definition:   Elements important in diagnosis of acute hepatitis in drug induced liver injury include:

1. Hepatocellular pattern of serum enzyme elevations with ALT levels rising to above 800 U/L (>20 times ULN) and Alk P levels of less than 3 times ULN (<345 U/L) at the time of peak ALT elevation
2. Latency of 2 to 24 weeks
3. Symptoms of fatigue and/or nausea
4. Bilirubin >2.5 mg/dL
5. If liver biopsy is obtained, changes of acute hepatocellular necrosis with lobular disarray and lymphocytic infiltration with minimal or no fibrosis.

 

A case can be considered “probable” if the peak ALT levels are between 400 to 800 U/L (~10 to 20 times ULN) and accompanying alkaline phosphatase levels are less than 2 times ULN (<230 U/L).  A case can be considered “anicteric acute viral hepatitis like” if all criteria are met, but bilirubin is between 1.2 and 2.5 mg/dL and direct bilirubin (if tested) is >0.3 mg/dL.  Drug induced acute hepatitis can be accompanied by immunoallergic and autoimmune features and can lead to acute liver failure and possibly cirrhosis.  Between 30% and 50% of cases of drug induced liver injury fit this phenotype of being acute viral hepatitis like.  This pattern is most likely to result in acute liver failure and the mortality rate of an acute hepatitis like phenotype of drug induced liver injury is at least 10% (so called “Hy’s Law”, in reference to Dr. Hyman J. Zimmerman).

 

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Representative Cases

 

Case 1.  Acute hepatitis due to isoniazid.
[DILIN Case #102-0056]

 

A 66 year old Hispanic man developed nausea followed by dark urine and jaundice 6 weeks after starting isoniazid for latent tuberculosis.  He had been in good health except for hypertension for which he had been taking enalapril for more than a decade.  Because of a positive purified protein derivative (PPD) tuberculin skin test, he was started on a 6 month course of isoniazid [300 mg daily with pyridoxine].  Laboratory tests taken before starting therapy were normal except for a slightly raised total serum bilirubin.  He remained asymptomatic until onset of nausea and indigestion during week 6 of therapy.  He denied fever or rash.  He had not taken any over-the-counter medications, herbals or acetaminophen.  He had a history of heavy drinking but had stopped 4 years previously.  Physical examination showed jaundice but no signs of chronic liver disease.  Laboratory tests showed a total bilirubin of 6.3 mg/dL and marked elevations in ALT, but minimal increase in alkaline phosphatase levels (Table).  Tests for hepatitis A, B and C were negative.  Serum antinuclear antibody (ANA) was strongly positive (1:20,480), but smooth muscle antibody was negative, and immunoglobulin levels were normal.  Liver imaging showed no evidence of biliary obstruction.  Liver biopsy was not done.  Isoniazid was stopped promptly and he began to improve within days.  Enalapril was restarted, but therapy for latent tuberculosis was not pursued.  One month later, he was asymptomatic and liver tests had returned to baseline.

 

Key Points

Medication:	Isoniazid (300 mg daily)
Pattern:	Hepatocellular (R=45.9)
Severity:	2+ (jaundice, but not hospitalized)
Latency:	6 weeks
Recovery:	4 weeks
Other medications:	Enalapril (chronically), pyridoxine

Laboratory Values

Time After Starting	Time After Stopping	ALT (U/L)	Alk P (U/L)	Bilirubin (mg/dL)	Other
Pre		29	71	1.7
0		Isoniazid (300 mg daily) started
6 weeks	0	2326	114	6.3	Isoniazid stopped
	1 day	2486	137	9.0	INR=1.2
	4 days	1836	113	9.5
7 weeks	1 week	773	104	6.1
2 months	2 weeks	199	80	2.6
3 months	5 weeks	32	64	1.3
Normal Values		<56	<130	<1.2

Comment

Isoniazid hepatotoxicity typically presents like acute viral hepatitis with a prodrome of fatigue, nausea, poor appetite and right upper quadrant pain, followed by dark urine and jaundice, arising 4 to 24 weeks after starting therapy.  Symptoms and signs may worsen for a few days after stopping isoniazid, but then usually improve rapidly.  Immunoallergic features are unusual and, if present, are mild.  Isoniazid therapy can induce ANA reactivity, but autoantibodies titers are usually low (making this case somewhat atypical) and not associated with other features that would suggest autoimmune hepatitis.  Age above 35 years is the single major risk factor for isoniazid hepatitis.  Alcohol use may also be a risk factor, but it is not clear whether the risk is related to concurrent use or with an alcohol history (probably the former).  Treatment of latent tuberculosis in persons over the age of 35 should be done with caution.  Patients should be informed of the risk of liver injury and warned of the signs and symptoms of liver injury.  Routine biochemical monitoring is prudent if there is preexisting liver disease or perceived increased risk for liver injury.  The mortality rate of isoniazid hepatitis with jaundice is at least 10%.

