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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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Last Update: January 10, 2020.



Methyldopa (alpha-methyldopa or α-methyldopa) is a centrally active sympatholytic agent that has been used for more than 50 years for the treatment of hypertension. Methyldopa has been clearly linked to instances of acute and chronic liver injury that can be severe and even fatal.


Methyldopa (meth" il doe' pa) is a centrally active sympatholytic agent that reduces sympathic drive to the heart and peripheral circulation, leading to decreased cardiac output and lowered peripheral arterial resistance. Introduced in 1960, methyldopa rapidly became a leading antihypertensive agent, but in the last two decades its use has decreased markedly, replaced by better tolerated and more effective antihypertensive medications. Currently, the major use of methyldopa is treatment of hypertension during pregnancy, a use based upon its established record of safety during pregnancy and breast feeding. Methyldopa is available generically and formerly under the trade name Aldomet as 125, 250 and 500 mg tablets. Fixed combinations with hydrochlorothiazide are also available (Aldoril). The recommended maintenance dose in adults is 500 mg to 2 g daily in 2-4 divided doses. Common side effects include nausea, diarrhea, headache, dizziness, sedation, dry mouth and rash. Rare but potentially severe adverse effects include hemolytic anemia (Coombs positive), lupus-like syndrome, mycocarditis, pancreatitis and hepatotoxicity.


Drug induced liver injury due to methyldopa was identified shortly after its introduction into medical use in the 1960’s. Chronic use of methyldopa is associated with mild and transient elevations in serum aminotransferase levels in 5% to 35% of patients, these elevations often resolving despite continuation of the medication. In contrast, clinically apparent or significant liver injury from methyldopa is relatively uncommon, although several hundred cases have been reported. Two patterns of hepatotoxicity have been described: an acute hepatitis that appears within weeks to months of starting treatment, and a chronic hepatitis that arises months to years after initiation of methyldopa therapy.

The acute liver injury from methyldopa generally arises within 2 to 12 weeks of starting therapy and is typically hepatocellular with marked elevations in ALT and AST (5- to 100-fold) and modest increases in alkaline phosphatase, although in a small proportion of patients the pattern of enzyme elevations is mixed or cholestatic (Case 1 and 2). Most patients become jaundiced. Symptoms resemble those of acute viral hepatitis, including fever, headache, fatigue, anorexia and nausea. Signs of hypersensitivity other than fever are uncommon. The injury can be severe and fatal. While some cases are associated with marked cholestasis and prolonged jaundice, most patients recover within 4 to 12 weeks. Autoantibodies including Coombs and antinuclear antibody positivity may be present (but also can arise independent of liver injury). Liver biopsy shows an acute hepatitis-like picture with marked inflammatory infiltrates and fatty change, with variable amounts of necrosis. Rechallenge leads to rapid recurrence of liver injury and can result in severe hepatitis, acute liver failure and death.

The chronic liver injury from methyldopa usually arises after 6 months, but may become first evident after several years of therapy (Case 3). This chronic hepatitis-like clinical picture has a more insidious onset typically with fatigue, weakness and nausea associated with mild or no jaundice. Clinical features may include liver enlargement and tenderness and spider angiomata. The clinical and laboratory pattern often resembles autoimmune hepatitis, with moderate to marked elevations in ALT and AST, modest alkaline phosphatase elevations, increases in immunoglobulin levels (particularly IgG), and high titers of autoantibodies such as antinuclear antibody (ANA) and smooth muscle antibody (SMA). Liver biopsy demonstrates findings of chronic active hepatitis with variable amounts of fatty change and fibrosis. Plasma cell infiltrates may be prominent. Cirrhosis and end stage liver disease can occur if the drug is continued. The disease resolves slowly but completely with discontinuation of methyldopa. Chronic liver injury now appears to be the most common form of drug induced liver injury from this agent. Some cases of methyldopa induced liver injury have features of both acute and chronic injury and the two forms of hepatic injury may share a common etiology.

African Americans appear to have a higher risk for liver injury from methyldopa than Caucasians or Hispanic individuals. The course may be more severe and outcome less favorable in Africans Americans as well. Granulomatous hepatitis can also occur with methyldopa therapy, usually in association with drug fever and systemic symptoms (and granulomas elsewhere), and sometimes with granulomatous myocarditis which can be fatal. In these situations, the liver injury is usually mild and anicteric.

