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 Table of Contents  
Year : 2022  |  Volume : 11  |  Issue : 2  |  Page : 176-180

Hepatopulmonary syndrome and portopulmonary hypertension coexisting in a case of wilson's disease cirrhosis: “Double trouble”

1 Department of General Medicine, Jawaharlal Nehru Medical College and Acharya Vinoba Bhave Rural Hospital, Wardha, Maharashtra, India
2 Department of Cardiology, Jawaharlal Nehru Medical College and Acharya Vinoba Bhave Rural Hospital, Wardha, Maharashtra, India
3 Department of Pathology, Jawaharlal Nehru Medical College and Acharya Vinoba Bhave Rural Hospital, Wardha, Maharashtra, India
4 Department of Pediatrics, Jawaharlal Nehru Medical College and Acharya Vinoba Bhave Rural Hospital, Wardha, Maharashtra, India

Date of Submission05-Dec-2021
Date of Decision05-Jan-2022
Date of Acceptance07-Jan-2022
Date of Web Publication08-Apr-2022

Correspondence Address:
Dr. V V. S. S. Sagar
Department of Medicine, Jawaharlal Nehru Medical College and Acharya Vinoba Bhave Rural Hospital, Sawangi(Meghe), Wardha, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijrc.ijrc_150_21

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Wilson's disease is one of the infrequent causes of hepatic failure with a wide clinical spectrum. Hepatic and neuropsychiatric manifestations are the most common, whereas atypical presentations were also reported as the complications of hepatic failure such as hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH). These are considered pulmonary complications of hepatic disease with underlying complex pathology and various vasoactive substances such as endothelin 1 and nitric oxide on the pulmonary blood vessels. HPS usually presents with breathlessness and central cyanosis. The triad of HPS comprises dilatation of pulmonary vasculature, intrapulmonary shunting, and hypoxia, whereas POPH causes vasoconstriction and vascular remodeling leading to increased resistance in pulmonary blood vessels and subsequent right ventricular dysfunction. In this case report, we highlight two antagonistic pathological processes coexisting in the same patient.

Keywords: Endothelin, hepatic, hypertension, hypoxia, neuropsychiatric

How to cite this article:
Sagar V V, Acharya S, Agrawal G, Shukla S, Kumar S, Akhil CV. Hepatopulmonary syndrome and portopulmonary hypertension coexisting in a case of wilson's disease cirrhosis: “Double trouble”. Indian J Respir Care 2022;11:176-80

How to cite this URL:
Sagar V V, Acharya S, Agrawal G, Shukla S, Kumar S, Akhil CV. Hepatopulmonary syndrome and portopulmonary hypertension coexisting in a case of wilson's disease cirrhosis: “Double trouble”. Indian J Respir Care [serial online] 2022 [cited 2022 Jun 29];11:176-80. Available from: http://www.ijrc.in/text.asp?2022/11/2/176/342785

  Introduction Top

Wilson's disease is an autosomal recessive condition due to defective copper metabolism, with a prevalence of 1.5/100,000.[1] The disease manifestations can be attributed to excessive copper deposition in the body organs resulting from decreased copper elimination leading to organ-specific features such as liver dysfunction, personality disorder, and a movement disorder. Biochemical parameters such as raised 24-h urinary copper levels and reduced serum ceruloplasmin and serum copper support the diagnosis.[2] However, the presentation may not always be typical, leading to diagnostic confusion due to atypical manifestations such as hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH).

The hallmark of HPS is intrapulmonary vascular dilatations (IPVDs) and shunt, whereas POPH is characterized by vasoconstriction and increased vascular resistance.

The classic triad of HPS comprises arterial deoxygenation, dilatation of intrapulmonary vessels, and liver disease. The degree of hepatic pathology can range from compensated chronic liver disease to decompensated cirrhosis.[3] HPS can be considered one of the rare and important atypical presentations of Wilson's disease manifesting with severe hypoxemia, breathlessness, bluish discoloration of lips, tongue, and digits, orthodeoxia, and platypnea, spider nevi.[4]

POPH is characterized by coexistent pulmonary arterial hypertension and portal hypertension, in which the etiology of portal hypertension need not be a hepatic disease.[5]

We report the case of a 19-year-old male who presented with dyspnea, cyanosis, and clubbing in this case. Suspecting congenital heart disease, two-dimensional echocardiography was done suggestive of pulmonary hypertension. On investigating further, the patient was found to have a hepatic disease, the etiology of which proved to be Wilson's disease evidenced by imaging, elevated urinary copper levels, and decreased serum ceruloplasmin. The presence of cyanosis, clubbing, hypoxia, platypnea, and orthodeoxia in the case of Wilson's disease led to the suspicion of HPS. This was confirmed on computed tomography (CT) pulmonary angiography evidenced by pulmonary artery dilatation and agitated saline contrast echocardiography depicting intrapulmonary vascular shunt.