 

Case 2.  Acute hepatitis due to fenofibrate therapy.
[Modified from:  Rigal J, Furet Y, Autret E, Breteau M. [Severe mixed hepatitis caused by fenofibrate? A review of the literature apropos of a case]. Rev Med Interne 1989; 10: 65-7. PubMed Citation]

 

A 74 year old woman developed jaundice having been on oral therapy with fenofibrate (200 mg daily) for two years.  She was not taking other medications and had no history of liver disease, alcohol use, or exposures to hepatitis.  On hospital admission, physical examination revealed jaundice but no fever or rash.  Laboratory findings included marked elevations in serum aminotransferase levels (Table) and bilirubin of 4.7 mg/dL.  Tests for hepatitis A and B were negative, as were autoantibodies.  Abdominal ultrasound and endoscopic retrograde cholangiopancreatography showed no evidence of biliary obstruction.  During the first week in the hospital, serum bilirubin rose to 13.3 mg/dL and prothrombin time decreased to 46% of normal.  At this point, fenofibrate was stopped and she then began to improve, with rapid regression of jaundice, allowing her to be discharged after 25 days in the hospital.  In follow up over the next year, her abnormal liver tests returned to normal.

 

Key Points

Medication:	Fenofibrate (200 mg daily)
Pattern:	Hepatocellular (R=12)
Severity:	4+ (jaundice, hospitalization, prolongation of prothrombin time)
Latency:	2 years
Recovery:	2 months
Other medications:	None mentioned

Laboratory Values

Time After Starting	Time After Stopping	AST (U/L)	GGT (U/L)	Bilirubin (mg/dL)	Other
		Started on fenofibrate for hyperlipidemia
2 years	0	1430	142	4.6	Alk P=315 (6 fold elevated)
+7 days	0	900	160	12.5
+10 days	0	800	160	13.3	Fenofibrate stopped
	4 days	540	200	12.8
	8 days	400		11.3
	12 days	440		8.8
	1 month		23	4.3
	2 months		30	0.7
Normal Values		<20	<25	<1.2

Comment

This patient developed a fairly severe, acute hepatitis while on long term fenofibrate therapy.  The long latency to onset of injury was unusual, and initially her physicians did not think that the fenofibrate was the cause.  Because of worsening jaundice over the next 10 days, however, the role of fenofibrate was reconsidered and it was stopped, whereupon she began to improve.  The hepatic injury was severe and associated with prolongation of prothrombin time and worsening liver function tests.  Liver biopsy was not performed and tests for hepatitis C were not available.  Nevertheless, fenofibrate is a known cause of an acute hepatitis like syndrome and was probably the cause of this acute injury.

 

Case 3.  Acute hepatitis after using weight loss supplement.
[Modified from:  Bonkovsky HL. Hepatotoxicity associated with supplements containing Chinese green tea (Camellia sinensis). Ann Intern Med 2006; 144: 68-71. PubMed Citation]

 

A 37 year old woman developed nausea, abdominal pain and jaundice 4 months after starting a weight loss supplement called The Right Approach Complex (Pharmanex, Provo, Utah), the major component of which was green tea extract (Camellia sinesis).  She denied history of liver disease, alcohol use, and risk factors for viral hepatitis.  On examination, she was jaundiced but had no fever or rash.  Laboratory tests showed a serum bilirubin of 11.7 mg/dL and marked elevations in serum aminotransferase levels (~20 times ULN) with minimal increases in alkaline phosphatase (Table).  Tests for hepatitis A, B and C were negative as were autoantibodies, except for antinuclear antibody which was weakly positive (1:40, speckled pattern).  Liver biopsy revealed marked interface necrosis and inflammation and mild lobular inflammation.  Cholecystectomy and intraoperative cholangiography were performed.  The patient began to improve rapidly and was discharged after two weeks in the hospital.  One month later, liver tests had improved significantly.  One year later, she was again admitted with a one week history of abdominal pain and jaundice.  She admitted to resuming The Right Approach Complex one month earlier, but stopped taking it one week before presentation when she developed dysphagia.  On admission, she was jaundiced.  She again improved rapidly and six months later all liver tests were normal.