Likelihood score: A (well known cause of clinically apparent liver injury).

Mechanism of Hepatotoxicity

Both the acute and chronic hepatic injury from methyldopa have features that suggest an immune etiology, although less allergic than autoimmune in character. These findings and metabolic studies suggest that methyldopa may induce an autoimmune liver injury (perhaps via a toxic metabolic intermediate serving as an antigenic hapten presented on the surface of hepatocytes) in susceptible hosts.

Outcome and Management

Both the acute and the chronic forms of liver injury from methyldopa can be severe, particularly if the medication is continued despite appearance of clinically significant injury. Recovery usually occurs within 6 to 8 weeks, but patients with chronic hepatitis can be left with inactive cirrhosis. Methyldopa ranks as one of the ten most common causes of acute liver failure due to medications, although its frequency is decreasing as its use has become more restricted. Because of its cost, methyldopa is still used widely for treatment of hypertension in developing nations, where cases of liver injury are likely to continue to arise. Patients with methyldopa induced liver injury should not be reexposed to this medication, but there is no evidence that there is cross susceptibility to liver injury with other antihypertensive agents. Prednisone has been used to treat both the acute and the chronic injury from methyldopa with unclear benefit. Management should focus on early withdrawal of methyldopa, and treatment with corticosteroids should be restricted only to severe or persistent cases and withdrawn in a timely manner.

Drug Class: Antihypertensive Agents


Case 1. Abnormal serum aminotransferase levels developing during methyldopa therapy.(1)

A 29 year old woman was found to have hypertension during the first trimester of her first pregnancy and was started on methyldopa in a dose of 500 mg twice daily. Eight weeks later, during a routine prenatal visit, she was found to have elevations in serum aminotransferase levels. She was without symptoms of liver disease and denied all previous history of hepatitis or jaundice and any exposures or high risk behaviors. Serum alkaline phosphatase levels were minimally elevated and bilirubin, albumin and prothrombin time were normal. An abdominal ultrasound showed no abnormality of the liver or bile ducts. Serum ANA was positive in a titer of 1:160. She also had equivocal tests for anti-HCV and VDRL, both of which were later shown to be false positives. Methyldopa was stopped and her liver tests were normal one month later.

Key Points

Pattern:Hepatocellular (R=28)
Severity:1+ (no jaundice)
Latency:8 weeks
Recovery:Complete within 1 month
Other medications:Nifedipine, multivitamins

Laboratory Values

Time After
Time After
Alk P
Methyldopa started
8 weeks08001250.5
8 weeks1 day442125
3 days327109
4 days296..
9 weeks9 days87940.7
10 weeks2 weeks20..
12 weeks1 month3057
10 months6 months13510.7
Normal Values <45 <125 <1.2


This case is typical of asymptomatic elevations in serum aminotransferase levels that can occur during methyldopa therapy. These were indentified on routine testing and not as a result of symptoms or specific monitoring for hepatotoxicity. Recovery was rapid. The co-occurrence of ANA positivity and false positive VDRL and anti-HCV reactivity was probably due to methyldopa induced immune activation and hyperglobulinemia.

Case 2. Acute hepatitis due to methyldopa.(2)

A 55 year old woman had been treated for hypertension intermittently with methyldopa in the past and then developed jaundice and fatigue 7 days after it was restarted. She had no other significant past medical history, took no other medications, did not drink alcohol and had no risk factors for viral hepatitis or liver disease. On admission, she was jaundiced and serum bilirubin was 6.8 mg/dL (5.0 mg/dL direct), AST 858 U/L and alkaline phosphatase 214 U/L (Table). A liver biopsy was compatible with acute drug induced liver injury. Markers of hepatitis B were negative. Further study showed that she had elevations in IgG, IgA and IgM, and was positive for smooth muscle (SMA) and antinuclear (ANA) antibodies and had a positive direct Coombs test. She was not anemic. Methyldopa was stopped and she recovered clinically quite rapidly; but biochemical and immunological abnormalities resolved only slowly over the next few months. Ultimately most abnormalities fell to normal or near normal, although SMA persisted in unchanging titers.

