Successful liver transplantation in common variable immune deficiency with reversal of hepatopulmonary syndrome

Abstract

Common variable immune deficiency (CVID) is a primary immunodeficiency disorder that is associated with abnormal liver function tests, however advanced liver disease is uncommon. Hepatopulmonary syndrome (HPS) is a rare but debilitating complication of CVID-associated liver disease. We report a case of CVID complicated by HPS that was successfully treated with orthotopic liver transplant, with the patient recovering to normal hepatic function and successfully weaning off domiciliary oxygen post-transplantation.

Background

Common variable immune deficiency (CVID) is the the most common primary immunodeficiency disorder and is characterised by hypogammaglobulinaemia and recurrent bacterial infections. CVID is associated with abnormal liver function tests in up to 40% of cases, most commonly in a cholestatic pattern. Chronic liver disease occurs less frequently in CVID, affecting approximately 10% of patients. The classic histopathological finding on liver biopsy is nodular regenerative hyperplasia (NRH), with varying degrees of lymphocytic infiltration.¹ Progression to end-stage liver disease with portal hypertension is thought to be uncommon and remains poorly characterised.^{2 3}

There is limited evidence to support orthotopic liver transplantation (OLT) in CVID as there have been approximately 20 cases reported in the literature and patients have experienced high rates of infective complications and graft rejection.^{4 5} There are only four case reports of hepatopulmonary syndrome (HPS) associated with CVID in the literature.^{4 6 7} Three of the cases of HPS were treated with OLT, of which two did not improve their respiratory failure,⁴ and one did not report the outcome data.⁷ Here we report the first case of OLT for HPS due to CVID-associated liver disease after which the patient was successfully weaned off domiciliary oxygen. This demonstrates that HPS in CVID can be successfully managed with transplantation and adds to the body of evidence that CVID-associated liver disease does not always follow a benign course.

Case presentation

We report the case of a 55-year-old female with established CVID, diagnosed in 1999 during investigation for recurrent respiratory tract infections. She had subsequently been managed with intravenous immunoglobulin infusions every 2 weeks. Bronchiectasis developed as a consequence of recurrent infections, but she remained otherwise well, with a past medical history otherwise significant only for osteopenia and gastro-oesophageal reflux.

Abnormal liver function tests were first identified in 2007, at the age of 46. Initial liver biopsy performed in 2008, revealed subtle NRH with a moderate non-specific chronic hepatitis, periportal shunt vessels, and patchy portal and sinusoidal fibrosis. Screening investigations revealed no specific cause for her liver dysfunction. Drug-induced liver injury was entertained although a detailed drug history did not reveal a specific offending agent.

Investigations

Breathlessness was first reported in 2014. Investigations, including an echocardiogram with echo contrast and a radionucleotide pulmonary shunt study performed using macro aggregated albumin (MAA), were consistent with a diagnosis of HPS with a calculated shunt of 23%. At the time of transplant referral in April 2015, pulmonary function was severely impaired, and she was oxygen-dependent, with an exercise tolerance of 200 metres despite the aid of a 4-wheel frame. On clinical examination, her resting heart rate was 100 bpm and oxygen saturation 94% on 4 L of oxygen therapy and she had marked digital clubbing. Her liver biochemistry was markedly abnormal with an albumin of 33 g/L, alkaline phosphatase 478 U/L, gamma-glutamyl transferase 339 U/L, alanine tranaminase 55 U/L, aspartate transaminase 82 U/L, bilirubin 19 µmol/L, INR 0.9 and platelets 138×10⁶/L.

A repeat liver biopsy was performed in 2015 to further investigate the cause of portal hypertension. At this time, the biopsy demonstrated chronic inflammation and advanced fibrosis (sinusoidal predominant with bridging) with prominent vascular and congestive changes, including NRH-like areas; thought to represent advanced CVID-associated liver disease. However the liver was not cirrhotic. She had evidence of portal hypertension with upper gastrointestinal endoscopy showing grade I oesophageal varices and portal hypertensive gastropathy and a liver ultrasound showing an enlarged, nodular liver spanning 21 cm.

Treatment

Her health continued to deteriorate with progressive malnutrition (body mass index 16 kg/m²) and reduced oxygen saturations to 89% on 4 L of oxygen. At the time of transplantation her Model for End-stage Liver Disease (MELD) score was only nine, confirming that, despite the presence of liver fibrosis and portal hypertension, liver function remained well-maintained. However she received special consideration due to her clinical deterioration and worsening gas exchange. The explant liver revealed features consistent with advanced CVID-associated liver disease (figure 1), including NRH, extensive sinusoidal fibrosis (without clear evidence of cirrhosis), cholestasis and T cell lymphocytic infiltration involving portal areas, sinusoidal spaces and biliary epithelium.

