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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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Thiazide Diuretics

Last Update: October 13, 2021.

OVERVIEW

Introduction

The thiazides are the most commonly used oral diuretics and are widely used in the therapy of hypertension and congestive heart failure, as well as the treatment of edema due to local, renal and hepatic causes. Only rare instances of clinically apparent liver injury have been linked to use of thiazide diuretics.

Background

The benzothiazide diuretics are structurally related drugs that act by inhibition of sodium (and chloride) transport in the distal convoluted tubule by binding to and inhibiting the Na+-Cl- symporter. As a result, there is increased excretion of sodium and water and an associated loss of potassium. Chronic therapy may also result in increased calcium and magnesium loss. The thiazide diuretics are grouped together based upon shared chemical, sulfonamide-like, structure. More recently non-benzothiazide drugs with a similar mechanism of action have been developed (metolazone, indapamide), which are referred to as thiazide-like diuretics. The thiazide and thiazide-like diuretics are all available generically and differ largely in their pharmacokinetic properties of oral availability, relative potency, serum and effective half-life and route of elimination. The general indications for the thiazide diuretics are treatment of hypertension, congestive heart failure and edema.

Thiazide diuretics are available in multiple forms and all are available generically. Bendroflumethiazide (ben' droe floo" me thye' a zide) is available in tablets of 2.5 mg in generic forms; recommended oral doses in adults are 2.5 to 10 mg in two divided doses. It is also available in a fixed dose (5 mg) with nadolol (40 or 80 mg) generically and under the brand name Corzide.

Chlorothiazide (klor" oh thye' a zide) is available in tablets of 250 and 500 mg generically and under the trade name of Diuril; recommended oral doses in adults are 500 to 1000 mg once or twice daily. It is also available as a lyophilized powder for injection in vials of 500 mg.

Chlorthalidone (klor thal' i done) is one of the most frequently used oral thiazide diuretics. It is available in tablets of 25 and 50 mg generically and under the brand name of Thalitone; recommended oral doses in adults are 25 to 100 mg once daily or 100 mg every other day.

Hydrochlorothiazide (hye' droe klor" oh thye' a zide) is available in tablets of 25 and 50 mg and as capsules of 12.5 mg generically and under the trade names of Hydrodiuril, Microzide and Esidrix; recommended oral doses in adults are 12.5 to 50 mg daily given in one or two divided doses.

Methyclothiazide (meth" i kloe thye' a zide) was previously available in tablets of 2.5 and 5 mg generically and under the trade name of Enduron; recommended oral doses in adults were 2.5 to 5 mg once daily.

Polythiazide (pol" ee thye' a zide) is available in tablets of 1, 2 and 4 mg generically and under the trade name of Renese; typical oral doses in adults are 2 to 4 mg in one or two divided doses daily.

Metolazone (me tol' a zone) is a thiazide-like diuretic that is available as tablets of 2.5 and 5 mg generically and under the trade name of Zaroxolyn; recommended oral doses in adults are 2.5 to 20 mg once daily.

Indapamide (in dap' a mide) is a thiazide-like diuretic that is available as tablets of 1.25 and 2.5 mg generically and under the trade name of Lozol; recommended oral doses in adults are 1.25 to 5 mg once daily.

The thiazide diuretics are some of the most commonly used medications and are usually well tolerated except in high doses. Common side effects of the thiazide and thiazide-like diuretics can include nausea, dizziness, headache, polyuria, dehydration, dry mouth, hyponatremia, hypokalemia and hypomagnesia. Chronic therapy may be associated with hyperuricemia and gout, hyperglycemia and hyperlipidemia, and possibly an increased risk of cholecystitis. Rare adverse reactions include pancreatitis and hypersensitivity reactions. Many of the thiazide diuretics are also available in fixed dose combination with other antihypertensive medications or with potassium-sparing diuretics.

Hepatotoxicity

The thiazide diuretics have not been shown to cause serum aminotransferase elevations to an appreciable extent, and are often used as a control group in assessing adverse events including serum aminotransferase elevations of newer antihypertensive medications. Despite their widespread use, the thiazide diuretics have only rarely been implicated in cases of clinically apparent acute liver injury. No clear signature or clinical pattern has been demonstrated in the rare case reports and in some instances other potentially hepatotoxic medications were being used and other possible diagnoses were present. The usual latency period to onset has been short (few days to several weeks) and the pattern of serum enzyme elevations has ranged from hepatocellular, to mixed and cholestatic (Cases 1 and 2). Immunoallergic features were uncommon as was autoantibody formation. Recovery was usually rapid upon stopping. At present, only hydrochlorothiazide has been implicated in more than 3 instances, while chlorothiazide, indapamide, metolazone and polythiazide have been implicated in one or two instances in causing drug induced liver injury. Hydrochlorothiazide is the most commonly used thiazide diuretic and it is not surprising that it has been implicated most commonly. Regardless, liver injury from thiazide diuretics is exceedingly rare. The similarity in chemical structure among the thiazide diuretics suggests that liver injury might be a class effect.

