Major advances in the management of patients with CGD have led to marked improvements in survival; however premature mortality due to repeated infectious complications is still the reality for patients with this disease. In an attempt to understand why after surviving repeated infections patients die from a given infectious episode, we examined predictors of mortality in a large cohort of well-characterized patients with CGD. Although all deaths were due to infection, regression analysis identified progressive thrombocytopenia, repeated ALP elevations and a history of liver abscess as independent predictors of mortality.
Beyond the predisposition to liver abscess, little is known about the impact of CGD on the liver. A recent description of this cohort showed that other liver abnormalities are common in CGD7
. Patients had frequent liver enzyme elevations but more importantly, of those that had a liver biopsy, 80% were found to have damage or obliteration of central and/or portal veins. Associated with this venopathy, NRH was seen in 9 liver biopsies including 6 of 12 autopsy specimens7
. NRH is a recognized cause of non-cirrhotic portal hypertension thought to result from a progressive vasculopathy with obliteration of small portal vein branches21–23
. NRH and venopathy increase resistance to sinusoidal blood flow leading to portal hypertensive changes, however, unlike in cirrhosis, there is no intrinsic impairment of hepatic synthetic function and minimal or no fibrosis.
The results of the mortality analysis suggest that the development of non-cirrhotic portal hypertension may herald a poor prognosis in CGD. Patients with CGD have many reasons to develop thrombocytopenia, including bone marrow suppression from infections and/or medications. However, bone marrow biopsy in a number of patients revealed no evidence of marrow dysfunction and full hematological evaluation including platelet antibodies was unrevealing. Progressive thrombocytopenia was associated with the most severe form of CGD (gp91phox
), splenomegaly, elevation of IgG and repeated ALT elevations as well as increased portal vein diameter, a reliable marker of portal hypertension20
. In this setting, ALT elevations may be markers of recurrent hepatic insults from infection and/or drug hepatotoxicity while IgG elevation and splenomegaly are likely consequences of portal hypertension24, 25
. The association with splenomegaly and the absence of platelet antibodies make autoimmune thrombocytopenia unlikely26
. Immunoglobulin levels are thought to increase in cirrhosis due to reduced antigenic clearance by the liver27
. Although this partially results from reduced Kupffer cell mass, structural abnormalities that lead to shunting are also likely important and are very similar to the findings seen with the venopathy and NRH found in many patients with CGD21
. Recurrent infections may also lead to splenomegaly, however without portal hypertension, splenic sequestration of platelets is less common28
. As a result, progressive thrombocytopenia, but not splenomegaly alone, was found to be a predictor of mortality in this cohort of patients with CGD.
Autopsy data, prospective evaluation of sinusoidal portal pressure and measurements of portal vein diameter support the connection between progressive thrombocytopenia and portal hypertension. Fifty percent of patients who died had a history of ascites compared to 7.8% who were alive at the end of follow-up (p<0.0001). Although factors other than portal hypertension may cause ascites, 10 of the 11 patients who died with a history of ascites had splenomegaly, one had hepatic encephalopathy and none had other known causes of ascites. Two patients with declining platelet counts were evaluated and had raised HVPG measurements. NRH and other causes of intrahepatic pre-sinusoidal portal hypertension have been reported to increase the HVPG29–32
. Although prospective evaluation of portal pressure was only available in two patients, portal vein diameter, a validated surrogate for portal hypertension, showed a strong correlation with platelet slope in the 68 patients for whom data was available20
. These findings suggest that declining platelet count is a sensitive and early maker for the development portal hypertension, likely as a consequence of venopathy and NRH in the setting of CGD.
ALP elevations were associated with hepatic and systemic infections, but also with signs of portal hypertension (splenomegaly and ascites), further suggesting that repeated infections likely play a role in the development of portal hypertension over time. Elevations of ALP are commonly observed with NRH21
, reinforcing the connection between infection, NRH, portal hypertension and mortality.
Together these data suggest that a subset of patients with CGD develop progressive non-cirrhotic portal hypertension likely as a consequence of damage to the hepatic microvasculature caused by repeated liver abscesses and possibly contributed to by drug-induced liver injury21, 32, 33
. Repeated systemic infections may also increase portal pressure through modulation of vasoactive substances, as has been described in cirrhosis34, 35
and recently in an animal model of non-cirrhotic portal hypertension36
. Once portal hypertension develops, patients with CGD generally do not die of direct sequelae of increased portal pressure, but rather of sepsis. Portal hypertension itself may increase the risk of subsequent infection through increased bacterial translocation, particularly in the setting of systemic immunosuppression37, 38
. This has also been described in patients with other causes of non-cirrhotic portal hypertension, namely congenital hepatic fibrosis (CHF) and schistosomiasis39–41
. As in the setting of cirrhosis, this interaction potentially sets up a vicious cycle with infections worsening portal hypertension and portal hypertension increasing the risk of infection. This relationship is borne out in this study population; patients with portal hypertension, as defined by platelet slope, had more episodes of infection than those without (6.8 vs. 4.0, p=0.032). Similarly, patients undergoing renal transplantation for autosomal recessive polycystic kidney disease (ARPKD), which is caused by the same genetic defect as CHF, were found to have an increased rate of infection and sepsis was the most common cause of mortality in this group39
. Which is cause and which is effect is difficult to discern. Once infection occurs, the hyperdynamic circulatory state associated with portal hypertension puts patients at greater risk of developing complications including ascites, spontaneous bacterial peritonitis and renal failure11, 12
Although CGD is a rare disease, the findings from this retrospective and prospective study highlight the importance of portal hypertension as a contributor to mortality outside the setting of cirrhosis, a factor that is likely under-recognized. A progressive decline in platelet count may provide a useful non-invasive means to evaluate progression of portal hypertension over time. Whether non-cirrhotic portal hypertension contributes to morbidity and mortality in other chronic conditions and how its effects can be modulated will require further investigation.