Sulphasalazine Induced Hepatotoxicity, A Risk factor of Meconium Aspiration Syndrome in neonates: A Case Study

 

SK. Mohammed Firdoz*, T. Vinay Kumar, P. Divya Jyothi, Undrakonda Ajay, G. V. Naveen Kumar, K. Paul Pratheek

Department of Pharmacology, Nirmala College of Pharmacy, Mangalagiri, Guntur, Andhra Pradesh, India.

*Corresponding Author E-mail: drvkcology@gmail.com

 

ABSTRACT:

Meconium aspiration syndrome (MAS) may be defined as a respiratory distress which develops due to the aspiration of meconium (first feces of newborn infant). It remains as one of the most common causes of neonatal respiratory distress. Among the maternal complication Maternal Hepatitis was most common 2(3.5%) which was supported in another study by Vineeta Gupta, B.D. Bhatia and O.P. Mishra (1996) in BHU showed of the various antenatal complications studied, where only hepatitis was significantly associated with Meconium aspiration syndrome.[2] In this case a pregnant woman suffering with high grade fever with chills and arthralgia was treated with sulphasalazine for 5 days then the liver parameters were elevated in her due to sulphaselazine hepatotoxicity, it further lead to the development of meconium aspiration syndrome in newborn baby. So the treatment with sulphasalazine was discontinued and the hepatotoxicity was treated with liver protectants. In this case as a clinical pharmacist our main intervention is to avoid the use of sulphasalazine in pregnant women.

 

KEYWORDS: Sulphasalazine hepatotoxicity, Meconium aspiration syndrome, Maternal Hepatitis, Respiratory distress and Rheumatoid arthritis.

 

 


INTRODUCTION:

The disease modifying anti -rheumatoid drug, sulfasalazine is commonly used to treat RA and psoriatic arthritis (PsA). The estimated incidence of serious hepatotoxicity was higher (4 per 1,000 users) in a cohort of patients with inflammatory arthritis. The majority of cases occur within the first month of starting sulfasalazine therapy, and these can present either as a hepatocellular or cholestatic pattern of liver injury. About 25% of patients are jaundiced and a proportion of these rapidly develop hepatic failure.[1] Among the maternal complication Maternal Hepatitis was most common 2(3.5%) which was supported in another study by Vineeta Gupta, B.D. Bhatia and O.P. Mishra (1996) in BHU showed of the various antenatal complications studied, where only hepatitis was significantly associated with Meconium aspiration syndrome.[2]

 

Meconium is a thick viscous, dark green substance which is composed of intestinal epithelial cells, mucus, lanugo, intestinal secretions such as bile.[3] Meconium aspiration syndrome (MAS) may be defined as a respiratory distress which develops shortly after birth with radiographic evidence of aspiration pneumonitis in the presence of meconium stained amniotic fluid (MSAF).[4,5] Meconium aspiration syndrome remains one of the most common causes of neonatal respiratory distress.[6] The overall frequency of MSAF varies between 5 to 25%. Meconium aspiration syndrome occurs in 5% of infants born through MSAF. [7]

 

Pathophysiology of MAS:

MAS results from aspiration of meconium during intrauterine gasping or during the first few breaths. Fetal hypoxic Stress can stimulate colonic activity, resulting in the passage of meconium and also stimulates fetal gasping movements that result in meconium aspiration in-utero. Mounting evidence suggests that a chronic in utero insult may be responsible for most cases of severe MAS as opposed to an acute peripartum event. [8, 9]

 

 

The pathophysiology of MAS is complex. Aspirated meconium can interfere with normal breathing by several mechanisms.

 

The pathophysiologic mechanisms of hypoxemia in MAS include

(a) Acute airway obstruction,

(b) Surfactant dysfunction or inactivation,

(c) Chemical pneumonitis with release of vasoconstrictive and inflammatory mediators, and

(d) PPHN (Persistent pulmonary hypertension of newborn) with right-to-left extra-pulmonary shunting.