Key Points

Pattern:Hepatocellular (R=8.6)
Severity:3+ (jaundice and hospitalization)
Latency:1 week (prior exposure)
Recovery:Complete by 6 months
Other medications:None

Laboratory Values

Time After
Time After
Alk P
Methyldopa, which had been used intermittently for at least a year, was given for 7 days
1 week08582146.8
1 month3001401.6SMA+, ANA+, Coombs+
3 months100950.8IgG 2300, IgA 600, IgM 300 mg/dL
5 months7809SMA+, ANA-, Coombs-
6 months6388
7 months4790IgG 1300, IgA 250, IgM 78 mg/dL
Normal Values <40 <86 <1.2


Although the latency period was very short, this case was otherwise typical of the acute hepatocellular injury caused by methyldopa. Aminotransferase levels were more than 20-fold elevated while alkaline phosphatase was minimally increased. Autoantibodies and hypergammaglobulinemia can develop with methyldopa induced liver disease and give a clinical picture that resembles an acute onset of autoimmune hepatitis. However, in this case, the disease improved with discontinuation of methyldopa and the autoantibodies and elevated immunoglobulin levels ultimately improved once the liver injury had settled. Nevertheless, the minor abnormalities of serum enzymes many months after the injury are a good reason to continue to follow the patient for evidence of an underlying liver disease. She should be cautioned against receiving methyldopa again.

Case 3. Chronic hepatitis caused by long term methyldopa therapy.(1)

A 25 year old woman developed signs and symptoms of chronic liver disease after 8 months of therapy with methyldopa. Methyldopa had been started in a dose of 250 mg twice daily during a pregnancy, but was then continued after she had a Caesarian section 3 months later. After being on methyldopa for 8 months, she had the insidious onset of nausea, dark urine, itching and jaundice. She was admitted to a local hospital and laboratory testing showed an ALT of 1292 U/L and bilirubin of 7.3 mg/dL. Tests for hepatitis A, B and C were negative. Both smooth muscle and antinuclear antibody were negative. CT scans and ultrasound of the liver were normal. A liver biopsy showed changes typical of chronic active hepatitis. Methyldopa was stopped, and she was placed on prednisone. Serum aminotransferases slowly improved. Six months later prednisone was stopped and in follow up her liver tests remained normal.

Key Points

Pattern:Hepatocellular (R=21)
Severity:3+ (jaundice and hospitalization)
Latency:8 months
Recovery:Complete after 6 month course of prednisone
Other medications:Triamterene

Laboratory Values

Time After
Time After
Alk P
Methyldopa started during pregnancy
8 months0129212610.3Methyldopa stopped
1 week105310119.3
2 weeks114015624.9Prednisone started
9 months4 weeks36216911.9
6 weeks881023.0
10 months8 weeks641132.0
11 months3 months80611.0Prednisone tapered
12 months4 months45741.0
14 months6 months29690.5Prednisone stopped
20 months12 months19831.0
Normal Values <60 <126 <1.2


This case represents an example of severe chronic active hepatitis induced by methyldopa. The use of prednisone is controversial, but the height of the bilirubin and ALT elevation led to its use. Importantly, once jaundice had resolved, the prednisone was withdrawn gradually and, in follow up, this patient was asymptomatic and had normal liver tests. Many cases of methyldopa induced acute and chronic hepatitis are accompanied by high levels of autoantibodies and immunoglobulin elevations. Comparison of cases with and without these autoimmune features, however, show little difference in clinical features, severity of injury, hepatic histology or outcome, suggesting that they are similarly immune mediated and that the autoantibodies do not play a pathogenetic role.



Methyldopa – Generic, Aldomet® (Currently discontinued)


Antihypertensive Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Methyldopa 555-30-6 C10-H13-N-O4 image 134976346 in the ncbi pubchem database


Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J., Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135:1924–34. [PMC free article: PMC3654244] [PubMed: 18955056]
Delpre G, Grinblat J, Kadish U, Livni E, Shoha B. Case report. Immunological studies in a case of hepatitis following methyldopa administration. Am J Med Sci 1979; 277: 207-13. PMID:37733. [PubMed: 37733]