  Case Report Top

A 19-year-old male was admitted with complaints of breathlessness at rest (New York Heart Association-Grade III), yellowish discoloration of eyes and urine, and bluish discoloration of the tongue, lips, and fingers for 5 years, aggravated by aggravated for the last 4 days. The patient also had recurrent episodes of hemoptysis for 1 year. Breathlessness aggravated on standing and relieved on lying down. On general examination, the patient was afebrile with a heart rate of 106/min, tachypneic with a respiratory rate of 26/min, blood pressure of 106/74 mm of Hg, jugular venous pressure was raised 7 cm from the sternal angle, pulse oximetry showed 84% saturation in the supine position on room air which had reduced to 76% on the upright position suggestive of orthodeoxia. He had cyanosis in the tongue, lips, fingers of upper extremities [Figure 1] and [Figure 2], clubbing of both upper extremities [Figure 3], jaundice noted in the sclera of both eyes, bilateral pitting type of pedal edema present. On systemic examination, cardiovascular examination revealed Grade 2 parasternal heave, diastolic shock on palpation. Auscultation revealed loud P2. The respiratory examination had normal vesicular breath sounds. Per abdomen, the examination revealed mild splenomegaly present. The central nervous system examination revealed normal.

Laboratory investigations revealed hemoglobin 17.1 g/dl, hematocrit 49.4, white blood cells 6800 cells/cu.mm, platelets 71,000 cells/cu.mm, coagulation profile suggestive of prothrombin time 14.6, activated partial thromboplastin time 36.2, international normalized ratio 1.24, urea 16 mg/dl, creatinine 0.6 mg/dl, serum sodium 139 mmol/l, serum potassium 3.8 mmol/l, total bilirubin 4.6 mg/dl, conjugated 0.7 mg/dl, unconjugated 3.9 mg/dl, serum glutamic oxaloacetic transaminase 61U/L, serum glutamic pyruvic transaminase 40U/L, and albumin 2.7 g/dl. Electrocardiogram showed right ventricular strain pattern and right axis deviation [Figure 4].
Figure 1: Showing bluish discoloration of lips

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Figure 2: Showing bluish discoloration of the tongue

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Figure 3: Shows clubbing of fingers

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Figure 4: Electrocardiogram showing right ventricular strain pattern, right axis deviation

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Suspecting congenital heart disease, two-dimensional echocardiography was done, which revealed mild tricuspid regurgitation, moderate pulmonary hypertension, pulmonary artery systolic pressure 55 mmHg, right ventricular systolic pressure 55 mmHg, TR Jet 3.1 m/s, ejection fraction was 65%.

CT of the abdomen was done suggestive of cirrhosis, splenomegaly with portal hypertension, and portosystemic collaterals [Figure 5]. Upper gastrointestinal endoscopy revealed a small esophageal varix with severe portal gastropathy [Figure 6]. Investigations were performed on further workup to rule out the etiology of cirrhosis: Viral markers such as hepatitis B and C were nonreactive, serum ferritin 99 ng/ml (17.9–464), antinuclear antibodies was done by indirect immunofluorescence, which was negative. Anti-smooth muscle antibody titer was negative. Serum IgG 10 g/l (7–16). Liver kidney microsomal 1 antibody level was done by enzyme-linked immunoassay −6.1 RU/ml, which was normal (negative <20 and positive >20).
Figure 5: Showing Axial section of CT abdomen showing caudate lobe hypertrophy with differential contrast uptake by liver suggestive of cirrhosis with splenomegaly and portosystemic collaterals

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Figure 6: Showing upper gastrointestinal endoscopy showing small esophageal varix