 

The common disturbances of lung function in MAS include hypoxemia and decreased lung compliance. [10]

 

A. Acute airway obstruction:

Depending on the consistency and amount of meconium aspirated, meconium may lead to either partial or complete airway obstruction leading to hyperinflation or atelectasis of the alveoli. The gas trapped may rupture resulting in air leak syndromes such as pulmonary interstitial emphysema, pneumothorax, and pneumomediatinum. [10]

 

B. Surfactant dysfunction or inactivation:

Presence of meconium in the alveoli can inactivate the endogenous surfactant and decrease the production of surfactant proteins A and B. [12,13] this causes atelectasis of the lung and can increase ventilation perfusion mismatch. The exact mechanisms for meconium-induced inactivation of pulmonary surfactant are not clearly understood. However, several components of meconium, especially fat-soluble (free fatty acids, cholesterol, and triglycerides), and water soluble (containing bilirubin, bile acids, enzymes, etc.) ones impair lung function. [13] Meconium can impair pulmonary surfactant by a combined action of cholesterol and bile acid present in meconium. [14] Meconium may also change the viscosity and ultrastructure of the surfactant, decrease the levels of surfactant proteins, and also accelerate the conversion from large, surface active aggregates into small, less active forms. The surfactant dysfunction is enhanced by leakage of plasma protein through an injured alveolar capillary membrane, as well as the proteolytic enzymes, and oxygen-free radical release from activated cells during the inflammation. [10]

 

C. Chemical pneumonitis with release of vasoconstrictive and inflammatory mediators:

Meconium aspiration leads to chemical pneumonitis. Meconium is a good chemo attractant for neutrophils [15]. Within a few hours, neutrophils and macrophages are found in the alveoli, larger airways, and lung parenchyma. Meconium is also a source of pro-inflammatory mediators such as interleukins (IL-1, IL 6, and IL 8), tumor necrosis factors. Thus it may induce inflammation either directly or indirectly through the stimulation of oxidative bursts in neutrophils and alveolar macrophages and may injure the lung parenchyma or lead to vascular leakage causing toxic pneumonitis and hemorrhagic pulmonary edema [16].

 

D. PPHN (Persistent pulmonary hypertension of newborn) with right-to-left extra-pulmonary shunting.:

Acute intrapulmonary meconium contamination induces a concentration dependent pulmonary hypertensive response, with 15–20% of infants with the MAS showing PPHN.

 

PPHN in infants with MAS may be caused by

(a) Pulmonary vasoconstriction secondary to hypoxia, hypercarbia, and acidosis,

(b) Hypertrophy of the postacinar capillaries as a result of chronic intrauterine hypoxia, and

(c) Pulmonary vasoconstriction as a result of pulmonary inflammation. [10]

 

CASE REPORT:

Maternal case report:

A 20 years pregnant woman (35 weeks gestation) admitted in the hospital with chief complaints of high grade fever with chills, joint pains and itching. There she was treated with

T. Hydroxychloroquine 200mg OD is given to treat Malaria.

T. Sulphaselazine 1gm OD is given to treat Arthritis.

T. Prednisolone 5mg OD is given to treat allergic reactions.

T. Naproxen 5oomg SOS

T. Cetrizine 10mg BD is given to treat itching

 

After 5 days, while receiving 1.5 g per day sulphasalazine, she developed high grade fever with chills, melena & icterus. Now she admitted here for further management. On physical examination, she had hepato-splenomegaly and cholelithiasis.

 

 

Table:1- Vitals

Parameter

D1

D2

D3

D4

D5

Temperature

100.2 F

100 F

98 F

98.6 F

98.6 F

Blood pressure

120/80 mmHg

100/60 mmHg

110/70 mmHg

100/60 mmHg

140/90 mmHg

Pulse rate

90/min

92/min

88/min

82/min

86/min

Respiratory rate

20/min

22/min

18/min

20/min

22/min

 

 

 


Table:2- Hematology

Parameter

D1

D2

D3

D4

D5

Haemoglobin

(11-14g/dl)

9.1

9

9.8

10.2

11

RBC

(3.8-5.8 million cells/cumm)

3.26

3.2

3

3.2

3.2

WBC

(4-11 thousand cells per microliter)

15100

11700

11100

12100

14000

Platelets

(1-4 lac cells/cumm)

2.36

2.68

3.4

3.6

3.78


 


Table:3- Liver function tests

Parameter

D1

D2

D3

D4

D5

Total bilirubin

(0.5-1.1mg/dl)

3.4mg/dl

4.36mg/dl

4.8mg/dl

6.9mg/dl

8.3mg/dl

Direct Bilirubin (0-0.6mg/dl)

3.16mg/dl

4.0mg/dl

4.7mg/dl

6.7mg/dl

7.7mg/dl

Indirect bilirubin (0-0.4mg/dl)

0.31mg/dl

0.36mg/dl

0.1mg/dl

0.2mg/dl

0.6mg/dl

SGOT (6-38 IU/L)

1616 IU/L

1962 IU/L

911 IU/L

1263 IU/L

1216 IU/L

SGPT (6-38 IU/L)