Hydrochlorothiazide likelihood score: C (probable rare cause of clinically apparent liver injury).

Chlorothiazide, indapamide, metolazone and polythiazide likelihood score: D (possible rare causes of clinically apparent liver injury).

Chlorthalidone, Bendroflumethiazide, and methyclothiazide likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

Mechanism of Injury

Some instances of hepatic injury attributed to the thiazide diuretics have appeared to be due to metabolic idiosyncrasy.

Outcome and Management

The few instances of hepatic injury attributed to thiazide diuretics have been self-limited and rapidly reversed upon stopping the medication. There have been no convincing instances of acute liver failure or prolonged jaundice or vanishing bile duct syndrome associated with the thiazide diuretics. There have been no reports of cross challenges among the different thiazide and thiazide-like diuretics.

Drug Class: Diuretics, Thiazide Diuretics

CASE REPORTS

Case 1. Acute anicteric liver injury due to hydrochlorothiazide.(1)

A 72 year old woman with hypertension developed anorexia, nausea and right upper quadrant abdominal pain 6 days after starting hydrochlorothiazide. She had no history of liver disease and had normal liver tests shortly before starting therapy. She took no other medications except for calcium and did not drink alcohol or have risk factors for viral hepatitis. Physical examination demonstrated tenderness over the liver, but no jaundice. Laboratory tests showed elevations in serum aminotransferase levels, alkaline phosphatase and gamma glutamyl transpeptidase (GGT) (Table). White blood cell counts were normal. Tests for hepatitis A, B and C were negative as were autoantibodies. Liver ultrasound was normal. Hydrochlorothiazide was stopped and symptoms resolved within days. Serum aminotransferase levels were normal within two weeks and alkaline phosphatase and GGT within three weeks of stopping treatment.

Key Points

Medication:Hydrochlorothiazide (25 mg daily)
Pattern:Mixed (R=3.4)
Severity:1+ (enzyme elevations and symptoms)
Latency:6 days to onset of symptoms
Recovery:2-3 weeks
Other medications:Calcium

Laboratory Values

Time After
Starting		Time After
Stopping		ALT*
(U/L)		Alk P*
(U/L)		GGT*
(U/L)		Other
PrePre187224
0Hydrochlorothiazide (25 mg daily) given for 6 days
1 week0236150363
3 weeks2 weeks30120186
4 weeks3 weeks207836
5 weeks4 weeks207530
Normal Values <41 <140 <60
*

Values estimated from Figure 1.

Comment

The acute liver injury was mild but associated with symptoms arising within days of starting a low dose of hydrochlorothiazide. While the rapidity of onset suggests a hypersensitivity reaction, there were no other manifestations of an immunoallergic reaction (fever, rash, eosinophilia). Hydrochlorothiazide is one of the most frequently used medications in the world, but has only rarely been implicated in acute liver injury. Most large cases series of drug induced liver injury have not included cases attributable to thiazide diuretics.

Case 2. Recurrent acute liver injury due to hydrochlorothiazide.(2)

A 47 year old man developed jaundice 20 days after starting hydrochlorothiazide (50 mg daily) for hypertension. He had no history of liver disease, jaundice, alcohol abuse or risk factors for viral hepatitis. He was taking no other medications. He complained of change in taste and abdominal upset, but no fever, rash or itching. Physical examination showed jaundice, but no evidence of chronic liver disease. Laboratory testing showed a total serum bilirubin of 9.5 mg/dL (direct 6.0 mg/dL) and marked elevations in serum aminotransferase levels (ALT 640 U/L, AST 1000 U/L), with minimal increase in alkaline phosphatase (5.4 Bodansky Units) and gamma glutamyl transpeptidase (60 U/L). The total white count was normal without eosinophilia. The prothrombin time and serum albumin values were normal. Tests for hepatitis B were negative as were autoantibodies. Hydrochlorothiazide was stopped and laboratory tests fell to normal within a month. Because of continuing hypertension, hydrochlorothiazide was restarted. Seventeen days later, he presented again with jaundice and serum aminotransferase levels were again elevated. A liver biopsy showed acute hepatocellular necrosis and inflammation compatible with an acute hepatitis due to a medication. Tests for hepatitis A and B and autoantibodies were negative. Hydrochlorothiazide was stopped again and laboratory values fell rapidly into the normal range. Several years later, he was seen at another medical center in another country and hydrochlorothiazide was restarted. Eighteen days later, he presented for the third time with jaundice. Stopping the medication led to improvements in laboratory tests that were normal two months later.