References updated: 15 January 2020

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    (Expert review of methyldopa induced liver injury from 1999. At least 150 instances of hepatoxicity from methyldopa have been described; usually a hepatocellular pattern of injury and can present as a chronic hepatitis; rash and esoinophilia are rare, but ANA is often present).
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    (6 cases of methyldopa hepatotoxicity in 2 year period, all women, ages 38-62 years, onset of symptoms in 1-2 weeks, jaundice after 2-6 weeks; bilirubin 11.8-29.4 mg/dL, ALT 122-710 U/L, Alk P < twice ULN; 1 died; 2 had rash).
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    (39 year old man developed acute hepatitis 3 years after starting methyldopa [bilirubin 6.8 mg/dL, AST 180 U/L, Alk P 188 U/L], resolving within 2 months of stopping).
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    (49 year old woman developed fever, myalgias and nausea within 2 days of starting methyldopa, minimal AST and Alk P elevations; liver biopsy showed granulomas; not so much hepatotoxicity as drug-fever, with systemic granulomas).
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    (Summary of 36 cases of methyldopa hepatotoxicity, 14 with acute presentation with hepatocellular or mixed injury and jaundice within 1-6 months and 22 with chronic onset, often insidiuous, injury usually mixed and anicteric arising within 12-24 months of starting; 4 cases occurred in one family).
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    (Seven cases of methyldopa hepatotoxicity with hepatocellular injury and jaundice occurring 6-12 weeks after starting methyldopa, only one with autoantibodies, one fatal, all jaundiced).
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    (Summary of 75 Swedish adverse event reports on methyldopa between 1966-75; fever in 166 [latency usually <3 weeks], hemolysis 67 [2 months to years], liver injury 29 [1 month to years], allergic reactions 23, gastrointestinal 17, psychiatric 13, other 27; those with fever often had mild ALT elevations).
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  • Delpre G, Grinblat J, Kadish U, Livni E, Shoha B. Case report. Immunological studies in a case of hepatitis following methyldopa administration. Am J Med Sci 1979; 277: 207-13. PMID: 37733. [PubMed: 37733]
    (55 year old woman developed acute hepatitis 7 days after starting methyldopa [bilirubin 6.8 mg/dL, AST 858 U/L, Alk P 214 U/L], with concurrent autoantibodies, ANA disappeared after stopping but SMA remained present; extensive immunologic tests also performed).
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    (12 patients with methyldopa hepatotoxicity, 9 with acute hepatocellular disease and jaundice with onset in 1-9 weeks, of whom 2 died; 3 patients developed chronic disease arising after 1-7 years of therapy accompanied by mild jaundice and ALT elevations, one not fully resolving by 8 months after stopping).
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    (55 year old woman presented with ascites and cryptogenic cirrhosis having been on methyldopa for 5 years, with normal ALT, AST and bilirubin; Coombs positive).
  • Beaugrand M, Gavillon C, Ferrier JP. [High levels of endoplasmic reticulum antibody titer in a case of alpha-methyldopa-induced chronic active hepatitis (author's transl)] Gastroenterol Clin Biol 1980; 4: 219-21. French. PMID: 7380145. [PubMed: 7380145]
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    (Comparison of 7 patients with acute icteric hepatitis after short term [3-6 months] and 24 with chronic usually anicteric hepatitis after long term [3-11 years] methyldopa; histology showed fat and some fibrosis in chronic cases, but also showed chronic hepatitis).
  • Arranto AJ, Sotaniemi EA. Histologic follow-up of alpha-methyldopa-induced liver injury. Scand J Gastroenterol. 1981;16:865–72. [PubMed: 7323716]
    (Follow up liver biopsies in 6 patients with chronic methyldopa injury, 7-24 months later; resolution of enzyme elevations and clinical improvement occurred, but liver biopsies showed persistence of of fat and fibrosis, one patient developed cirrhosis).
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    (52 year old woman developed liver injury 4 months after starting methyldopa, which resolved rapidly upon stopping and recurred within 3 weeks of reexposure [bilirubin 0.9 mg/dL, ALT 354 U/L, Alk P 2 times ULN]; biopsy suggested chronic active hepatitis).