991 IU/L

1328 IU/L

1018 IU/L

859 IU/L

773 IU/l

Alkaline phosphatase (36-142 IU/L)

407 IU/L

390 IU/l

375 IU/l

342 IU/l

331 IU/L

Serum Albumin (3.5-5.5gm/dl)

3.05gm/dl

3.03gm/dl

3.02gm/dl

3gm/dl

2.6gm/dl

Serum Globulin (2-3.5gm/dl)

3.17gm/dl

3.75gm/dl

4gm/dl

4.7gm/dl

3.9gm/dl

 


 

Graph: 1 - Level of Bile salts

 

 

Graph: 2- Levels of SGOT , SGPT& Alkaline phospatase

 

 

 

Graph:3 - Levels of Serum Albumin and Globulin:

 

Methods:

The criteria used for diagnosing meconium aspiration syndrome were:

·      Presence of meconium stained amniotic fluid.

·      Tachypnea, retractions, grunting or other abnormal signs on physical examination consistent with pulmonary disease (i.e. onset of respiratory distress within 24 hours of life).

·      Need for supplemental oxygen or ventilator support.

·      A compatible chest radiograph (Abnormal chest roentgenograms consistent with aspiration pneumonitis). [11]

 

Neonatal case report:

New born Baby has chief complaints of respiratory distress and severe pulmonary artery hypertension due to the aspiration of meconium.

 

 

 

The chest x-ray reveals that patchy pneumonitis on right side

 

 

 

Fig1: -Chest X-ray of newborn

 

Neurosonogram shows mild increased echogenicity noted in bilateral periventricular white matter.

 

 

Fig2:-Neurosonogram of newborn

 

2D ECHO shows left ventricular ejection fraction of 68%

 

Table:4 – Vitals of Neonate

vitals

D1

D2

D3

HEART RATE

148/min

145/min

143/min

PULSE RATE

40/min

50/min

48/min

SPO2 %

92%

94%

96%

 

 

Management:

After delivery endotracheal intubation was done and bag and tube ventilation was given. Only Oro-tracheal suctioning was done.

 

Stomach wash was given to prevent further vomiting and aspiration of meconium stained fluid from stomach.

Treatment chart:

1.    O2 inhalation

2.    Inj. Ceftazidime 65mg OD

3.    Inj. Amikacin 37.5mg OD

4.      Inj. Metronidazole 7.5mg/kg IV OD

5.      10% dextrose 60ml/kg/day

 

DISCUSSION:

In our case a pregnant woman was treated with sulphasalazine. Liver toxicity from sulfasalazine is a rare but serious side effect. It can range from mild elevation in liver function tests to hepatic failure and cirrhosis. After reaching the gut, sulfasalazine is broken down by the colonic bacteria into its metabolites, i.e., sulfapyridine and 5-aminosalicylic acid. Sulfapyridine is absorbed in the gut and eliminated after acetylation by enzyme N-acetyltransferase which can have variable activity based on the patient’s genotype. Patients who have genotypes for slow acetylation are found to be more predisposed to sulfasalazine-induced liver toxicity. [17, 18] Hepatotoxicity can arise either from direct toxicity of the drug or its metabolites. Injury can be hepatocellular which presents with disproportionate elevation in serum aminotransferases or cholestasis which presents with disproportionate elevation in alkaline phosphatase. The pattern of liver injury can have elevation in bilirubin and abnormal tests for liver synthetic function. [19, 20] It further lead to development of meconium aspiration syndrome in her baby which was aspirated.

 

CONCLUSION:

In this case study we have found that treatment of pregnant women for arthralgia and other related complications with sulphasalazine can cause severe hepatotoxicity depending up on genotypes which in turn causes a rare respiratory distress meconium aspiration syndrome in neonates. We conclude that the clinical pharmacist intervention is to replace sulphasalazine in slow acetylates with an alternative drug.

 

ACKNOWLEDGEMENTS:

We would like to thank Manipal super-specialty hospital for permitting us to conduct the study and we thank and pray for those patients whose information we have used for the study.

 

REFERENCES:

1.     Jobanputra P. et al. Hepatotoxicity associated with sulfasalazine in inflammatory arthritis: a case series from a local surveillance of serious adverse events. BMC Musculoskeletal Disorder. 2008; 9: 48.