Key Points

Medication:Hydrochlorothiazide (50 mg daily)
Pattern:Hepatocellular (R=13)
Severity:3+ (jaundice, hospitalization)
Latency:17-20 days to onset of jaundice on three occasions
Recovery:4-8 weeks
Other medications:None mentioned

Laboratory Values

Time After
Starting		Time After
Stopping		ALT
(U/L)		Alk P
(U/L)		Bilirubin
(mg/dL)		Comments
0Hydrochlorothiazide (50 mg daily) given for 20 days
3 weeks06405.49.5Admission
7 weeks4 weeksNormalNormalNormal
0Hydrochlorothiazide (50 mg daily) given for 17 days
2.5 weeks09005.8
9 weeks7 weeksNormalNormalNormal
Hydrochlorothiazide (50 mg daily) given for 18 days
2.5 weeks014508.2
10 weeks8 weeksNormalNormalNormal
Normal Values <35 <4.5 <1.2

Comment

A remarkably convincing case history of recurrent acute hepatitis arising 2 to 3 weeks after starting hydrochlorothiazide for hypertension. With each exposure the pattern of injury was hepatocellular, and the clinical phenotype was a mild acute hepatitis with rapid recovery upon stopping the medication. With each reexposure, the liver injury appeared again, each time without signs of hypersensitivity (no rash, fever or eosinophilia) and without shortening of the latency or worsening of the clinical syndrome. These features suggest that metabolic idiosyncrasy rather than hypersensitivity was the cause of the hepatic injury. Despite their use in millions of patients worldwide over the previous 50 years, this is one of the only convincing published cases of hepatotoxicity from thiazide diuretics.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Bendroflumethiazide – Generic, Naturetin®

Chlorothiazide – Generic, Diuril®

Chlorthalidone – Generic, Hygroton®

Hydrochlorothiazide – Generic, Esidrix®

Indapamide – Generic, Lozol®

Methyclothiazide – Generic

Metolazone – Generic, Zaroxolyn®

Polythiazide – Generic, Renese®

DRUG CLASS

Diuretics

COMPLETE LABELING (Bendroflumethiazide)

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULAS AND STRUCTURES

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Bendroflumethiazide 73-48-3 C15-H14-F3-N3-O4-S2 image 134972798 in the ncbi pubchem database
Chlorothiazide 58-94-6 C7-H6-Cl-N3-O4-S2 image 134972119 in the ncbi pubchem database
Chlorthalidone 77-36-1 C14-H11-Cl-N2-O4-S image 135269872 in the ncbi pubchem database
Hydrochlorothiazide 58-93-5 C7-H8-Cl-N3-O4-S2 image 134972118 in the ncbi pubchem database
Indapamide 26807-65-8 C16-H16-Cl-N3-O3-S image 134997709 in the ncbi pubchem database
Methyclothiazide 135-07-9 C9-H11-Cl2-N3-O4-S2 image 134975247 in the ncbi pubchem database
Metolazone 17560-51-9 C16-H16-Cl-N3-O3-S image 134993048 in the ncbi pubchem database
Polythiazide 346-18-9 C11-H13-Cl-F3-N3-O4-S3 image 134975128 in the ncbi pubchem database

CITED REFERENCES

1.
Arinzon Z, Alexander P, Berner Y. Hydrochlorothiazide induced hepato-cholestatic liver injury. Age Ageing. 2004;33:509–10. [PubMed: 15271638]
2.
Anez MS, Dickson G, Zabala R, Zabaleta P, Pacheco A, Briceno D. Gastroenterol Hepatol. 1981;4:476–8. [Acute hepatitis due to hydrochlorothiazide: report of a case]

ANNOTATED BIBLIOGRAPHY

References updated: 13 October 2021

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    (47 year old man developed jaundice 20 days after starting hydrochlorothiazide without rash, fever or eosinophilia [bilirubin 9.5 mg/dL, ALT 640 U/L, Alk P 1.3 times ULN], with recurrence twice 17 and 18 days after [bilirubin 5.8 and 8.2 mg/dL, ALT 900 and 1450 U/L], resolving in 6 weeks: Case 2, thiazide diuretics).
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