  • Bezahler GH. Fatal methyldopa-associated granulomatous hepatitis and myocarditis. Am J Med Sci. 1982;283:41–5. [PubMed: 7055158]
    (78 year old woman developed drug fever after years of methyldopa therapy, sudden death and autopsy showed granulomatous myocarditis, many granulomas in liver and elsewhere, minimal ALT elevation and no jaundice, indicative of drug fever with systemic granulomas).
  • Breland BD, Hicks GS Jr. Hepatitis and hemolytic anemia associated with methyldopa therapy. Drug Intell Clin Pharm. 1982;16:489–92. [PubMed: 7094845]
    (56 year old man presented with jaundice after 7 years of methyldopa therapy [bilirubin 41 mg/dL, AST 105 U/L, Alk P 122 U/L, ANA negative, Coombs positive]; liver biopsy showed cirrhosis with slow and incomplete recovery and associated hemolytic anemia that resolved more rapidly upon stopping).
  • Dossing M, Andreasen PB. Drug-induced liver disease in Denmark. An analysis of 572 cases of hepatotoxicity reported to the Danish Board of Adverse Reactions to Drugs. Scand J Gastroenterol. 1982;17:205–11. [PubMed: 6982502]
    (Review of 572 Danish cases of drug induced liver injury between 1968-78, methyldopa accounted for 11 cases, 8 with acute and 3 with chronic presentations).
  • Seeverens H, de Bruin CD, Jordans JG. Myocarditis and methyldopa. Acta Med Scand. 1982;211:233–5. [PubMed: 7080870]
    (Autopsy series of 6 patients who died suddenly due to granulomatous myocarditis while receiving methyldopa [for 16 days to 3 years], most also had granulomas in liver or chronic hepatitis; no clinical information).
  • Orozco López P, Romá¡n Martínez J, Sorribes Puelles R, Trilla Soler M, Pujol Fernández C. [Carbamazepine and methyldopa: a hepatotoxic combination?] Med Clin (Barc) 1983; 81: 40-1. Spanish. PMID: 6888059. [PubMed: 6888059]
  • Shalev O, Mosseri M, Ariel I, Stalnikowicz R. Methyldopa-induced immune hemolytic anemia and chronic active hepatitis. Arch Intern Med. 1983;143:592–3. [PubMed: 6830396]
    (76 year old man developed mild hepatitis [bilirubin 2.1 mg/dL, ALT 205 U/L] and hemolytic anemia after 3 years of methyldopa therapy [Coombs positive, SMA positive]; delayed recovery on stopping methyldopa, but rapid response to prednisone and no recurrence upon withdrawal).
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    (9 cases of methyldopa hepatotoxicity; 5 with acute liver failure, 3 acute self-limited hepatitis, 1 chronic active hepatitis arising 7 weeks to 3 years after starting methyldopa; 5 had antibody mediated cytotoxicity to rabbit hepatocytes exposed to methyldopa and a microsomal enzyme inducer).
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    (75 year old man developed jaundice having been on methyldopa for 6 years [bilirubin 26.3 mg/dL, ALT 960 U/L, Alk P 1120 U/L], resolving within 5 months of stopping).
  • Picaud A, Walter P, de Préville G, Nicolas P. [Fatal toxic hepatitis in pregnancy. A discussion of the role of methyldopa] J Gynecol Obstet Biol Reprod (Paris) 1990; 19: 192-6. French. PMID: 2324442. [PubMed: 2324442]
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    (Among 1100 liver adverse event reports in Denmark, methyldopa accounted for 13, ranking 17th).
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    (30 year old woman developed jaundice 3 weeks after starting methyldopa during pregnancy [bilirubin 6.6 mg/dL, ALT 2415 U/L], with slow recovery and then recurrence with reexposure).
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    (Adverse event reporting over 20 year period from New Zealand identified 943 liver injuries from medications; top 10 drugs included methyldopa [n=38], which decreased in ranking from 3rd [before 1980] to 4th [1980-87] to <20th [1988-94]).
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    (37 year old woman developed jaundice with hepatocellular pattern of enzymes 9 weeks after starting methyldopa therapy during pregnancy [bilirubin 13.9 mg/dL, ALT 898 U/L, Alk P 95 U/L], resolving within 4 weeks of stopping).
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    (Case control study of 317 cases of hepatocellular carcinoma found no association of cancer with taking medications including methyldopa).
  • Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, Garcia-Ruiz E, Garcia-Munoz B, et al. Spanish Group for the Study of Drug-Induced Liver Disease. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology. 2005;129:512–21. [PubMed: 16083708]