Figure 1.

Liver explant biopsy—nodular regenerative hyperplasia, cholestasis and T cell lymphocytic proliferation involving portal areas, sinusoidal spaces and biliary epithelium.

Outcome and follow-up

The patient had induction immune suppression with prednisolone, tacrolimus and azathioprine. She had an uncomplicated postoperative course other than a bile leak with t-tube removal at 3 months requiring biliary stenting. She received prophylaxis against Pneumocystis jirovecii with dapsone for 6 months due to Bactrim intolerance, and treatment of low level cytomegalovirus viraemia with valganciclovir for 12 months. Both her physical function and biochemistry rapidly improved, with weight gain of 6 kg, and currently she mobilises without aids or oxygen. The patient’s oxygen saturations improved to 96% on room air within 10 weeks of transplantation and her liver function tests normalised. She suffered moderately severe acute cellular rejection 12 months post-OLT and thus remains on triple immunosuppression, with prednisolone 5 mg once a day, tacrolimus 0.5 mg two times per day and azathioprine 100 mg. She has had chronic diarrhoea related to chronic norovirus shedding and has had no other serious infective complication post OLT. She continues on IVIG for maintenance of her CVID. She is now 18 months post-liver transplantation and has no pulmonary limitations to her exercise tolerance.

Discussion

We report the first case to our knowledge of a successful OLT for HPS associated with CVID-associated liver disease. Despite the presence of chronic bronchiectasis, transplantation was followed by a complete resolution of the patient’s severe hypoxia within 10 weeks, indicating that it was directly related to her underlying liver disease.

This case is a reminder that CVID-associated liver dysfunction does not always follow a benign course, and monitoring for complications of portal hypertension and progression to end-stage liver disease are required in those with abnormal liver function tests. The frequency of abnormal liver function tests is high in CVID, with a prevalence of 47 out of 108 patients in one case series.² The most common histological feature is NRH; however, the natural history and potential to progress to cirrhosis or portal hypertension are not well described.³

HPS has very rarely been described in CVID, with only five known previous case reports of this complication.^{6 7} Two of these cases were in monozygotic teenage twins, suggesting a genetic basis or triggering environmental factor. Three of the five cases had NRH consistent with CVID-associated liver disease but not cirrhosis on liver biopsy. These previously documented cases illustrate that while HPS usually occurs in patients with end stage cirrhosis, it can also occur in patients with non-cirrhotic portal hypertension.

Importantly, our case provides evidence that even with existing respiratory disease, the intrapulmonary shunts associated with HPS can be reversed in CVID patients, as evidenced by our patient’s hypoxaemia resolving around 2 months post-transplant despite her pre-existing bronchiectasis. Our case contrasts with the two previously reported cases of OLT for HPS in CVID patients where the respiratory failure did not resolve.⁴ The recovery of our patient’s respiratory function 2 months post OLT is consistent with previously reported studies in non-CVID patients with HPS that have reported resolution within two to ten months post-transplantation.^{8 9} This contrasts with the two previously reported cases of OLT for HPS in CVID patients where the respiratory failure did not resolve.⁴

Reports of OLT in subjects with CVID for any reason are rare. One report of two cases of successful OLT for adults with CVID were for liver disease related to hepatitis C virus and hepatitis B virus infection, respectively, as opposed to CVID-associated liver disease itself.¹⁰ A second study reported two living donor OLTs performed for severe hepatitis with classic signs of CVID-associated liver disease, including endothelial CD8+ T cell infiltration and lymphocytic cholangitis. Unfortunately both of these patients suffered early acute cellular rejection with a pattern suggesting possible concomitant recurrence of CVID-associated liver disease, with one requiring retransplantation and the second developing recurrent cirrhosis.⁵ Our patient has experienced moderate acute cellular rejection and chronic norovirus infection but has no evidence of disease recurrence.

In conclusion, this case highlights the potential life-threatening nature of CVID-associated liver disease, and the potential for successful transplantation even in the context of severe hypoxemia due to HPS.

Learning points.

• Common variable immune deficiency (CVID) patients may develop severe hypoxia from hepatopulmonary syndrome.

• Orthotopic liver transplantation can be a suitable treatment option for patients with CVID despite their pre-existing immune defects, although rates of rejection and infection are high.

• The hypoxia from hepatopulmonary syndrome in CVID patients can be reversed with orthotopic liver transplantation even in the presence of pre-existing bronchiectasis.