Cystic Fibrosis with Severe Anaemia and Hypoproteinaemia

1Dr. Md Abu Bakkar Siddique, MBBS, MD Junior Resident, 2Dr. Kalimuddin Khan, MBBS. MD Junior Resident, 3Dr. Aparajita Bera, MBBS. MD Junior Resident, 4Dr. Sudipta Ghorai, MBBS. MD Senior Resident, 5Dr. Jasmine Mallik, MBBS. MD Junior Resident, 6Dr. Suman Sarkar, MBBS. MD, Associate Professor. All from the Chittaranjan Seva Sadan College of Obstetrics, Gynaecology and Child Health, Paediatric Medicine, Kalighat, Kolkata, West Bengal, India. Abstract


Introduction
C ystic fi brosis (CF) is an autosomal recessive disorder characterized by impaired chloride transport across the apical membrane of cells as a result of mutations of the CFTR gene 1 .In most patients with CF, pulmonary symptoms initially prevail 2 .Another predominant feature is mal-digestion that frequently begins in early childhood.Pancreatic exocrine dysfunction causes mal-digestion characterised by failure to thrive, diarrhoea, hypoproteinaemia, oedema and anaemia.Severe anaemia as the initial manifestation was described rarely 3,4 .Prospectively, the frequency of clinically signifi cant anaemia has been estimated to develop in 4% of CF infants 5 .
We describe a male patient with severe anaemia, diarrhoea with oedema and failure to thrive at diagnosis, who developed recurrent respiratory tract infection later.

The Case
A two month old male infant presented with complaints of frequent passage (40-50 times/day) of dark green stools with oily in consistency.Associated with vomiting, abdominal distension and generalised swelling of whole body for last one and half months.There was no history of fever, cough or breathing diffi culty.
He was born at 34 weeks gestation after an uncomplicated pregnancy and weighed 2.1 kg.He was on breast and bottle feed.
On systemic examination, abdomen was soft and distended with hepatomegaly but no splenomegaly.There was bi-lateral vesicular breath sounds and soft S1, S2, no murmur and no subcostal or intercostal recessions.
Laboratory investigations showed a haemoglobin 4.5 gm% with a normal mean corpuscular and mean corpuscular haemoglobin concentration and reticulocyte count of 1.5%.The blood smear showed a normochromic normocytic and microcytic hypochromic, anisocytosis, few target cells and tear drop cells seen.The white blood cell count was 9480/cumm with a normal diff erential count.The number of platelets was normal.Serum electrolytes, renal function tests, serum triglycerides, cholesterol, amylase and lipase were normal.Levels of aspartate aminotransferase (AST) were-202 U/L, alanine aminotransferase (ALT): 240 U/L, alkaline phosphatase (ALP): 462 U/L.The total bilirubin level was 0.8 mg/dL with a direct bilirubin level of 0.3 g/dL.Total proteins was 3.4 g/dL, with an albumin of1.5 g/dL.Prothrombin (PT) and partial thromboplastin times (PTT) were both normal.Results of serum iron, TIBC were normal but serum ferritin was 518 ng/ml, bone marrow smear, and immunoglobulin panels and anti TG2 IgA antibody were all normal.Parents' Hb electrophoresis were normal pattern.Blood culture and urine culture were found negative.Stool routine and microscopic results revealed fat droplets in stool.Sudan stain of the stool showed abundant neutral and split fats (>60/HPF) with faecal elastase < 15 mcg/gm of stool, which is signifi cant, no reducing substance and occult blood in stool.Sweat chloride estimation test was done.It reveals 167.2 mEq/L.The test was repeated after two week, which showed positive result 119 mEq/L.Blood for Common four mutation of CF (Delta F508, G542X, G551D and R553X ) were negative.
The infant was treated with albumin, packed red cells transfusion, antibiotics and pancreatic enzymes(lipase), vitamins A (4000 IU/day), D (400 IU/ day), E (400 u/day) and water soluble vitamins were added.The baby was discharged after four weeks with signifi cant weight gain, normalised blood count and serum albumin with subsidence of oedema.
During next four months, the infant had consistent weight gain.However over that period, baby was admitted in ward several times for respiratory distress.

