Portal hypertension: not a common Niemann

Description

A 26-year-old woman, born out of third degree consanguineous marriage, at term, with normal psychomotor development, presented to our hospital with exertional fatigue and breathlessness of 10 years duration. She is a mother of two children, had no medical illness in pregnancy. She had menorrhagia for the last 10 years and had received one packed red blood cell transfusion 2 years ago.

On examination, she had pallor and splenomegaly. Laboratory results showed pancytopenia (haemoglobin 56 g/L, total leucocyte count of 3.2×10⁹/L, platelet count 46×10⁹/L), low reticulocyte count (0.0026 red cells), high red cell distribution width (0.21) with microcytic hypochromic blood picture. Iron profile was suggestive of iron deficiency anaemia (serum ferritin 6.9 µg/L, serum iron 3.5 µmol/L and total iron binding capacity 68 µmol/L).

Ultrasonography revealed coarse echotexture of liver with portal vein diameter of 14 mm, minimal ascites and splenomegaly. Upper Gastrointestinal endoscopy (figure 1) showed four columns of grade II varices in the oesophagus. Serum albumin and globulin were 37 and 38 g/L. Prothrombin time was prolonged by 4 s compared with the control. Aspartate and alanine aminotransferases (1.81 and 3.2 µkat/L, respectively) were elevated. She does not consume alcohol. Hepatitis B surface antigen (HBsAg) and Hepatitis C antibody (anti-HCV) were negative. Serum copper and serum ceruoplasmin were normal (19.42 µmol/L and 265 mg/L, respectively). No Kayser-Fleischer (KF) ring on slit lamp examination of eye. Serology workup for autoimmune hepatitis was negative.

Figure 1.

Upper GI endoscopy showing grade II varices in the oesophagus.

Bone marrow studies (figures 2 and 3) revealed cluster of macrophages with finely vacuolated cytoplasm (foamy macrophages) suggestive of Niemann-Pick’s disease (NPD). Acid sphingomyelinase (ASM) activity in the peripheral blood leucocyte was low (test 2.8 nmol/17 hours/mg, control 11.1 nmol/17 hours/mg, measured by fluorimetric assay). Chest X-ray and pulmonary function test were normal. No cherry red spot on fundus examination. She was managed conservatively with blood transfusion, iron supplementation, beta blockers. One year of follow-up is uneventful, with no decompensation of chronic liver disease.

Figure 2.

Bone marrow aspiration (200×) showing cluster of macrophages with finely vacuolated cytoplasm (foamy macrophages) suggestive of Niemann-Pick’s cells (arrows).

Figure 3.

Bone marrow aspiration (400×).

NPD is a rare autosomal recessive lysosomal storage disorder due to accumulation of sphingomyelin in reticuloendothelial system. Type A (MIM# 257200) is a severe, neurodegenerative form, presents within 6 months of age with hepatosplenomegaly, developmental delay, cherry red spot in macula. Rapid, progressive and profound loss of neurological function leading to death occurs by 2–3 years of age. In contrast, type B (MIM# 607616) is a non-neuronal form, presents from early childhood to adulthood, as hepatosplenomegaly, infiltrative lung disease, dyslipidaemia and bone abnormalities. There is an intermediate form with variable combination of both. Both the types are due to mutation in SPMD1 gene and consequent deficient activity of ASM enzyme (E.C.3.1.4.12), aptly called as ASM-deficient disease, as it is a spectrum of manifestation of mutation in a single gene. Type C is genetically and phenotypically distinct form due to mutation in NPC1 gene (MIM# 257220) and NPC2 gene (MIM# 607625) resulting in defects of intracellular trafficking of low-density lipoprotein (LDL) cholesterol.¹ NPD C have disease onset in early childhood to adult. These patients typically have cerebellar involvement with gait ataxia, slow cognitive deterioration, dystonia, dysarthria, seizures, psychiatric disturbance, and infiltrative hepatic and pulmonary disease.

Our patient had hepatic and haematological involvement. She had normal psychomotor development and her neurological examination was normal. Chest X-ray did not show reticulonodular shadow and pulmonary function test was normal.

Hepatic involvement in NPD is underestimated. It can presents as asymptomatic elevation of liver enzymes or acute liver failure or chronic liver disease with cirrhosis. In phase I trial of enzyme replacement therapy with recombinant human acid sphingomyelinase (rhASM),² 17 patients had undergone liver biopsy prior to enzyme replacement. Fifteen out of 17 biopsy sample showed varying grades of fibrosis (grade 1–4), 2 had frank cirrhosis (grade 4). Acute liver cell failure was reported from two paediatric patients in a French cohort.³ Twenty-three of 29 patients had stable liver cell dysfunction in the form of elevation of AST/ALT in a 10-year longitudinal study.⁴

The probable mechanism of fibrosis appears to be increased expression of cathepsin B/D in hepatic stellate cells secondary to decreased ASM activity with parallel increased expression of fibrinogenic markers smooth muscle actin-α, transforming growth factor beta (TGF-β) and alpha collagen 1A-α, as demonstrated in ASM knockout mouse model.⁵

Transplantation, either bone marrow or liver in case of acute liver failure is the treatment option. In a recent study of morbidity and mortality in NPD, with largest number of patients of 103, 10 patients had hepatic involvement, 6 had acute liver failure and 3 had cirrhosis of liver. Three of the six patients with ALF died, two had undergone liver cell transplantation and survived. One patient had hepatocellular carcinoma.⁶

In conclusion, cirrhosis of liver in the NPD needs to be recognised.

Learning points.

• Niemann-Pick disease (NPD) is a rare autosomal recessive lysosomal storage disorder.

• Hepatic involvement in NPD is underestimated.

• A thorough clinical examination and detailed workup is must in every case.