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Twenty-four hour urinary copper was 568.5 mcg/24 h. Serum ceruloplasmin was low 0.12 m/l leading to a diagnosis of Wilson's disease. Magnetic resonance imaging of the brain was done, which revealed mild T1 hyperintensity in bilateral globus pallidus and posterior limb of the internal capsule and anterior cerebral peduncle suggestive of Wilson's disease [Figure 7].
Figure 7: Showing magnetic resonance imaging brain axial T1 image showing mild T1 hyperintensity seen in bilateral globus pallidus and posterior limb of the internal capsule and anterior cerebral peduncle suggestive of Wilson's disease

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The presence of cyanosis, clubbing, hypoxia, platypnea, and orthodeoxia in the case of Wilson's disease led to the suspicion of HPS. Hence, Bubble contrast echocardiography was done to discern pulmonary AV malformations. The patient was subjected to contrast echocardiography with intravenous agitated saline. The agitated microbubbles appeared in the left heart by the 7th beat confirming intrapulmonary shunting [Figure 8] and [Video 1].
Figure 8: Contrast echocardiography showing appearance of agitated saline in left atrium after 7th beat from panel A to panel C

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Contrast-enhanced computed tomography of the thorax revealed aneurysmal dilatation of the main pulmonary trunk, a solitary pulmonary nodule in the lateral segment of the right middle lobe. CT pulmonary angiogram was done to confirm the finding of pulmonary hypertension obtained by clinical examination and echocardiography, along with the suspicion of POPH. It was suggestive of changes of pulmonary hypertension, main pulmonary artery, right and left pulmonary artery enlarged in caliber [Figure 9].
Figure 9: Showing CT pulmonary angiogram showing increased calibre of right and left pulmonary artery

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The patient was treated with penicillamine, tablet zinc 50 mg once a day, tablet sildenafil 25 mg twice a day, tablet bosentan 62.5 mg once a day, tablet lasilactone 20/50 mg once a day, supplemental oxygen. The patient was advised for liver transplantation.

  Discussion Top

The etiology of breathlessness and central cyanosis in a patient with hepatic failure can be related to various causes unrelated to liver disease, such as cardiorespiratory diseases on one hand. On the other hand, pulmonary complications due to liver disease can lead to such symptoms as HPS and POPH.[6]

HPS is more common in the context of cirrhotic portal hypertension. However, a few cases have also been noted with portal hypertension without cirrhosis and vice versa.[7] The ventilation-perfusion mismatch is due to the IPVD and the resultant left-to-right shunt, causing an increased alveolar-arterial oxygen pressure gradient. The following mechanisms can explain hypoxemia due to IPVD: Increased circulatory ET-1 levels, altered pulmonary vasomotor control due to decreased hepatic products due to parenchymal disease or reduced hepatic venous flow, elevated pro-inflammatory enzymes such as NO synthase in the lung leading to pulmonary vasodilatation.[8]

In our case, the patient presented with hypoxia, orthodeoxia, cyanosis, clubbing, and splenomegaly, which led to the suspicion of HPS and portal hypertension. On further workup, the etiology of portal hypertension was cirrhosis, with Wilson disease being a root cause.

The intrapulmonary vascular shunt can be detected by transthoracic echocardiography enhanced by contrast Contrast Echocardiography-Transthoracic echocardiography (CE-TTE), and technetium macroaggregated albumin lung perfusion scan. During CE-TTE, injection of intravenous agitated saline produces microbubbles that appear in the right atrium initially later enter into the left atrium. Intracardiac and intrapulmonary shunts can be differentiated by the number of beats till the bubbles reach the left atrium. Intracardiac shunt bubbles are seen within three beats and intrapulmonary shunts within 4–6 beats. In our case, bubbles in the left atrium at the 7th beat suggest intrapulmonary shunt.

HPS can be classified based on pulmonary angiography into Type I with diffuse vascular dilatations and type II with discrete arteriovenous malformations.