 

Key Points

Medication:	The Right Choice (383.3 mg Camellia sinensis extract per 3 capsules)
Pattern:	Hepatocellular
Severity:	3+
Latency:	4 months initially, 1 month on reexposure
Recovery:	1 month
Other medications:	None mentioned

Laboratory Values

Time after starting	Time after stopping	ALT (U/L)	AST (U/L)	Alk P (U/L)	Bilirubin (mg/dL)	Other
		Started The Right Approach (~1 gram of green tea extract daily)
16 weeks	0	1788	1783	238	11.7	Liver biopsy, interface necrosis and lobular inflammation
18 weeks	2 weeks	92	79	-	1.9
		Restarted The Right Approach 1 year later
4 weeks	0	1131	977	165	11.7	INR: 1.3
5 weeks	1 week	877	816	165	2.9
2 months	5 weeks	69	80	-	1.2
7 months	6 months	25	27		1.0
Normal		<35	<35	<130	<1.2

Comment

This case demonstrates the typical acute viral hepatitis like presentation of green tea hepatotoxicity with jaundice, accompanied by marked elevations in serum aminotransferase levels and minimal increases in alkaline phosphatase.  Recurrence with a similar pattern of liver injury upon reexposure to the same product provided clear evidence of a causal association.  Green tea extract was the major ingredient of the supplement and its other components have not been reported to cause liver injury (calcium, chromium, magnolia extract, epimedium extract, banaba leaf extract, β-sitosterol and vanadium).  The hepatotoxicity of herbal products has become an increasing problem with the increasing use of these agents.  Interestingly, the liver injury is usually hepatocellular and resembles acute viral hepatitis.

 

Case 4.  Acute hepatitis and jaundice after disulfiram in an alcoholic patient with chronic hepatitis C.
[DILIN Case #105-0050]

 

A 42 year old male with chronic hepatitis C was started on disulfiram (Anabuse) for chronic alcohol abuse and lisinopril for hypertension.  A few days later he developed diarrhea and stopped lisinopril.  One to two weeks later he developed fatigue, nausea, vomiting and poor appetite, but he continued taking disulfiram until he developed jaundice 30 days after starting.  He sought medical attention 2 days later and was hospitalized for evaluation.  He had a history of type 2 diabetes for which he had been taking metformin for several years.  He claimed to have had no alcohol intake since starting Antabuse and admission serum alcohol level was negative.  His chronic hepatitis C (genotype 1, HCV RNA 32,300 IU/mL) was considered mild and had never been treated.  Physical examination showed no fever, rash or signs of chronic liver disease.  He was mildly jaundiced.  Laboratory tests revealed a total serum bilirubin of 5.9 mg/dL with marked elevations in ALT (1715 U/L) and AST (919 U/L), but normal alkaline phosphatase levels (95 U/L).  Tests for hepatitis A and B were negative as were autoantibodies.  An abdominal ultrasound showed a normal liver texture and no evidence of biliary obstruction which was confirmed by magnetic resonance cholangiography.  Over the next few days, he began to improve and serum bilirubin was normal one week later.  In follow up, his symptoms resolved and serum ALT levels fell to baseline values.  Importantly, HCV RNA was undetectable during the acute injury, but reappeared once it had resolved.  One year after this episode, he again had detectable serum HCV RNA and ALT levels were mildly elevated.  He was subsequently treated with a course of peginterferon and ribavirin and achieved a sustained virological response.  In recent follow up, he has had normal serum aminotransferase levels and no detectable HCV RNA.

 

Key Points

Medication:	Disulfiram (100 mg daily)
Pattern:	Hepatocellular (R=41)
Severity:	3+ (jaundice, hospitalization)
Latency:	32 days
Recovery:	Uncertain timing
Other medications:	Metformin (3 years), lisinopril (for 1 week, 3 weeks before presentation)

