Hepatic veno-occlusive disease with immunodeficiency

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Hepatic veno-occlusive disease with immunodeficiency (VODI) is characterized by

Primary immunodeficiency and
terminal hepatic lobular vascular occlusion and hepatic fibrosis manifest as hepatomegaly and/or hepatic failure.

Onset is before age 12 months. The immunodeficiency comprises severe hypogammaglobulinemia, clinical evidence of T-cell immunodeficiency with normal numbers of circulating T cells, absent lymph node germinal centers, and absent tissue plasma cells. Bacterial and opportunistic infections including Pneumocystis jerovici infection, mucocutaneous candidiasis, and enteroviral or cytomegalovirus infections occur. Hepatic veno-occlusive disease with immunodeficiency (also called VODI) is a hereditary disorder of the liver and immune system. Its signs and symptoms appear after the first few months of life.

Hepatic veno-occlusive disease is a condition that blocks (occludes) small veins in the liver, disrupting blood flow in this organ. This condition can lead to enlargement of the liver (hepatomegaly), a buildup of scar tissue (hepatic fibrosis), and liver failure.

Children with VODI are prone to recurrent infections caused by certain bacteria, viruses, and fungi. The organisms that cause infection in people with this disorder are described as opportunistic because they ordinarily do not cause illness in healthy people. These infections are usually serious and may be life-threatening. In most people with VODI, infections occur before hepatic veno-occlusive disease becomes evident.

Pathophysiology

Genetics

This condition is inherited in an autosomal recessive pattern

VODI results from mutations in the SP110 gene. This gene provides instructions for making a protein called SP110 nuclear body protein, which is involved in the normal function of the immune system. This protein likely helps regulate the activity of genes needed for the body's immune response to foreign invaders (such as viruses and bacteria).

Mutations in the SP110 gene prevent cells from making functional SP110 nuclear body protein, which impairs the immune system's ability to fight off infections. It is unclear how a lack of this protein affects blood flow in the liver.

Epidemiology and Demographics

VODI appears to be a rare disorder; approximately 20 affected families have been reported worldwide. Most people diagnosed with the condition have been of Lebanese ancestry. However, the disorder has also been identified in several individuals with other backgrounds in the United States and Italy.

Natural history, Complications and Prognosis

Many people with VODI live only into childhood, although some affected individuals have lived to early adulthood. VODI is associated with 90% mortality overall and 100% mortality if unrecognized and untreated with intravenous immunoglobulin (IVIG) and Pneumocystis jerovici prophylaxis.

Diagnosis

Clinical and Immunologic Features of Hepatic Veno-Occlusive Disease with Immunodeficiency (VODI)

Phenotype	Patients I, F, H with Novel Mutations ¹
Clinical Features	Patients from Sydney with VODI	Comments
Presenting <6 months	20/20		2/3
Hepatic failure at initial presentation	4/20	1/12 post HSCT 3/12 no obvious precipitant	0/3
Hepatomegaly at initial presentation	9/20	3/6 P. jerovici 2/6 hepatomegaly without SOS	2/3 1/3 enterovirus and disseminated CMV (F)
P. jerovici infection	12/20	7/12 proven 5/12 suspected	1/3 suspected (F) 1/3 proven (I)
Mucocutaneous candidiasis	2/20		1/3
Other features	1/20	By age 19 years	1/3 lung fibrosis (H)
Death	19/20		0/3
Recovery from initial SOS	4/20	1 completely well 1 chronic liver disease requiring hepatic transplantation 1 SOS post HSCT 1 developmental disability, chronic aspiration	3/3
Neurologic abnormalities	6/20	4/7 cerebral infarction 1/7 Toxoplasma? 1/7 porencephalic cyst	0/3
Panhypogammaglobulinemia	19/19	1/18 loss of normal immunoglobulins at age 4 mos	3/3 1/3 low normal levels of IgA and IgM after commencing IVIg
Normal number of lymphocytes	10/11		3/3
Normal NK cells	12/12		3/3
Decreased intracytoplasmic IFNγ, IL2, IL4, IL10	4/5	Low levels at 4 hours, normal/increased levels at 48 hours	1/1 (F)
Decreased number of memory T and B cells	3/4		2/3 (I,H)