POPH describes the correlation between pulmonary hypertension and portal hypertension in including or excluding hepatic illness. Criteria to diagnose POPH are portal hypertension, elevated resting mean pulmonary artery pressure >25 mmHg, mean pulmonary capillary wedge pressure <15 mmHg, and pulmonary vascular resistance >240 dyn·s·cm−5.[9] Endotoxemia and bacterial translocation are the examples of inflammatory conditions that might contribute to pulmonary vascular remodeling. Portosystemic collaterals have their part in POPH by helping transport mediators metabolized in the liver, injuring pulmonary vasculature. In advanced stages of POPH, shortness of breath, syncope, and hemoptysis can occur.[10]

The general goals of POPH therapy are to relieve symptoms, enhance the quality of life and exercise ability, and make liver transplantation more successful. Epoprostenol, an intravenous prostacyclin analog, is the best drug with proven benefit in POPH by improving pulmonary hemodynamics and cardiac output. Similar results were seen with intravenous iloprost. Bosentan, an endothelin receptor antagonist, can be administered orally. Recently, sildenafil and tadalafil (PDE inhibitors) were proved beneficial in the treatment of POPH. Liver transplantation is the definitive treatment used to treat the underlying hepatic pathology.

In terms of quality of life, HPS has been demonstrated to impact one's perception of general health, particularly in domains related to the mental component of a short form. Mortality among patients with HPS at 2.5 years has been reported to be between 40% and 60%. POPH leads to right ventricular dysfunction with consequent corpulmonale, which correlates with survival and mortality in POPH. Robalino et al. demonstrated the survival of 40% at 1 year. Le Pavec et al., in their study, proved that the prognosis of POPH was related to cardiac index and severity of hepatic disease, even in the worst cases with poor prognosis, the 5-year survival rate was 58%.[11]

  Conclusion Top

Wilson's disease affects various systems with manifestations that are not always confined to the brain and liver. According to this case report, Wilson's disease may manifest itself first in the form of HPS and POPH. The identification of patients who are likely to benefit from liver transplantation is an essential element in treating POPH and HPS. Novel approaches to the treatment of POPH and HPS help excavate newer techniques in the management that may widen the scope of transplantable patients, which ultimately aids in the betterment of outcomes.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Pham DM, Subramanian R, Parekh S. Coexisting hepatopulmonary syndrome and portopulmonary hypertension: Implications for liver transplantation. J Clin Gastroenterol 2010;44:e136-40.  Back to cited text no. 1
Rezaeetalab F, Mozdourian M. Pulmonary hypertension as an initial presentation of Wilson's disease: A case report. Rev Clin Med 2020;6:178-81.  Back to cited text no. 2
Aldenkortt F, Aldenkortt M, Caviezel L, Waeber JL, Weber A, Schiffer E. Portopulmonary hypertension and hepatopulmonary syndrome. World J Gastroenterol 2014;20:8072-81.  Back to cited text no. 3
Lahiri D, Agarwal R, Mondal D, Roy MK, Sarkar N, Mukhopadhyay J. Hepatopulmonary syndrome as the first manifestation of Wilson disease. JCR 2015;5:37-41.  Back to cited text no. 4
Chávez-Tapia NC, Uribe M, López E. Pulmonary complications of liver cirrhosis: portopulmonary hypertension and hepatopulmonary syndrome. The paradox of pulmonary vasoconstriction and vasodilation. Gac MedMex 2007;143:333-9.  Back to cited text no. 5
Restrepo R, Singer EF, Baram M, Restrepo R, Singer EF, Baram M. Hepatopulmonary syndrome and portopulmonary hypertension. Hosp Pract (1995) 2013;41:62-71.  Back to cited text no. 6
Naeije R. Hepatopulmonary syndrome and portopulmonary hypertension. Swiss Med Wkly 2003;133:163-9.  Back to cited text no. 7
Ramsay MA. Portopulmonary hypertension and hepatopulmonary syndrome, and liver transplantation. Int Anesthesiol Clin 2006;44:69-82.  Back to cited text no. 8
Mandell MS. Hepatopulmonary syndrome and portopulmonary hypertension in the Model for End-Stage Liver Disease (MELD) era. Liver Transpl 2004;10:S54-8.  Back to cited text no. 9
Krowka MJ. Hepatopulmonary syndrome and portopulmonary hypertension: Implications for liver transplantation. Clin Chest Med 2005;26:587-97.  Back to cited text no. 10
Le Pavec J, Souza R, Herve P, Lebrec D, Savale L, Tcherakian C, et al. Portopulmonary hypertension: survival and prognostic factors. Am J Respir Crit Care Med 2008;178:637-43. doi: 10.1164/rccm.200804-613OC. Epub 2008 Jul 10. PMID: 18617641.  Back to cited text no. 11


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]


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