Discussion
In view of the multiple manifestations of cystic fi brosis, the following discussion will be limited to a discussion of FTT, anaemia and hypoproteinaemia as it presents in infants with cystic fi brosis.
The symptom complex of hypoproteinaemia, anaemia, and FTT (as seen in our patient), occurs in 5%-13% of patients with cystic fi brosis and is a direct consequence of protein energy malnutrition 6,7,8,9 .
It is frequently misdiagnosed initially as milk protein intolerance, often resulting in formula changes, with further delay in diagnosis and worsening of nutritional status 6,810,11 .
The syndrome has been reported in breast-fed infants more often than those fed cows' milk formula.This symptoms complex occurs most commonly in soy formula-fed infants 6,9,10,11 .
The degree of malnutrition may be underestimated in this group of infants as a result of oedema secondary to hypoproteinaemia.Oedema within the fi rst three months may be suffi ciently severe to produce shock 12 .
The precise aetiology of hypoproteinaemia is yet to be established.Hypoproteinaemia is also seen in patients with CF as results of extensive hepatic disease with secondary liver synthetic dysfunction and in patients with severe chronic pulmonary disease, cor pulmonale and increased plasma volume 13 .It may be that the milk intake is insuffi cient to compensate for the protein loss due to malabsorption.It has been established that there is no leakage of protein into the gut.Liver dysfunction is unlikely to be the cause as liver function tests and biopsy may be normal' and, if abnormal, there is a rapid reversion to normality with a change in diet and correction of the hypoproteinaemia 3,6 .
The cause of anaemia in this syndrome is also not clear.The anaemia showed mixed type of picture, normochromic normocytic, microcytic hypochromic with anisocytosis.Most previous studies describe the anaemia as haemolytic, implicating the malabsorption of fat-soluble vitamin E 5,14,15,16,17,18,19 , which appears to act as a protective antioxidant toward peroxidation of membranous polyunsaturated fatty acids 20 .It has also been shown, however, that vitamin E defi ciency in CF patients is irrespective of pancreatic function, body weight, and even the administration of pancreatic enzymes and lipid soluble vitamins 21 .Among infants newly diagnosed with CF, the frequency of vitamin E defi ciency has been found to be very high, ranging from 38 to 59% 22,13 .Interestingly, only approximately 4% of these children develop clinically signifi cant anaemia 4,5 , suggesting that additional modifying factors most likely contribute to the manifestation of severe anaemia in CF patients.Although in our patient, the only intimation of haemolysis was mild reticulocytosis and other features did not contribute to typical haemolytic anaemia, due to lack of the data we could not rule out the importance of vitamin E defi ciency in the initiation of anaemia.Although after the diagnosis of CF, vitamin E was supplemented in low levels according to present guidelines, signs of haemolytic anaemia did not reoccur.The hyperchromic macrocytosis detected is harder to explain.One reason could be a defi ciency of folic acid due to malabsorption, or increased folate utilisation by rapidly-proliferating bone marrow in chronic haemolytic anaemia, or a combination of both.Although anaemia in our patient was not prolonged, persistent malnutrition plausibly contributed to the manifestation of anaemia.Shahidi et al. 10 attributed the anaemia to protein defi ciency which led to a reduced iron binding capacity and, in turn, to a low serum iron concentration.

Conclusion
The spectrum of presentation of CF is wide and varied.CF can presents with severe anaemia and hypoproteinaemia.In rare cases of CF, anaemia may be the leading symptom present together with malnutrition.More investigations are needed to clarify the mechanisms of early anaemia in CF and to assess the possible prognostic value of clinically signifi cant anaemia in CF babies.