Hepatic venoocclusive disease with immunodeficiency

Other Names: VODI 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-immunodeficiency syndrome is characterized by the association of severe hypogammaglobulinemia, combined T and B cell immunodeficiency, absent lymph node germinal centers, absent tissue plasma cells and hepatic veno-occlusive disease.

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.

Many people with VODI live only into childhood, although some affected individuals have lived to early adulthood.

Epidemiology

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.

Cause

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.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

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.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormal serum interferon-gamma level
• Abnormal serum interleukin level
• Panhypogammaglobulinemia

30%-79% of people have these symptoms

• Absence of lymph node germinal center
• Cough(Coughing)
• Decrease in T cell count(Low T cell count)
• Decreased proportion of memory B cells
• Failure to thrive in infancy(Faltering weight in infancy)
• Hepatomegaly(Enlarged liver)
• Hepatosplenomegaly(Enlarged liver and spleen)
• Recurrent enteroviral infections
• Recurrent gastroenteritis
• Recurrent respiratory infections(Frequent respiratory infections)

5%-29% of people have these symptoms

• Anemia(Low number of red blood cells or hemoglobin)
• Ascites(Accumulation of fluid in the abdomen)
• Bilateral tonic-clonic seizure(Grand mal seizures)
• Chronic hepatic failure(Chronic liver failure)
• Chronic mucocutaneous candidiasis
• Diarrhea(Watery stool)
• Elevated hepatic transaminase(High liver enzymes)
• Hemiparesis(Weakness of one side of body)
• Inappropriate antidiuretic hormone secretion
• Jaundice(Yellow skin)
• Leukodystrophy
• Pancytopenia(Low blood cell count)
• Paraparesis(Partial paralysis of legs)
• Paraplegia(Leg paralysis)
• Portal hypertension
• Pulmonary fibrosis
• Pulmonary hemorrhage
• Recurrent abscess formation
• Recurrent aspiration pneumonia
• Recurrent ear infections(Frequent ear infections)
• Thrombocytopenia(Low platelet count)
• Urinary retention

1%-4% of people have these symptoms

• Abnormal natural killer cell count
• Microcephaly(Abnormally small skull)

Diagnosis

The diagnosis of VODI is established in a proband with the following clinical diagnostic criteria:

Clinical evidence of primary immunodeficiency

• Hepatomegaly or evidence of hepatic failure in a proband or a first-degree relative
• Onset usually before age six months
• Family history consistent with autosomal recessive inheritance
• Identification of biallelic pathogenic variants in SP110 on molecular genetic testing establishes the diagnosis if clinical features are inconclusive.

Laboratory features

• Low serum concentrations of IgA, IgM, and IgG

Note: Immunoglobulin levels are age specific and laboratory specific and thus should be compared against appropriate local reference ranges.

• Normal lymphocyte numbers and CD4 and CD8 percentages
• Normal lymphocyte proliferative responses to mitogens
• Low intracellular cytokine production

Radiographic features Hepatic ultrasonography. Features consistent with hepatic veno-occlusive disease (hVOD) may include hepatosplenomegaly, gallbladder wall thickening, increased portal vein diameter, reduced hepatic vein diameter, ascites, and re-canalization of the ligamentum teres.

Doppler ultrasound examination. Features consistent with hVOD may include reduced portal venous flow, flow in the para-umbilical vein, and increased resistance in the hepatic artery.

Treatment

Hypogammaglobulinemia is treated via intravenous immunoglobulin (IVIG), which should commence at the diagnosis of VODI or in presymptomatic sibs confirmed to have homozygous SP110 pathogenic variants. An appropriate dose is 0.4 g/kg every four weeks adjusting the dose to maintain a trough IgG level greater than 6 g/L.

Pneumocystis jirovecii 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.

Hepatic transplantation may be considered, but appears to have a high rate of complications in the VODI cohort studied to date .

Bone marrow transplantation. Ganaiem et al [2013] reported that this may be an efficacious treatment modality with appropriate conditioning therapy.

Prognosis

Mortality reaches 85% if the syndrome remains unrecognised and untreated.

NIH genetic and rare disease info

• NIH info on Hepatic venoocclusive disease with immunodeficiency

Hepatic venoocclusive disease with immunodeficiency is a rare disease.

Hepatic venoocclusive disease with immunodeficiency Resources
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