Laboratory Values

Time After Starting	Time After Stopping	ALT (U/L)	Alk P (U/L)	Bilirubin (mg/dL)	Other
Pre	Pre	49	52	0.9
5 days	0	Fatigue, nausea, anorexia
30 days	0	Jaundice, disulfiram stopped
32 days	2 days	1715	95	5.9
33 days	3 days	1305	93	5.1	HCV RNA negative
35 days	5 days	1238	137	5.6
40 days	10 days	562	109	2.0
41 days	11 days	406	98	1.6
1 year	1 year	59	83	0.3	HCV RNA 385,000 IU/mL
		Treated with peginterferon and ribavirin with sustained virological response
4 years	4 years	26	97	0.8	HCV RNA negative
Normal Values		<42	<115	<1.2

Comment

Despite having chronic hepatitis C and alcoholism, the acute injury that began within a month of starting disulfiram was clearly due to this medication rather than HCV or alcoholic hepatic injury.  Disulfiram typically causes an acute hepatitis like syndrome 2 to 12 weeks after starting the medication that can be severe and lead to acute liver failure or need for liver transplantation.  Alcoholic liver injury can cause jaundice and symptoms, but rarely causes serum aminotransferase elevations above 5 to 8 times the upper limit of normal and AST values are usually higher than ALT values.  Chronic hepatitis C can be associated with flares of disease activity, but these are rarely associated with symptoms or jaundice unless cirrhosis is present.  Importantly, HCV RNA levels usually increase or are stable during flares of hepatitis C but fall markedly (and may be below the level of detection) during acute superimposed forms of liver injury.

 

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Hepatic Histology of Acute Hepatitis

 

Histologically, acute hepatitis is charactized by diffuse parenchymal injury.  The hepatocytes may show cell swelling or apoptosis and in most cases there are numerous small foci of lobular inflammation.  The inflammation may consist of any combination of lymphocytes, macrophages and plasma cells.  Portal inflammation may be present, but is not necessary.  Lobular disarray results when there is disruption of the sinusoidal architecture by cell injury and inflammation.  Hepatocyte rosettes and mitotic figures may be seen as evidence of liver regeneration.  Cholestasis in the form of visible bile in canaliculi and hepatocyte cytoplasm is sometimes seen in acinar zone 3.  When the cholestasis is prominent compared to the inflammation, the case should be classified as cholestatic hepatitis rather than acute hepatitis.  In severe cases there may be multiacinar or bridging necrosis and these changes can lead to submassive or massive hepatic necrosis and hepatic failure.  Mild cases may show only foci of lobular inflammation or hepatocyte apoptosis.  The presence of significant fibrosis (more than portal fibrotic expansion) should suggest acute hepatitis superimposed on chronic hepatitis.  Cases that are in a resolving phase will often show only clusters of pigmented macrophages in the parenchyma and portal areas.

 

 

Histologic Images

Photomicrographs by
David E. Kleiner, MD, PhD
Laboratory of Pathology
National Cancer Institute
(See high resolution images)

 

 

	Case A. Acute Hepatitis Ascribed to Green Tea Containing Herbal Product Histologic Features to Note: Acute hepatitis with zone 3 necrosis. There is a loss of the hepatocytes around the hepatic vein (V), but unlike cases of acute hepatic necrosis, there is abundant lymphocytic inflammation within and around the area of necrosis. (See high resolution image)
	Case A. Acute Hepatitis Ascribed to Green Tea (continued) Histologic Features to Note: There is a loss of hepatocytes between the portal area (P) and the vein (V), a change known as bridging necrosis. (See high resolution image)
	Case B. Acute Hepatitis Probably Due to Azithromycin Histologic Features to Note: There are apoptotic hepatocytes (arrows) and many small foci of lymphocytic inflammation associated with loss of sinusoidal architecture (lobular disarray). (See high resolution image)
	Case C. Acute Hepatitis Due to Etanercept Histologic Features to Note: There is lobular disarray with hepatocyte regeneration. The inflammation is not marked, but scattered foci of lymphocytic infiltration are present. (See high resolution image)
	Case C. Acute Hepatitis Due to Etanercept (continued) Histologic Features to Note: At higher magnification there are many hepatocyte rosettes (fat arrows) and a few apoptotic hepatocytes (thin arrows). (See high resolution image)
	Case D. Acute Hepatitis Due to Isoniazid Histologic Features to Note: There is marked inflammation with hepatocyte rosette formation and lobular disarray. There is also an area of confluent necrosis (N) with pigmented macrophages. (See high resolution image)
	Case D. Acute Hepatitis Due to Isoniazid (continued) Histologic Features to Note: This photo shows a portal area on the left and the hepatocellular parenchyma on the right. The hepatocyte interface is obscured by inflammation. (See high resolution image)

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