    (Reports to a Spanish network identified 570 cases of drug induced liver disease between 1994-2005, methyldopa not mentioned).
  • Björnsson E, Jerlstad P, Bergqvist A, Olsson R. Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol. 2005;40:1095–101. [PubMed: 16165719]
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  • Fernández-Marcote Menor EM, Pérez-Bedmar Delgado J. [Methyldopa-induced acute toxic hepatitis] Rev Esp Enferm Dig 2005; 97: 840-1. Spanish. PMID: 16438629. [PubMed: 16438629]
    (43 year old woman was given methyldopa during pregnancy and developed jaundice when she continued it afterwards [bilirubin 11 mg/dL, ALT 1904 U/L, ANA positive], resolving within 6 weeks of stopping).
  • Phadnis SV, Sangay MR, Sanusi FA. Alpha-methyldopa-induced acute hepatitis in pregnancy. Aust N Z J Obstet Gynaecol. 2006;46:256–7. [PubMed: 16704485]
    (40 year old woman developed fatigue within 2 weeks and jaundice within 4 weeks of starting methyldopa during pregnancy [bilirubin 2.0-5.4 mg/dL, ALT 2511 U/L, Alk P 216 U/L, ANA 1:180], resolving within 6 weeks of stopping).
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    (Guidelines to therapy of hypertension during pregnancy).
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    (Treatment of mild-to-moderate hypertension during pregnancy has little effect on outcomes; beta blockers are more effective than methyldopa in reducing blood pressure).
  • Yusuff KB, Ajayi A, Joseph YB. Laboratory monitoring of hematological and hepatic parameters in ambulatory patients receiving alpha-methyldopa in a Nigerian tertiary care setting. Curr Drug Saf. 2008;3:163–6. [PubMed: 18690994]
    (Retrospective chart review of whether ALT and AST monitoring was done in 260 patients given methyldopa; found no testing performed during first 6-12 weeks of therapy).
  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J., Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135:1924–34. [PMC free article: PMC3654244] [PubMed: 18955056]
    (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, 5 cases were attributed to methyldopa).
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    (33 year old woman developed jaundice 6 weeks after starting methyldopa during pregnancy [bilirubin 19.9 mg/dL, ALT 1303 U/L, Alk P 134 U/L, ANA negative], resolving rapidly with prednisone treatment).
  • Reuben A, Koch DG, Lee WM., Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology. 2010;52:2065–76. [PMC free article: PMC3992250] [PubMed: 20949552]
    (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury including 2 due to methyldopa).
  • Björnsson E, Talwalkar J, Treeprasertsuk S, Kamath PS, Takahashi N, Sanderson S, Neuhauser M, Lindor K. Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology. 2010;51:2040–8. [PubMed: 20512992]
    (Retrospective analysis of 261 cases of autoimmune hepatitis, 24 [9%] of which were due to a medication; 11 nitrofurantoin and 11 minocylcine, but none due to methyldopa; drug induced cases resembled idiopathic cases in all regards except in ability to stop corticosteroids without relapse).
  • Ozsvár Z, Solymossi Z, Monostory K. [Methyldopa-induced acute reactive hepatitis in pregnancy, drug-metabolizing capacity of the liver]. Orv Hetil 2010; 151: 457-61. Hungarian. PMID: 20211808. [PubMed: 20211808]
    (A 35 year old pregnant woman developed hepatitis at gestational week 23 [bilirubin 6.1 mg/dL, ALT 1190 U/L, Alk P 266 U/L, ANA negative], resolving rapidly on stopping methyldopa therapy).
  • Ozaslan E. Drug-induced autoimmune hepatitis: an easily reversible type of liver fibrosis? Hepatology. 2011;53:370. [PubMed: 20848612]
    (Letter in response to Björnsson [2010] discussing the reversibility of early fibrosis in cases of drug induced autoimmune hepatitis).
  • Slim R, Ben Salem C, Hmouda H, Bouraoui K. Hepatotoxicity of alpha-methyldopa in pregnancy. J Clin Pharm Ther. 2010;35:361–3. [PubMed: 20831537]
    (A 34 year old woman developed jaundice and pruritus 4 weeks after starting methyldopa during pregnancy [bilirubin 9.4 mg/dL, ALT 685 U/L, Alk P 301 U/L], resolving within 10 weeks of stopping).
  • Czaja AJ. Drug-induced autoimmune-like hepatitis. Dig Dis Sci. 2011;56:958–76. [PubMed: 21327704]
