Hepatic veno-occlusive disease with immunodeficiency

# 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.

# Treatment
Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with hepatic veno-occlusive disease with immunodeficiency (VODI), the following evaluations are recommended:
- Assessment of immune function including serum immunoglobulin levels, T- and B-cell numbers and percentages, and T-cell proliferative response to mitogens
- More extensive immune testing for number of memory B and T cells and intracellular cytokine (IL2, IL4, IL6, and IFN) responses to stimulation, if available
- Complete blood count (CBC)
- Assessment of hepatic function (including serum concentrations of aminotransferases, bilirubin, and albumin) and assessment for sequelae of portal hypertension (including anemia and thrombocytopenia)
A clotting profile and a hepatic Doppler ultrasound examination should be undertaken prior to consideration of hepatic biopsy for a histologic diagnosis of hepatic veno-occlusive disease (hVOD). Evidence of impaired clotting and/or portal hypertension are contraindications to hepatic biopsy.
Treatment of Manifestations
Hypogammaglobulinemia is treated via intravenous immunoglobulin, which should commence at the diagnosis of hepatic veno-occlusive disease with immunodeficiency (VODI) or in presymptomatic siblings confirmed to have homozygous SP110 mutations. An appropriate dose is 0.4g/kg every four weeks adjusting the dose to maintain a trough IgG level greater than 6 g/L.
Pneumocystis jerovici prophylaxis with cotrimoxazole pediatric suspension (5 mL = trimethoprim 40 mg and sulfamethoxazole 200 mg) should be ongoing in children with VODI who tolerate this medication. This may be administered as a single daily dose or as a single dose three days per week. The recommended dose is 5 mg trimethoprim per kg (0.625 mL/kg) or 150 mg/M2 (3.75 mL/M2).
Infections with specific agents should be treated with appropriate supportive care and antibacterials or antivirals.
HSCT and hepatic transplantation may be considered, but appear to have a high rate of complications in the VODI cohort studied to date
Prevention of Primary Manifestations
Initiation of regular intravenous immunoglobulin at the time of diagnosis to prevent infection related to severe hypogammaglobulinemia and cotrimoxazole prophylaxis to prevent Pneumocystis jerovici infection is appropriate
Prevention of Secondary Complications
Some evidence suggests that treatment of immunodeficiency early in VODI may reduce the risk of development or recurrence of hVOD.
Surveillance
- Regular surveillance of hepatic function, platelet count, and hemoglobin level in children with VODI as hepatic failure and portal hypertension may occur
- Measurement of immunoglobulin concentrations prior to IVIG infusions
- Broncho-alveolar lavage to diagnose Pneumocystis jerovici infection; viral cultures or lung function studies as needed
Agents known to predispose to hVOD such as cyclophosphamide and senecio alkaloids/bush teas should be avoided.
Bone marrow transplantation is not recommended.
Evaluation of Relatives at Risk
The majority of children with VODI present before age six months; however, as one child presented at age 11 months, molecular genetic testing should be considered in sibs of a proband who are younger than age 12 months.
Penetrance is complete (i.e., 100%) in the individuals with VODI described to date; thus, molecular genetic testing of healthy at-risk sibs of a proband who are older than age 12 months is not recommended.