2.     Gupta V, Bhatia BD, Mishra OP. Meconium stained amniotic fluid antenatal intrapartum and neonatal attributes. Ind Pediatr 1996; 33:293-297

3.     Ashtekar SD, et al. Clinical study of meconium aspiration syndrome in relation to birth weight and gestational maturity at general hospital Sangli. Med Pulse Int Med J. 2014; 1(5):189-92.

4.     Unnisa S, et al. Maternal and fetal out come in meconium stained amniotic fluid in a tertiary center. Int J Reprod Contracept Obstet Gynecol. 2016; 5(3):813- 17.

5.     Ross MG. Meconium aspiration syndrome – more than intrapartum meconium. N Engl J Med. 2005; 353(9):946-48.

6.     Wiswell TE, Bent RC. Meconium staining and the meconium aspiration syndrome: unresolved issues. Pediatric Clin North Am. 1993; 40(5):955-81.

7.     Nath GDR et al, Study of clinical profile of meconium aspiration syndrome in relation to gestational age and birth weight and their immediate outcome at Narayana Medical College Hospital, Nellore, India International Journal of Contemporary Pediatrics, 2017 Nov;4(6):2142-2150

8.     S. C. Blackwell, et al., “Meconium aspiration syndrome in term neonates with normal acid-base status at delivery: is it different?” American Journal of Obstetrics &Gynecology, vol. 184, no. 7, pp. 1422–1426, 2001.

9.     A. Ghidini and C. Y. Spong, “Severe meconium aspiration syndrome is not caused by aspiration of meconium,” American Journal of Obstetrics Gynecology, vol. 185, no. 4, pp. 931–938, 2001.

10.   Kamala Swarnam et al, Advances in the Management of Meconium Aspiration Syndrome, International Journal of Pediatrics Volume 2012, Article ID 359571, 7 pages doi:10.1155/2012/359571

11.   Sarika Sukesh Nair. Clinical Management of Amniotic Fluid Embolism. Asian J. Nur. Edu. and Research.2017; 7(1): 120-122.

12.   Do-Jin Kim, Jong-Hyuck Kim. Relationship between Cardiopulmonary function Metabolic Syndrome Indices. Research J. Pharm. and Tech 2017; 10 (11): 3868-3872.

13.   P. Maheshwari, I. Somasundaram. Health Related Quality of Life Measurement in Asthma and Chronic Obstructive Pulmonary Disease. Research J. Pharm. and Tech. 2016; 9(5): 518-520.

14.   R. R. Shah, M. S. Kondawar, S. S. Shinde, N. D. Shah. Formulation and Evaluation of Spray-dried Combination Respirable Powder Based on Selection of Excipients for Pulmonary Delivery: Comparison between Lactose and Mannitol. Research J. Pharm. and Tech. 4(10): Oct. 2011; Page 1604-1614.

15.   Sarika Sukesh Nair. Clinical Management of Amniotic Fluid Embolism. Asian J. Nur. Edu. and Research.2017; 7(1): 120-122.

16.   Wal Pranay, Wal Ankita, Srivastava Rishabh, Rastogi Prateek, Rai Awani K. Antibiotic Therapy in Pediatric Patients. Research J. Pharm. and Tech. 3(1): Jan.-Mar. 2010; Page 118-120.

17.   R. Malathi S. Ahamed John, A. Cholarajan. Tylophora asthmatica L. Prevents Lipid Peroxidation in Acetaminophen Induced Hepato Toxicity in Rats. Asian J. Res. Pharm. Sci. 1(3): July-Sept. 2011; Page 71-73.

18.   P, Karthikeyan.J. Modulation of Antioxidant Potential in Liver of Albino rats by seeds of Nelumbo nucifera Gaertn. in 1,4 Dichlorobenzene induced hepato toxicity. Research J. Pharm. and Tech. 5(4): April 2012; Page 538-540.

19.   S. R Peter. An exploratory study to assess the level of satisfaction of post natal mothers regarding the nursing care given to their neonates in a selected hospital Dhamtari (CG). Asian J. Nur. Edu. and Research 3(2): April.- June 2013; Page 122-123.

20.   K. V Shyamala, V. Ravichandra, N. K. Subbalakshmi, R. Sheila Pai, K. Raghuveera. Iron Status Indicators of Neonates of Mild to Moderate Anaemic Mothers. Research J. Pharm. and Tech. 5(2): Feb. 2012; Page 203-206.

 

 

 

 

 

 

Received on 12.10.2018         Modified on 17.11.2018

Accepted on 18.12.2018      © RJPT All right reserved

Research J. Pharm. and Tech. 2019; 12(3): 1201-1205.

DOI: 10.5958/0974-360X.2019.00200.2