    (Review of drug induced autoimmune hepatitis, the principal causes being minocycline and nitrofurantoin; other causes were methyldopa, hydralazine, statins, fibrates, diclofenac, anti-TNF agents, interferons, propylthiouracil, and isoniazid).
  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144:1419–25. [PubMed: 23419359]
    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period none of which were attributed to methyldopa or other antihypertensive medications).
  • deLemos AS, Foureau DM, Jacobs C, Ahrens W, Russo MW, Bonkovsky HL. Drug-induced liver injury with autoimmune features. Semin Liver Dis. 2014;34:194–204. [PubMed: 24879983]
    (Review of autoimmune drug induced liver injury which provides an example in a 39 year old African American woman treated with methyldopa shortly after pregnancy who developed jaundice 1 month later [bilirubin 19.9 mg/dL, ALT 1869 U/L, Alk P 205 U/L, ANA positive], resolving spontaneously within 6 months of stopping methyldopa).
  • Kashkooli S, Baraty B, Kalantar J. α-Methyldopa-induced hepatitis during the postpartum period. BMJ Case Rep. 2014;2014:bcr2014203712. pii. [PMC free article: PMC3939412] [PubMed: 24577181]
    (A 34 year old woman developed hepatitis two months after delivery and while on methyldopa [bilirubin 18.8 mg/dL, ALT 1018 U/L, Alk P 275 U/L, INR 1.2 rising to 1.7, ANA positive], resolving within 2 months of stopping drug).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A, Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America: an analysis of published reports. Ann Hepatol. 2014;13:231–9. [PubMed: 24552865]
    (Among 176 reports of drug induced liver injury from Latin America published between 1996 and 2012, 2 were attributed to methyldopa, one of which was fatal).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52. e7. PMID: 25754159. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 39 [4%] were attributed to antihypertensive drugs including 11 to methyldopa).
  • Koizumi T, Furuya K, Baba M, Sadaoka K, Sekiya C, Hattori A, Goto R, et al. [Case Report; A case of subacute fulminant hepatitis induced by methyldopa]. Nihon Naika Gakkai Zasshi 2015; 104: 586-9. Japanese. PMID: 26571747. [PubMed: 26571747]
    (A 40 year old woman developed severe hepatitis while receiving methyldopa [bilirubin 18.4 mg/dL, ALT 1685 U/L, Alk P 833 U/L, INR 2.17, ANA positive], with progressive hepatic failure and death).
  • Firoz T, Webber D, Rowe H. Drug-induced fulminant hepatic failure in pregnancy. Obstet Med. 2015;8:190–2. [PMC free article: PMC4935052] [PubMed: 27512479]
    (A 39 year old pregnant woman developed jaundice 8 weeks after starting labetalol and 4 weeks after methyldopa [bilirubin 17.8 mg/dL, ALT 1406 U/L, Alk P 159 U/L, INR 3.1, ANA positive], resolving rapidly after stopping both medications and a complicated delivery).
  • Stine JG, Northup PG. Autoimmune-like drug-induced liver injury: a review and update for the clinician. Expert Opin Drug Metab Toxicol. 2016;12:1291–301. [PubMed: 27402321]
    (Review of drug induced liver injury with autoimmune features discusses methyldopa as a frequent cause).
  • Chalasani N, Reddy KRK, Fontana RJ, Barnhart H, Gu J, Hayashi PH, Ahmad J, et al. Idiosyncratic drug induced liver injury in African-Americans is associated with greater morbidity and mortality compared to Caucasians. Am J Gastroenterol. 2017;112:1382–8. [PMC free article: PMC5667647] [PubMed: 28762375]
    (Among 985 patients with drug-induced liver injury enrolled in a prospective US database between 2004 and 2016, methyldopa accounted for 4% of cases among 144 African Americans compared to <1% of 841 caucasians, and disease severity and worse outcomes were more frequent in African American subjects both overall and for methyldopa).
  • de Boer YS, Kosinski AS, Urban TJ, Zhao Z, Long N, Chalasani N, Kleiner DE, Hoofnagle JH., Drug-Induced Liver Injury Network. Features of autoimmune hepatitis in patients with drug-induced liver injury. Clin Gastroenterol Hepatol. 2017;15:103–12.e2. [PMC free article: PMC5370577] [PubMed: 27311619]
    (Analysis of 88 cases of liver injury due to medications known to induce autoimmune markers [including methyldopa, hydralazine, nitrofurantoin and minocycline] found that clinical features were similar in those with and those without an autoimmune phenotype and that HLA Class I and II alleles associated with spontaneous autoimmune hepatitis were not increased among patients with drug induced autoimmune liver injury).


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